Lebanese Medical Journal - Volume 63 No. 4

LMJ LEBANESE MEDICAL JOURNAL October-December 2015 Octobre-Décembre Vol. 63 (4) - pp 171-232 JOURNAL MEDICAL LIBANAIS JML

ISSN 0023-9852 Indexed by • Index Medicus • Embase (Excerpta Medica) • Cab Abstracts and Global Health - CABI Publishing

VOLUME 63 No 4

Octobre-Décembre October-December

2015

Rédacteur en chef Editor in Chief Adel BERBARI Rédacteurs en chef adjoints Associate Editors Michel DAHER Ghassan K. ABU-ALFA (USA) Elie BERBARI (USA) Eileen O’REILLY (USA) Directeur de la rédaction Managing Editor Charles JAZRA

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Secrétaire général General Secretary Salim KABALAN

R. AKOUM, E. K. ABDALLA, M. SAADE, A. AWDEH, F. ABI-AAD N. BEJJANI, A GHOSSAIN, E. BRIHI, A. AUDI ................................................... 171

Parotid tumors: Is surgery always the only way?

Comité de rédaction Editorial Board George ARAJ Elias ARBID David ATALLAH Nizar BITAR Jamal BLEIK Zaki GHORAYEB Zuheir EL IMAD Abdo JURJUS Kamal KALLAB Roland KASSAB Adib MOUKARZEL Mariam RAJAB Fouad EL SAYED Georges YARED Majed YAZBECK Fouad ZAAROUR

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C. FARAH, C. GHORRA, C. NASSIF, B. TABCHY, A. HADDAD ......................... 179

Effects of preoperative enoxaparin on bleeding after coronary artery bypass surgery http://www.lebanesemedicaljournal.org/articles/63-4/original3.pdf

M. ABI GHANEM, E. SALIBA, J. IRANI, R. DARWISH, N. KAWKABANI T. YARED, C. NAIM, B. ABU KHALIL ................................................................... 185

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R. EL-HAYECK, R. BADDOURA, P. FADEL, A. WEHBÉ A. ZOGHBY, M. BERTHEL ..................................................................................... 191

False and true acute rheumatic fever A Lebanese experience http://www.lebanesemedicaljournal.org/articles/63-4/original5.pdf

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II Lebanese Medical Journal 2015 • Volume 63 (4)

ISSN 0023-9852 Indexed by • Index Medicus • Embase (Excerpta Medica) • Cab Abstracts and Global Health - CABI Publishing

ARTICLE ORIGINAL / ORIGINAL ARTICLE PREDICTORS OF INFLAMMATORY LOCAL RECURRENCE AFTER BREAST-CONSERVING THERAPY FOR BREAST CANCER: MATCHED CASE-CONTROL STUDY http://www.lebanesemedicaljournal.org/articles/63-4/original1.pdf 1

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Riad AKOUM , Eddie K. ABDALLA , Michel SAADE , Adnan AWDEH , Fouad ABI-AAD , Noha BEJJANI 2 3 5 Antoine GHOSSAIN , Emile BRIHI , Akram AUDI

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Akoum R, Abdalla EK, Saade M, Awdeh A, Abi-Aad F, Bejjani N, Ghossain A, Brihi E, Audi A. Predictors of inflammatory local recurrence after breast-conserving therapy for breast cancer: Matched case-control study. J Med Liban 2015 ; 63 (4) : 171-178.

Akoum R, Abdalla EK, Saade M, Awdeh A, Abi-Aad F, Bejjani N, Ghossain A, Brihi E, Audi A. Facteurs prédictifs de récidive locale inflammatoire après chirurgie conservatrice du cancer du sein : Étude comparative cas-témoins. J Med Liban 2015 ; 63 (4) : 171-178.

ABSTRACT • Background : Inflammatory local recurrence (ILR) after breast-conserving surgery for noninflammatory breast cancer (BC) is associated with dismal prognosis. Risk factors for ILR are not well defined. Methods : Between 2001 and 2010, twelve patients at our hospital developed ILR after breast-conserving surgery, adjuvant chemotherapy, and radiotherapy for BC. We compared their clinico-pathological characteristics to those of 24 patients with noninflammatory local recurrence (non-ILR), 24 patients with distant metastases, and 48 disease-free controls, matched for age and observation period. Results : The median time to ILR was 10 months.

In univariate analysis, extent of lymph node involvement (p < 0.05), multifocality (p < 0.05), c-erbB2 overexpression (p < 0.05), and lymphovascular invasion (LVI) (p < 0.001) affected the risk of ILR. Conditional logistic regression analysis showed a significant association between ILR and combined LVI and high histopathological grade. The odds ratio (OR) for ILR versus non-ILR was 6.14 (95% confidence interval [CI] 1.48-25.38) and for ILR versus distant metastases it was 3.05 (95% CI 0.09-97.83) when both LVI and high histopathological grade were present. Patients with family history of BC were more likely to present with ILR than non-ILR (OR 5.47; 95% CI 1.55-19.31) or distant relapse (OR 5.62; 95% CI 0.26-119.95). Conclusions: Pre- and postmenopausal women with high-grade BC and LVI are at increased risk to develop ILR, especially in the presence of family history of BC. Identification of risk factors for this lethal form of recurrent BC may lead to more effective preventive treatment strategies in properly selected patients.

Keywords : Inflammatory breast cancer, local recurrence, inflammatory local recurrence, chemotherapy, radiotherapy, mastectomy

RÉSUMÉ • Objectifs : La récidive locale inflammatoire (RLI) après traitement conservateur du cancer du sein est associée à un mauvais pronostic. Les facteurs de risque d’une telle récidive ne sont pas encore bien connus. Méthodes : Entre 2001 et 2010, douze patientes présentant une RLI après chirurgie conservatrice, chimio- et radiothérapie adjuvantes ont été traitées dans notre département. Nous avons réalisé une analyse comparative des caractéristiques clinico-pathologiques de ces patientes avec 24 patientes présentant une récidive locale non inflammatoire, 24 patientes présentant des métastases à distance et 48 patientes en rémission persistante. La stratification a tenu compte de l’âge et de la date du diagnostic. Résultats : La RLI survenait après une période moyenne de 10 mois. L’analyse univariée a montré une corrélation significative des facteurs suivants: atteinte lymphatique (p < 0,05), multifocalité (p < 0,05), surexpression de c-erbB2 (p < 0,05) et invasion des vaisseaux lymphatiques (IVL) (p < 0,001). La régression logistique conditionnelle a montré une corrélation significative entre RLI et IVL associée au haut grade histologique [OR 6,14; CI 95% pour la comparaison RLI avec récidive locale non inflammatoire et OR 3,05; CI 95% pour la comparaison RLI avec métastases à distance]. La comparaison de ces mêmes groupes de patients en considérant la présence d’antécédents familiaux de cancer du sein a donné des ORs plus significatifs : 5,47 et 5,62. Conclusion: Les femmes pré- et postménopausées présentant un cancer du sein de haut grade histologique avec invasion lymphovasculaire sont à risque élevé de développer une RLI surtout en présence d’antécédents familiaux de cancer du sein.

L’identification des facteurs de risque de cette RLI pourrait contribuer à l’élaboration d’une stratégie thérapeutique plus efficace.

INTRODUCTION

sive clinicobiological behavior that heralds the appearance of distant metastases in many cases [1,6-7]. A small but important subset of patients with local recurrence develops inflammatory local recurrence (ILR), which is associated with a distinctly poorer prognosis. An uncommon finding representing 7% to 20% of recurrences [812], sometimes referred to as “secondary” inflammatory breast cancer, ILR typically occurs within two years of BCS, exhibits clinical and pathological characteristics of

Ipsilateral breast tumor recurrence (IBTR) after breastconserving surgery (BCS) and whole-breast radiation occurs in 4% to 10% of patients [1-3]. Late local recurrence (> 2 years) in a conserved breast can usually be treated by further surgery with curative intent and remains associated with a favorable prognosis [4-5]. Early local recurrence (< 2 years) may indicate a more aggres-

Divisions of Medical Oncology1, Surgical Oncology2, Radiation Oncology3, Department of Pathology4, Internal Medicine Resident5, Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon.

Correspondence: Riad Akoum MD. e-mail : riad.akoum@umcrh.com Fax: +961 1 200816

Lebanese Medical Journal 2015 • Volume 63 (4) 171

inflammatory breast cancer, and is surgically and oncologically difficult to control. Patients with ILR have only a 14% rate of 5-year overall survival compared to 50% for those with noninflammatory local recurrence (nonILR) [4,8,13-15].

Pathological risk factors for IBTR after BCS include close or positive surgical margins [1,3,12,16], presence of extensive intraductal component (EIC) in and/or around the tumor [1,17-18], presence of lymphovascular invasion (LVI) with or without positive axillary lymph nodes [1,3,7,16,19], histological multifocality [7,16], high histopathological grade [16], negative hormonal receptor status [7], and c-erbB2 oncogene overexpression [20]. Clinical risk factors for IBTR include tumor size [16-17], young age [2-3,18-19], and gross multicentricity [9]; however, a strong family history of breast cancer has been associated with late IBTR and whether these are true recurrences or actually new tumors is controversial [21]. Skin involvement has been reported in 3% to 22% of breast recurrences in general [6,22].

ILR is diagnosed clinically, based on the appearance of diffuse redness and edema of the breast. The histopathological examination frequently reveals cancer emboli in the lymphatic vessels. However, the absence of this characteristic does not rule out the diagnosis. When the clinical criteria are missing, and a dermal lymphatic invasion is seen in the pathological specimen, the term “occult inflammatory breast cancer” has sometimes been used. However, whether occult inflammatory breast cancer carries as poor a prognosis as inflammatory breast cancer is still a matter of debate. Some studies report an outcome similar to that reported for inflammatory breast cancer [23-24]; others describe “occult inflammatory breast cancer” as a more benign process. This type of recurrence has been associated with multicentricity [7, 10-11], multifocality [25-26], positive resection margins [7,16], high number of positive lymph nodes [7,25], and LVI [4,7-8,12-15].

The aim of this study was to determine whether identifiable clinico-pathological characteristics in women with primary noninflammatory, invasive breast cancer affected their risk of ILR after BCS. MATERIAL AND METHODS

Study design To assess potential risk factors for ILR after BCS for breast cancer, we designed a case-control study in a hospital-based population. Data on cases and controls were extracted from the hospital radiotherapy registry. All cases and controls had primary noninflammatory, invasive breast cancer and were treated between 2001 and 2010 with BCS, doxorubicin and taxane chemotherapy, and radiation therapy at the same dose. Patients with a positive estrogen and/or progesterone receptor received hormonal therapy. Patients with c-erbB2 positive status treated after 2007 received adjuvant Trastuzumab.

Patients who developed ILR were compared with three 172 Lebanese Medical Journal 2015 • Volume 63 (4)

control groups: • patients who presented with non-ILR (selected in a 2:1 ratio) • patients who presented with metachronous distant metastases (2:1) and • patients with no evidence of disease at least three years after the initial treatment (4:1). All controls received adjuvant chemotherapy containing a taxane and doxorubicin, and all of them received adjuvant radiation therapy delivering 50 Gy to the whole breast in 25 sessions, followed by a boost of 10 Gy in five sessions to the involved quadrant.

The following data were analyzed: age, tumor size, time to recurrence, pathological grading, lymph node status, surgical margins, lymphatic vessel invasion by tumor cells, multifocality, presence of EIC, and immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and c-erbB2 oncoprotein expression.

Clinical data were also analyzed, including common comorbidities: diabetes mellitus, obesity, and infectious mastitis that had completely resolved on antibiotic therapy. The last updated follow-up was in 2011. Internal mammary relapse was considered as metastatic disease. Resection margins ≤ 1 mm in width were considered positive margins.

Local recurrences in cases and controls were histopathologically confirmed and found to be identical to the corresponding initial tumors with regards to grade and ER, PR, and c-erbB2 status.

Statistical analysis The clinical and pathological variables were compared using χ2 test, Fisher’s exact test, and Student’s t test. Family history, ER and PR status, menopausal status, c-erbB2 status, LVI, EIC, and multifocality were coded as dichotomous variables. Tumor size, grade, and lymph node status were coded as categorical variables. Logistic regression was used to evaluate the association of each potential risk factor with the occurrence of ILR. A conditional logistic regression model adapted for case-control studies with 2 or 4 matched controls per case was applied. The significance threshold was set at p < 0.05, and odds ratios (ORs) and 95% confidence intervals (CIs) were determined. Intercooled Stata software, version 9.0 (StataCorp, 2005), was used for the statistical analysis.

This retrospective review was conducted in accordance with institutional policy.

RESULTS

We identified 12 pre- or postmenopausal women with ILR, mean age 53 years (range, 30-65 years). All ILR cases exhibited intradermal lymphatic vessel invasion that was absent in their initial tumors (Figure 1). All ILR occurred within 20 months from the completion of therapy. The median time to recurrence was 10 months, significantly shorter than in the non-ILR and metastatic control groups (26 and 36 months respectively, p < 0.001).

Table I summarizes the baseline patient and tumor characteristics of cases and matched controls. Tumor size, EIC, negative ER and PR status, triple negative receptor R. AKOUM et al. – Inflammatory recurrence after breast surgery

a

FIGURE 1

b

c

a. Photomicrograph of histopathological specimen from the initial breast tumor of a patient with a typical infiltrating ductal carcinoma of colloid type (hematoxylin and eosin x 20). b. Photomicrograph of the inflammatory local recurrence from the same patient showing tumor emboli within the intradermal llymphatic vessels (hematoxylin and eosin x 20). c. A photograph of the skin involvement in the same patient with inflammatory local recurrence despite chemotherapy and electron beam radiation to the skin.

TABLE I BASELINE CHARACTERISTICS of PATIENTS with INFLAMMATORY LOCAL RECURRENCE and MATCHED CONTROLS

Mean age / years (range) Median TTR / months(range) I Grade II III 1 T Class 2 3 0 N Class 1-4 >4 Free Free after Surgical margins re-resection Positive No Multifocality Yes No EIC Yes Positive ER Negative Positive PR Negative Negative c-erbB2 Positive Yes Triple negative* Absent LVI Present Personal history Positive Family history Positive Diabetes Present Obesity Present Present Mastitis ** < 20 months TTR > 20 months

Inflammatory local recurrence (n = 12) 53 (30-65) 10 (3-20) 0 4 (33%) 8 (67%) 0 9 (75%) 3 (25%) 1 (8%) 3 (25%) 8 (67%) 8 (67%)

Noninflammatory local recurrence (n = 24) 54 (29-65) 26 (4-130) 3 (13%) 13 (54%) 8 (34%) 4 (17%) 17 (71%) 3 (13%) 9 (38%) 8 (34%) 7 (29%) 19 (79%)

2 (16%)

3 (13%)

2 (16%) 7 (58%) 5 (42%) 6 (50%) 6 (50%)

2 (9%) 22 2 (9%) 20 4 (17%) 22 2 (9%) 19 5 (21%) 14 (58%) 10 (42%) 1 (4%) 16 8 (34%) 1 (4%) 3 (13%) 2 (9%) 5 (21%) 12 (50%) 12 (50%)

17 (71%) 7 (29%)

3 (25%) 9 (75%) 3 (25%) 2 (16%) 10 (84%) 2 (16%) 0 12 (100%) 0 1 (8%) 2 (16%) 3 (25%) 0 12 (100%)

NED (n = 48)

57 (32-66) 36 (8-130) 3 (13%) 15 (63%) 6 (23%) 1 (4%) 18 (76%) 5 (21%) 2 (8.5%) 15 (63%) 7 (29%) 17 (71%)

54 (29-67)

5 (21%)

3 (5%)

2 (8%) 24 0

1 (2%)

NS

4 (9%)

< 0.05

7 (29%) 19 (79%) 5 (21%) 14 (58%) 10 (42%) 14 (58%) 10 (42%) 0 17 7 (29%) 1 (4%) 1 (4%) 1 (4%) 4 (17%)

21 (44%) 37 (76%) 11 (24%) 36 (74%) 12 (26%) 34 (70%) 14 (30%) 5 (11%) 43 5 (11%) 1 (2%) 4 (9%) 1 (2%) 4 (9%) 6 (13%)

NS

< 0.001 7 (15%) 33 (69%) 8 (17%) 22 (46%) 24 (50%) 2 (4%) 29 (62%) 16 (34%) 3 (5%)

NED: no evidence of disease TTR: time to recurrence NS: not statistically significant EIC: extensive intraductal component PR: progesterone receptor *Triple negative: negative ER, negative PR and negative c-erbB2 LVI: lymphovascular invasion **Mastitis: breast cellulitis complicating breast conservation surgery

R. AKOUM et al. – Inflammatory recurrence after breast surgery

p

Distant metastases (n = 24)

0.06

NS

< 0.05

NS NS < 0.05 NS ≤ 0.001 NS NS NS NS < 0.0001 0.05

ER: estrogen receptor

Lebanese Medical Journal 2015 • Volume 63 (4) 173

status (ER, PR, c-erbB2), and positive surgical margins were not significantly correlated with the type of recurrence. The risk of ILR was significantly affected by the extent of lymph node involvement (p < 0.05), multifocality (p < 0.05), LVI (p < 0.001), and positive c-erbB2 status (p < 0.05). Histopathological grade did not significantly distinguish between recurrence groups (p = 0.06).

Six disease-free controls (12.5%) developed infectious mastitis within 15 months from the BCS; none of these patients developed ILR, and none of the cases with ILR or the controls with non-ILR developed this benign postoperative condition (p < 0.0001). Obesity, diabetes mellitus, and personal and family history of breast cancer were not associated with the type of recurrence.

Survival analysis Complete follow-up data were available on 100% of ILR patients. All ILR patients received cisplatin-based chemotherapy. Three patients developed distant metastases shortly afterwards. Four patients underwent mastectomy after a partial response to chemotherapy, and four patients developed extensive skin involvement; however, they all died with metastatic disease within 18 months. One patient remains alive with disease at current follow-up, four

years after the ILR, with extensive centrifugal skin invasion without distant metastasis.

Univariate logistic regression Histopathological grade III was significantly associated with the occurrence of ILR rather than non-ILR (OR 5.62; 95% CI 1.34-23.50; p = 0.02), distant metastases (OR 3.89; 95% CI 1.00-15.00; p = 0.05), or long-term remission (OR 9.11; 95% CI 2.31-35.80; p = 0.002). Lymphovascular invasion was significantly more likely to be associated with ILR (p < 0.0001) than with other outcomes. Multifocal tumors were more likely to predict ILR than to predict non-ILR (OR 27.70; 95% CI 1.28-598.00; p = 0.001), distant metastasis (OR 11.00; 95% CI 1.7569.00; p = 0.01), or no evidence of disease (OR 11.25; 95% CI 2.44-51.70; p = 0.002). Positive margins, tumor size, lymph node status, EIC, ER, PR, and c-erbB2 status, and family history of breast cancer were not significant predictors of ILR (Table II).

Unconditional multivariate logistic regression In comparing ILR cases with non-ILR controls using multivariate logistic regression, LVI, high grade, and multifocality were predictors of ILR (data not shown).

EIC: extensive intraductal component ER: estrogen receptor LVI: lymphovascular invasion NS: not significant PR: progesterone receptor TTR: time to recurrence +: positive or positive findings *Variable “perfectly” predicts outcome

174 Lebanese Medical Journal 2015 • Volume 63 (4)

R. AKOUM et al. – Inflammatory recurrence after breast surgery

EIC: extensive intraductal component ER: estrogen receptor LVI: lymphovascular invasion NS: not significant PR: progesterone receptor TTR: time to recurrence +: positive or positive findings *Log likelihood not sufficient to enable conditional regression for these variables

In comparing ILR cases with distant metastases controls, LVI predicted ILR perfectly, whereas multifocality and high grade were less significantly predictors of outcome.

family history of breast cancer was added to this combination of risk factors, the ORs remained greater than 4 (Figure 2).

Conditional logistic regression Based on univariate regression models, tumor grade, LVI, multifocality, EIC, negative ER and PR status, positive c-erbB2 status and family history were entered into conditional logistic regression models. These variables gave better fits by comparing the log likelihood of the models.

Comparison of ORs in the univariate and multivariate conditional logistic regression analyses further clarified the relationship of the association of two or more factors in the prediction of ILR. Odds ratios remained significantly high for LVI and pathological grading as predictors of ILR (Table III).

Family history of breast cancer had no significant role in predicting recurrence; however, patients with family history of breast cancer were more likely to present with ILR than with non-ILR (OR 3.53; 95% CI 0.22-54.60) or distant relapse (OR 48.40; 95% CI 0.07-31,287).

When all variables were included in the conditional logistic regression analysis to tease out the effects of each factor, controlling for the others, only LVI and grade III were strongly associated with ILR as compared to non-ILR, distant metastasis, and no evidence of disease (ORs: 6.14 [95% CI 1.48-25.38], 3.05 [95% CI 0.095-97.83], and 28.43 [95% CI 2.33-346.17], respectively, when both LVI and grade III were present). When

DISCUSSION

R. AKOUM et al. â&#x20AC;&#x201C; Inflammatory recurrence after breast surgery

This case-control study is the largest reported to date that examines risk factors for ILR that can be identified at the time of treatment of the primary tumor. The results of conditional multivariate regression demonstrated a consistent trend toward a higher likelihood of LVI and high grade among women with unilateral, invasive breast cancer who developed ILR compared with women matched for age, adjuvant treatment modalities, and diagnosis period who did not develop ILR. These characteristics were also potent risk factors for the development of ILR in patients with a positive family history of breast cancer.

Until new molecular prognostic factors and new markers of inflammatory breast cancer are found, the presence of LVI and grade III could be signals of elevated risk of ILR. Two previous studies attempted to correlate histological characteristics with the risk of ILR after BCS for noninflammatory breast cancer [8,13]. One of them collected nine cases from 18 Japanese centers over a 9-year period [8]. The other collected seven cases from the New York Presbyterian Hospital over a 5-year period [13]. In both studies more than 10 risk factors were analyzed: tumor size and location, histological grade and type, lymph node

Lebanese Medical Journal 2015 â&#x20AC;˘ Volume 63 (4) 175

Figure 2. Results of multivariate conditional logistic regression analysis. Comparison of the odds ratios for inflammatory local recurrence of breast cancer when histopathological grade III and lymphovascular invasion (LVI) were present. • Upper panel: No family history of breast cancer • Lower panel: Family history of breast cancer present in addition to grade III and LVI. ILR: inflammatory local recurrence

Non-ILR: noninflammatory local recurrence

involvement, resection margins, LVI, ER and PR status, and adjuvant treatment. In the first study, Nishimura et al., using a case-control design and unconditional logistic regression analysis, observed that LVI was the major predictor of ILR, whereas lymph node involvement, positive surgical margins, and lack of adjuvant radiation therapy were not predictors [8]. They concluded that ILR is mainly due to “occult” inflammatory breast cancer, since all recurrences occurred within 12 months. In the second study, only lymph node involvement and ER status were correlated with the time to ILR and with the overall survival time [13]. Unusual cases of ILR occurring 3 years after BCS were reported.

In a review of immunohistological c-erbB2 expression in 1,794 patients with primary breast cancer in Italy, Menard et al. found that ductal type, LVI, high nuclear grade, and negative ER and PR status were associated with high c-erbB2 expression [20]. Higher c-erbB2 expression was also associated with higher relapse rates, even in node-negative patients. However, conditional logistic regression in the present study did not highlight c-erbB2 expression as a major determinant in predicting ILR. Some histological prognostic factors, such as LVI and multifocality, have not always been considered important enough to be incorporated into guidelines for more aggressive adjuvant therapy. Lymphovascular invasion

176 Lebanese Medical Journal 2015 • Volume 63 (4)

NED: no evidence of disease.

has been associated with an increased risk of local failure in some series [1,7,19] but not all [17]. The importance of tumor grade in local recurrence is still controversial [7,16]. The current study highlights its role in association with LVI as a predictor of ILR. Hormonal receptor and c-erbB2 status are relevant prognostic factors [20], and multifocality has been associated with high risk of local recurrence [9,17], but these factors seem to be unrelated to the inflammatory nature of the local recurrence in this study.

Lymphovascular invasion is a widely recognized prognostic factor in node-negative breast cancer. Its significance as an independent prognostic factor in node-positive breast cancer remains uncertain [27]. The present case-control study demonstrated that LVI is a strong predictor of ILR in both situations, especially in coexistence with high-grade tumor and family history of breast cancer.

Cutaneous and subcutaneous LVI by cancer cells have been seen in up to 80% of inflammatory breast cancer, whereas less than 2% of operable noninflammatory cases exhibit such pathological features [28-29]. Recent studies have attributed these pathological findings to what is described as “occult inflammatory breast cancer,” while recurrent tumors with obvious clinical features of inflammatory breast cancer are described as “secondary inflammatory breast cancer” [28-29]. As such, LVI may be a selection factor for more aggressive

R. AKOUM et al. – Inflammatory recurrence after breast surgery

treatment for these patients up front in order to lower their risk of post-treatment recurrence.

Whether ILR is a secondary characteristic acquired by the recurrent lesion or related to the primary cancer remains to be clarified. The findings of this study may be interpreted to indicate that the coexistence of high histological grade and LVI in a breast tumor suggests an aggressive behavior; thus, these findings could be used to alert the oncologist to higher risk of ILR and may formulate the basis of a future study population.

The main methodological limitation to this study is the relatively small number of cases, though this is the largest reported series of patients with ILR. However, matching controls to cases on the year of diagnosis and the age group minimized the effects of periodic or physiological differences. The study design, the homogeneity of therapeutic approaches, and the complete pathologic follow-up enabled relatively in-depth analysis of this rare condition.

Unfortunately, no therapeutic approach has been proven to prevent ILR. Whether our patients with highgrade tumors, family history of breast cancer, and LVI should have been initially more aggressively treated raises a relevant question in the era of growing tendency towards conservative surgery and sentinel lymph node biopsy in early-stage patients such as in the Z0011 trial [30].

Identification of patients at elevated risk of ILR could lead to more effective strategies of treatment at the time of therapy for the primary tumor, designed to lower the incidence of recurrence of this lethal disease. Next steps may include larger cohort and case-control studies or analyses based on prospective datasets that include more biochemical and molecular factors. These would identify more precisely which group of patients are at risk and allow development of methods of reducing the risk of such recurrences.

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ACKNOWLEDGMENTS

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The authors thank Faith Reidenbach for editorial assistance, which they sponsored, and declare to have no conflicts of interest to disclose.

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Voogd AC, Peterse JL, Crommelin MA et al. Histological determinants for different types of local recurrence after breast-conserving therapy of invasive breast cancer.

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Huston TL, Simmons RM. Inflammatory local recurrence after breast-conservation therapy for noninflammatory breast cancer. Am J Clin Oncol 2005; 28 (4): 431-2.

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Touboul E, Buffat L, Belkacemi Y et al. Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer. Int J Radiat Oncol Biol Phys 1999; 43 (1): 25-38.

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R. AKOUM et al. â&#x20AC;&#x201C; Inflammatory recurrence after breast surgery

ARTICLE ORIGINAL / ORIGINAL ARTICLE PAROTID TUMORS: IS SURGERY ALWAYS THE ONLY WAY? http://www.lebanesemedicaljournal.org/articles/63-4/original2.pdf 1

2

1

1

Chadi FARAH , Claude GHORRA , Charbel NASSIF , Bassam TABCHY , Amine HADDAD

1

Farah C, Ghorra C, Nassif C, Tabchy B, Haddad A. Parotid tumors : Is surgery always the only way ? J Med Liban 2015 ; 63 (4) : 179-184.

Farah C, Ghorra C, Nassif C, Tabchy B, Haddad A. Tumeurs parotidiennes : La chirurgie est-elle toujours le seul traitement ?

J Med Liban 2015 ; 63 (4) : 179-184.

ABSTRACT • Aim of the study : To analyze the characteristics and management of parotid tumors in a tertiary care center. Study design : Retrospective cohort study. Methods : All cases of parotid tumors (or masses) in our department between Jan 1, 1999 and December 31st, 2012 were studied.

Demographic data, clinical characteristics, histopathology and management were analyzed. We also evaluated the diagnostic value of fine needle aspiration cytology (FNAC) in our center. Results: Of the 216 parotid tumors, 164 underwent parotidectomy and 52 were not managed surgically; 73.1% had a benign tumor (36.6% had Warthin’s tumor) and 16.7% had a malignant one. In our center, FNAC was found to have a sensitivity for reporting malignancy of 71.4% and a specificity to rule in malignancy of 100%. Conclusion : In our series, Warthin’s tumor was the most frequent mass probably related to the high tobacco use. The prevalence of malignant tumors was relatively high in our series. Primary malignant tumors and pleomorphic adenomas should always be treated surgically, however, lymphomas, metastatic and benign inflammatory masses and cases of Warthin’s tumors could be managed nonsurgically.

Keywords : benign parotid tumors, malignant parotid tumors, parotidectomy, nonsurgical management, fine needle aspiration cytology

INTRODUCTION

RÉSUMÉ • Objectif de l’étude : Analyser les caractéristiques des tumeurs parotidiennes et leur prise en charge dans un centre de soins tertiaires. Type d’étude : Étude de cohorte rétrospective. Matériels et méthodes : Tous les cas de tumeurs (ou masses) parotidiennes traités dans notre département entre le 1/1/1999 et le 31/12/2012, ont été inclus dans cette étude. Les données démographiques, les caractéristiques cliniques, ainsi que les résultats histopathologiques et le type de prise en charge dans chaque cas ont été analysés. En plus, la valeur diagnostique de la cytoponction à l’aiguille fine réalisée dans notre centre a été évaluée. Résultats : Parmi les 216 cas de tumeurs parotidiennes inclus dans l’étude, 164 ont bénéficié d’une parotidectomie et 52 ont été traités non chirurgicalement ; 73,1% avaient une tumeur bénigne (tumeur de Warthin : 36,6%) et 16,7% une tumeur maligne. Dans notre centre, la cytoponction à l’aiguille fine s’est révélée avoir une sensibilité pour rapporter une tumeur maligne de 71,4% et une spécificité d’éliminer la présence d’une tumeur maligne de 100%. Conclusion: Dans notre série, la tumeur de Warthin a été la plus fréquente probablement en raison du taux élevé de tabagisme. La prévalence de tumeurs malignes était relativement élevée. Les tumeurs malignes primaires de la parotide et les adénomes pléomorphes doivent toujours être traités chirurgicalement. Par contre, les lymphomes, les métastases et les masses inflammatoires bénignes ainsi que certains cas de tumeur de Warthin peuvent être traités médicalement.

Salivary gland neoplasms are rare tumors and account for 2-3% of all head and neck tumors. About 70% to 85% of all salivary gland tumors are located in the parotid gland [1-5]. The majority (80%) of parotid masses are benign neoplasms with pleomorphic adenoma being the most common type [1,3,5]. Parotidectomy is a common surgical procedure for parotid tumors while some tumors can be nonsurgically managed such as inflammatory masses, Warthin’s tumors that are not esthetically disturbing and some malignant tumors (lymphoma and metastasis to the parotid gland).

Due to the possibility of major postoperative complications such as facial nerve paresis or paralysis that can

occur in 10-30% of cases [6], especially with regard to the treatment of benign tumors, the adequate extent of surgery is always the question.

The majority of the studies in the literature consider surgery as the main treatment option in the management of parotid tumors. In our study, we presented two groups of patients having a parotid mass; one managed surgically and the other consisting of patients who didn’t undergo surgery in our center.

The objective of the study was to analyze the profile and the management options of parotid tumors, and the diagnostic value of fine needle aspiration cytology (FNAC) in our center.

1

Department of Otolaryngology - Head and Neck, Hôtel-Dieu de France University Hospital, St Joseph University School of Medicine (HDF-USJ), Beirut, Lebanon.

2 Department of Pathology, HDF-USJ. Correspondence : Chadi Farah, MD. e-mail : chadifarah86@hotmail.com

METHODS

The study protocol was reviewed and accepted by the ethics committee of Hôtel-Dieu de France hospital.

We reviewed retrospectively the medical and pathology records of all the patients who presented with a

Lebanese Medical Journal 2015 • Volume 63 (4) 179

parotid mass to the Otolaryngology Department in HôtelDieu de France Hospital, Beirut, Lebanon, a tertiary care center, between January 1st, 1999 and December 31st, 2012.

These patients were divided into two groups in relation with the different management options. We had a group of tumors managed surgically and another group not managed surgically.

For the two groups we reviewed the medical and pathology records and noted the age, sex, tobacco use, clinical signs and symptoms and their duration, diagnostic tests, cytology results (if present), and location of the parotid tumor. For the surgical group we also noted the date of the surgery, surgical technique, hospital stay, postoperative histopathology results, early and late complications and recurrence.

Our results regarding epidemiology, clinical characteristics, diagnostic tests, management and follow-up, were tabulated for each group using Excel sheets. For the surgically managed group, we also calculated the percentages of the different postoperative complications and recurrence rates. As for the types of tumors, we noted the overall percentages of benign and malignant ones and the specific distribution of the different types in each group.

Concerning the diagnostic value of FNAC in our center, we used a 2 x 2 table to calculate the sensitivity for reporting malignancy, the specificity to rule in malignancy, the positive predictive value (PPV), the negative predictive value (NPV) and the overall accuracy. These results were calculated in the group of patients who underwent a FNAC in our center preoperatively, comparing the cytology results with the final histopathology results. All the non-diagnostic cytology results were not included.

RESULTS

Patients From January 1st, 1999 to December 31st, 2012, 215 patients complaining of a parotid mass presented to the Otolaryngology Department at Hôtel-Dieu de France hospital, a tertiary care center. One patient had a bilateral parotid mass that was managed in our center. Of the 216 parotid masses studied, 164 were managed surgically and 52 were not. In the study population, the age range was between 2 and 92 years with male sex predominance.

TABLE I PATIENTS’ BASELINE CHARACTERISTICS Surgical group (n = 164)

Management Nonsurgical group (n = 52)

Mean age (years) 51.1 54.1 Sex ratio (M/F) 1.45 1.6 Tobacco use (%) 51.2 31* Side: Right/Left 90/74 22/28 (2 unknown) * 42 patients had medical records & tobacco use was noted for only 13 patients.

180 Lebanese Medical Journal 2015 • Volume 63 (4)

In the nonsurgically managed group, 10 of the 52 patients didn’t have a medical record as outpatients but all of them had pathology records and only 13 patients of the 42 were noted to have tobacco use.

The patients’ baseline characteristics of each group of parotid masses are detailed in Table I. Clinical presentation In our study, the most common clinical presentation in the two groups was the presence of a mass in the parotid region (100%).

In 23 patients of the nonsurgically managed group, the duration of symptoms was not noted. The mean duration of symptoms for the 19 remaining patients (with medical records) was 34.6 months. In the surgically managed group, the mean duration of symptoms was approximately 40 months. Table II shows the details related to clinical presentation in the two groups.

TABLE II CLINICAL PRESENTATION Management Surgical group Nonsurgical group (n = 164) (n = 52) [only 42 had medical records]

Mean symptoms 40 34.6 * duration (months) Mass 164 (100%) 42 (100%) Recurrent swelling 1 (0.61%) 0 Pain 14 (8.5%) 2 (4.76%) Facial weakness 9 (5.5%) 2 (4.76%) *Only in 19 cases of the 42 with records, the symptoms duration was noted.

Management Of the 164 surgically managed parotid tumors in 163 patients, 12 had surgeries elsewhere for the same tumor and were reoperated in our center for recurrence or incomplete resection. Four patients had bilateral parotid tumors including one that was operated in our center in the study time period and was included in the study. As of the other three patients: one was operated elsewhere, one was operated before 1999 in our center and the last one was not operated for the second tumor because he was diagnosed as having a lymphoma. The mean postoperative hospital stay was 1.5 days.

Three patients were readmitted for total parotidectomy after undergoing a superficial one and diagnosed as having a malignant tumor.

Seventy-three tumors had a preoperative pathology diagnosis; 71 underwent a FNAC (only 31 in our center) and 2 had a revision of a previous pathology diagnosis done elsewhere. Details related to other diagnostic tests are mentioned in Table III. The most frequent surgical approach in our study was superficial parotidectomy (75%) followed by total (20.1%) and subtotal parotidectomy (4.3%) and one patient (0.6%) had an extensive mass that was managed by a debulking

C. FARAH et al. – Management of parotid tumors

Number of parotid tumors

tory lesion and 5.1% had a normal or a nonspecific pathology result. The exact distribution of the pathology results for each group is detailed below (Table IV).

TABLE IV PATHOLOGY RESULTS in the TWO GROUPS of PAROTID TUMORS

FIGURE 1.

Surgical techniques

(Figure 1). Eighteen patients had a neck dissection, 10 cases of malignant tumors received an adjuvant radiation therapy, 1 an adjuvant chemotherapy and radiation therapy and 1 only chemotherapy. One patient, who was diagnosed with a metastasis of a papillary thyroid carcinoma, received postoperatively radioactive iodine therapy. All parotidectomies were performed under intraoperative facial nerve monitoring (or nerve stimulation).

As for the location of the tumors in the surgical group; 135 were in the superficial parotid lobe (82.3%) and 29 were in the deep lobe (17.7%).

In the nonsurgically managed group, 50 patients had a FNAC in our center and the other 2 patients had a revision of a previous pathology diagnosis done elsewhere.

Three patients (2 pleomorphic adenomas and one atypical cytology) didn’t return for surgery and the others were managed medically (inflammatory lesions, Warthin’s tumors, lymphomas, metastases). Pathology details will be discussed in the next section.

Of the 42 patients who had medical records, 20 had only a cervical CT scan, 4 only a cervical MRI, 4 a CT scan and a MRI and one had a PET scan.

Pathology results Of the 216 parotid tumors: 73.1% were benign with Warthin’s tumor being the most frequent one (36.6%), 16.7% were malignant (4.2% lymphomas and 3.7% mucoepidermoid carcinomas), 5.1% consisted of an inflammaTABLE III DIAGNOSTIC TESTS in the SURGICALLY MANAGED GROUP Surgically managed group (n = 164) Fine needle aspiration cytology Revision of pathology results Cervical CT scan Cervical MRI Cervical ultrasound PET scan

71 2 110 42 15 2

C. FARAH et al. – Management of parotid tumors

PATHOLOGY

Surgically managed group (%)

Nonsurgically managed group (%)

Benign

131 (79.9)

27 (51.9)

Pleomorphic adenoma Warthin’s tumor Lymphoid tissue with follicular hyperplasia (Warthin’s tumor v/s lymph node) Basal cell adenoma Lymphoepithelial cyst Epidermoid cyst Lipoma Cavernous hemangioma Desmoid/Fibromatosis Sebaceous cyst Sabaceous lymphadenoma Oncocytic lipoadenoma Myoepithelioma Neurofibroma plexiform Malignant Mucoepidermoid carcinoma Salivary duct carcinoma Basal cell carcinoma Carcinoma ex pleomorphic adenoma Squamous cell carcinoma Lymphoma Cylindroma (adenoid cystic carcinoma) Acinic cell carcinoma Epithelial myoepithelial carcinoma Rhabdomyosarcoma Carcinomatous lymphangitis Metastasis Inflammatory Non specific inflammation/ granulation tissue Abscess Granuloma No specific lesion/Normal tissue TOTAL

55 (33.54) 58 (35.4)

3 (5.8) 21 (40.4)

0

2 (3.8)

3 (1.83) 3 (1.83) 3 (1.83) 2 (1.2) 1 (0.61) 1 (0.61) 1 (0.61) 1 (0.61) 1 (0.61) 1 (0.61) 1 (0.61)

0 0 1 (1.9) 0 0 0 0 0 0 0 0

29 (17.7)

7 (13.5)

6 (3.7) 2 (1.2) 0

2 (3.8) 0 1 (1.9)

2 (1.2)

0

3 (1.83) 7 (4.3)

0 2 (3.8)

2 (1.2)

0

2 (1.2)

0

1 (0.61)

0

2 (1.2) 1 (0.61) 1 (0.61)

0 0 2 (3.8)

2 (1.2)

9 (17.3)

2 (1.2)

2 (3.8)

0 0

5 (9.6) 2 (3.8)

2 (1.2)

9 (17.3)

164 (100)

52 (100)

Lebanese Medical Journal 2015 • Volume 63 (4) 181

Diagnostic value of FNAC Thirty-one patients underwent a preoperative FNAC in our center; 4 results (13%) were not diagnostic and 27 were diagnostic. In order to determine the diagnostic value of FNAC in our center we took into consideration only the diagnostic results and we compared them with the final histopathology results. We had no false positive results and two false negative ones: one considered as a benign lymphoid inflammatory reaction on cytology was found to be a lymphoma, and one considered as pleomorphic adenoma was found to be a cylindroma (Table V). The sensitivity for reporting malignancy was 71.4 % and the specificity to rule in malignancy was 100%. PPV was 100%, NPV was 90.9% and the overall accuracy was 92.6%.

Follow-up In the surgically managed group, of the 164 cases in this group, 27 were lost to follow-up and 137 were followed for a mean period of 18.8 months.

The most frequent postoperative complication was facial weakness in 26 cases (15.8%); 8 presented a total facial palsy and 18 a facial paresis. Seven of these cases had already preoperatively a facial weakness which persisted postoperatively and 17 (10.4%) had a newly onset nerve dysfunction. Two cases who presented with facial weakness preoperatively had a complete resolution of their symptoms in the immediate postoperative period.

(Figure 2). Six patients of the 24 who had a persistent facial weakness were noted to have a total recovery during the follow-up.

The second most common complication was the salivary fistula found in 12 patients (8.8%) followed by a reported Frey’s syndrome in 7 patients (5.1%) and a salivary collection in 5 patients (3.6%). The recurrence rate in this group was 2.2% (3 patients of the 137 cases who had a follow-up), where one patient who had a cavernous hemangioma had a recurrence 11 years later and was reoperated in our center, another one who had a pleomorphic adenoma had a recurrence 11 years later and didn’t return for surgery and the last one, who had a nonspecific lesion on the pathology result, presented a

TABLE V DIAGNOSTIC VALUE of FNAC* Malignant histopathology 5 2 7

Benign histopathology 0 20 20

Total

Malignant FNAC 5 Benign FNAC 22 Total 27 *4 cytology results were not diagnostic FNAC: fine needle aspiration cytology

recurrence of his mass two years later and was operated by a plastic surgeon in our center with a final diagnosis of pleomorphic adenoma.

In the nonsurgically managed group, and of the 42 patients who had medical records, 17 were lost to follow-up and only 25 patients were followed for a mean period of 14.8 months. Other than the three patients who didn’t return for surgery, all the cases of lymphoma and metastasis (Table IV) were referred to the oncology and radiation therapy departments. As for the two cases of mucoepidermoid carcinomas (Table IV), one didn’t have a medical record and the other was lost to follow-up and the 3rd case of pleomorphic adenoma didn’t have a medical record. The two cases diagnosed with a granulomatous disease were referred to the internal medicine department.

DISCUSSION

In our study, we reviewed 216 cases of parotid tumors over a 14-year period with two different management approaches in a tertiary care center. The majority of our patients were males with an age range of 2 to 92 years.

Parotid gland tumors typically present with a palpable mass, recurrent swelling, pain or facial nerve dysfunction.

In our study, the most common clinical presentation was a slowly growing mass followed by pain and facial weakness, which is consistent with the literature results [4,7-8].

Parotid gland surgery nowadays is established as standard therapy throughout the world. Superficial and total parotidectomy are recognized as a standard procedure for removal of parotid gland tumors [9].

FIGURE 2. Facial weakness 182 Lebanese Medical Journal 2015 • Volume 63 (4)

C. FARAH et al. – Management of parotid tumors

In our surgical group, parotid tumors were most frequently found in the superficial lobe (82.3%) and the most frequent surgical approach was superficial parotidectomy (75%) followed by total parotidectomy in 20.1% of cases and subtotal parotidectomy in 4.3% of cases.

According to the literature, the preferred surgical management of benign parotid tumors confined to the superficial lobe is the partial superficial parotidectomy, while complete superficial parotidectomy or total parotidectomy were performed in cases where tumors were large or recurrent tumors with involvement of the deep lobe [1,3,9]. Partial superficial parotidectomy was found to reduce postoperative morbidity especially facial nerve dysfunction and Frey’s syndrome [9].

As for the malignant tumors, management requires a combination of treatment modalities. According to the stage and grade of the tumor, we have a choice of parotidectomy alone if the tumor was in an early stage and a low grade or parotidectomy plus adjuvant radiation therapy in the early stage and high grade or parotidectomy plus neck dissection and adjuvant radiation therapy in the advanced stages [1]. In our study, malignant tumors were managed according to the stage and grade of the tumor with combination of treatment modalities.

In the group of patients who were not managed surgically, the majority had Warthin’s tumor (40.4%) that was not esthetically disturbing and the others were diagnosed of having lymphomas, metastases and inflammatory lesions that were better managed medically. Six patients should have had a surgical treatment (3 had primary malignant tumors and 3 had pleomorphic adenomas) but 3 of them didn’t return for surgery and the other 3 were lost to follow-up.

Although pleomorphic adenoma of the parotid gland is considered as a benign disease, it should be managed surgically because of the possibility of malignant transformation (carcinoma ex pleomorphic adenoma) and distant metastases [10].

In a review of the literature, we found that most of the parotid tumors were benign accounting for approximately 60.6 to 80% with pleomorphic adenoma being the most frequent one followed by Warthin’s tumor [1,3, 5]. Twelve to seventeen percent of the tumors were malignant [11] with mucoepidermoid carcinoma being the most frequent (3-4% of all tumors) [1,3,7,12]. Lymphoma was reported to be found in 1 to 5% of parotid tumors [13-14]. In our study, the results of benign tumors were consistent with the literature (79.9% in the surgical group) but we have found that Warthin’s tumor was the most frequent tumor even in the surgically managed group (35.4%). This result is probably related to high tobacco use (51.2%) and male predominance in this group, as it was shown by Cardoso et al. [15]. As for the malignant tumors, we have found a number in the high reported ranges (17.7%) in the surgical group with a slight predominance of lymphoma (4.3% of all the tumors and 24% of the malignant tumors in the surgical group) over mucoepidermoid carcinoma (3.7%)

C. FARAH et al. – Management of parotid tumors

but still consistent with the literature ranges.

FNAC is considered by many authors as a safe and accurate diagnostic test that helps the surgeon in his management plan. Throughout the literature, FNAC is found to have a sensitivity for reporting malignancy of 64-99% and a high specificity to rule in malignancy of 96.3-100% and an overall accuracy of 81-98% [1,3,1617]. In our series, 31 patients had a preoperative FNAC in our center with 13% of nondiagnostic results. The sensitivity was 71.4% but the specificity was found to be 100% (no false positive results) and the overall diagnostic accuracy was 92.6%. In our center, FNAC can be considered as a reliable tool to rule in malignancy and to help the surgeon in his management plan.

Although FNAC is not reliable to diagnose lymphoma, it could guide the surgeon, when finding lymphoid cells in the specimen, toward nonradical management of these tumors (a biopsy instead of a parotidectomy).

Parotidectomy carries the risk of postoperative complications affecting the patient’s quality of life.

Facial nerve dysfunction is considered as the major and the most frequent complication found transiently in 10-68% of cases and permanently in 0-19% of cases [9,18]. In our experience it was encountered in 15.8% of cases with only 10.4% of newly onset postoperative nerve dysfunction and 11.6% with permanent dysfunction over the follow-up period.

Frey’s syndrome is always underestimated and is usually noted if the patient complains. The reported Frey’s syndrome in the literature accounts for 2 to 96% [9,19].

In our series, we had only 5.1% of Frey’s syndrome reported by the patients.

Salivary fistula (8.8%) and salivary collection (3.6%) were also found in our series and were consistent with the literature results [9].

The use of a more conservative surgery especially for benign tumors and intraoperative monitoring (or stimulation) of facial nerve, in our experience and in the literature [20], helped us reduce the risk of postoperative complications especially nerve dysfunction.

In our study, we had a low recurrence rate (2.2%) with no malignant tumor recurrence in a mean follow-up period of 18.8 months which is consistent with the published rates (0-12%) depending on extent of surgery and tumor histology [9], and even in some studies, 40 to 45% recurrence rates were noted for benign and malignant tumors [1,5,21].

Our study had some limitations regarding its design (retrospective) carrying the problem of information collection from nonstandardized medical records. We tried to limit the effect of this bias by collecting each patient’s information from three different sources; the hospital medical records, the private clinics medical records and the pathology records. On another hand, in our series, sur-geries were mainly performed by two experienced head and neck surgeons but the fact that all of them were made under facial nerve monitoring and in merely the same surgical techniques according to standardized indications, reduced the surgical technique-related bias.

Lebanese Medical Journal 2015 • Volume 63 (4) 183

CONCLUSION

Parotid tumors are rare neoplasms with a predominance of benign over malignant ones. In our series, we found Warthin’s tumor to be the most frequent tumor in the two groups related most probably to high tobacco use and male sex predominance. Malignant tumors were found to be in the high reported ranges.

In our experience, parotid tumors were managed surgically or nonsurgically according to the tumor’s type and patient’s preferences. The use of a surgical approach adapted to the tumor’s type and extent and the use of intraoperative facial nerve monitoring have shown a reduced risk of postoperative complications and recurrence rate.

In our center, FNAC was found to be an effective tool in the diagnosis and treatment planning of parotid tumors and should be more frequently performed in order to reduce non necessary radical treatments.

Although we tend to think of primary malignant neoplasms in the context of a parotid gland mass, which should be treated radically, we should keep in mind the possibility of having a lymphoma to guide our management toward a simple biopsy instead of a parotidectomy.

Moreover, benign inflammatory masses or metastatic masses in the parotid gland should be treated medically by a multidisciplinary team.

Finally, we should also consider a nonsurgical management of some cases of Whartin’s tumor especially in elderly patients having comorbidities and with no esthetical disturbance in order to avoid anesthetic and surgical risks in this special population.

ACKNOWLEDGEMENTS

This work was presented at the 10th Annual Middle East Update in Otolaryngology Conference at Dubai, United Arab Emirates on April 21-23, 2013.

We would like to thank Simon Rassi, MD, and Nayla Matar, MD, for their contribution to our study by giving us valuable advice regarding the form and the contents of this paper and access to their patients’ medical records.

REFERENCES 1. Lin CC, Tsai MH, Huang CC, Hua CH, Tseng HC, Huang ST. Parotid tumors: a 10-year experience. American Journal of Otolaryngology 2008; 29 (2): 94-100.

2. Spiro RH. Salivary neoplasms: Overview of a 35-year experience with 2,807 patients. Head & Neck Surgery 1986; 8 (3): 177-84.

3. Upton DC, McNamar JP, Connor NP, Harari PM, Hartig GK. Parotidectomy: ten-year review of 237 cases at a single institution. Otolaryngology-Head & Neck Surgery 2007; 136 (5): 788-92.

4. Mohammed F, Asaria J, Payne RJ, Freeman JL. Retrospective review of 242 consecutive patients treated surgically for parotid gland tumours. Otolaryngology-Head & Neck Surgery 2008; 37 (3): 340-6.

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5. Bradley PJ. Pleomorphic salivary adenoma of the parotid gland: which operation to perform? Current Opinion in Otolaryngology & Head and Neck Surgery 2004; 12 (2): 69-70.

6. Silvoniemi A, Pulkkinen J, Grénman R. Parotidectomy in the treatment of pleomorphic adenoma - analysis of longterm results. Acta Oto-Laryngologica 2010; 130 (11): 1300-5.

7. Lee YM, Choi HJ, Kim JW, Kim JH. Parotid gland tumors in a Korean population. Journal of Craniofacial Surgery 2012; 23 (3): e205-e209.

8. Sungur N, Akan ÌM, Ulusoy MG, Özdemir R, Kilinç H, Ortak T. Clinicopathological evaluation of parotid gland tumors: a retrospective study. Journal of Craniofacial Surgery 2002; 13 (1): 26-30.

9. Koch M, Zenk J, Iro H. Long-term results of morbidity after parotid gland surgery in benign disease. The Laryngoscope 2010; 120 (4): 724-30.

10. Andry G, Hamoir M, Locati LD, Licitra L, Langendijk JA. Management of salivary gland tumors. Expert Review of Anticancer Therapy 2012; 12 (9): 1161-8.

11. Papadogeorgakis N, Goutzanis L, Petsinis V, Alexandridis C. Management of malignant parotid tumors. Oral and Maxillofacial Surgery 2012; 16 (1): 29-34.

12. Ungari C, Paparo F, Colangeli W, Iannetti G. Parotid glands tumours: overview of a 10-years experience with 282 patients, focusing on 231 benign epithelial neoplasms.

European Review for Medical and Pharmacological Sciences 2008; 12 (5): 321-5.

13. Mehle ME, Wood BG, Tucker HM, Lavertu P, Tubbs R, Kraus DH. Lymphoma of the parotid gland. The Laryngoscope 1993; 103 (1): 17-21.

14. Tiplady C, Taylor P, White J, Arullendran P, Proctor S. Lymphoma presenting as a parotid tumour: a populationbased study of diagnosis, treatment and outcome on behalf of the Scotland and Newcastle Lymphoma Group.

Clinical Oncology 2004; 16 (6): 414-19.

15. Cardoso S, do Nascimento Souza KC, de Faria P et al.

Warthin’s tumor at the Brazilian National Cancer Institute: Additional evidence of homogeneous sex prevalence and association with other neoplasms. ORL 2008; 70 (6): 339-43.

16. Awan MS, Ahmad Z. Diagnostic value of fine needle aspiration cytology in parotid tumors. JPMA 2004; 54 (12): 617-19.

17. Piccioni L, Fabiano B, Gemma M, Saranria D, Bussi M. Fineneedle aspiration cytology in the diagnosis of parotid lesions. Acta Otorhinolaryngologica Italica 2011; 31 (1): 1-4.

18. Yuan X, Gao Z, Jiang H et al. Predictors of facial palsy after surgery for benign parotid disease: Multivariate anal-ysis of 626 operations. Head & Neck 2009; 31 (12): 1588-92.

19. Singh N, Kohli M, Kohli H. Innovative technique to reduce incidence of Frey’s syndrome after parotid surgery. The American Surgeon 2011; 77 (3): 351-4.

20. Olsen KD, Daube JR. Intraoperative monitoring of the facial nerve: an aid in the management of parotid gland recurrent pleomorphic adenomas. The Laryngoscope 1994; 104 (2): 229-32.

21. Zbären P, Tschumi I, Nuyens M, Stauffer E. Recurrent pleomorphic adenoma of the parotid gland. The American Journal of Surgery 2005; 189 (2): 203-7.

C. FARAH et al. – Management of parotid tumors

ARTICLE ORIGINAL / ORIGINAL ARTICLE EFFECTS OF PREOPERATIVE ENOXAPARIN ON BLEEDING AFTER CORONARY ARTERY BYPASS SURGERY http://www.lebanesemedicaljournal.org/articles/63-4/original3.pdf 1

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Moussa ABI GHANEM , Elie SALIBA , Jihad IRANI , Roula DARWISH , Nadine KAWKABANI 1 4 1 Toni YARED , Charbel NAIM , Bassam ABU KHALIL

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Abi Ghanem M, Saliba E, Irani J, Darwish R, Kawkabani N, Yared T, Naim C, Abu Khalil B. Effects of preoperative enoxaparin on bleeding after coronary artery bypass surgery. J Med Liban 2015 ; 63 (4) :185-190.

Abi Ghanem M, Saliba E, Irani J, Darwish R, Kawkabani N, Yared T, Naim C, Abu Khalil B. Effets de l’énoxaparine reçue en préopératoire sur le saignement après chirurgie de pontage coronarien. J Med Liban 2015 ; 63 (4) : 185-190.

ABSTRACT • Background : Low molecular weight heparins are replacing unfractionated heparin in practice prior to cardiac surgery. This study examines postoperative (post-op) bleeding indicators in patients who received enoxaparin and underwent elective isolated first time coronary artery bypass graft.

Methods : A total of 125 consecutive patients who underwent this procedure between 2009 and 2011 at one tertiary center were reviewed and divided into three groups : Group A (n = 50) received the last dose of enoxaparin between 12 and 24 hours before surgery, Group B (n = 25) received the last dose before 24 hours and Group C (n = 50) did not receive enoxaparin.

Perioperative bleeding indicators and transfusion rates were compared. Results : Preoperative patients’ characteristics were comparable between the three groups. There were no perioperative deaths, return to the operating room for any reason, nor major bleeding. Post-op bleeding indicators were similar in the three groups. The average chest tube drainage at 24 hours post-op was 880 mL, 695 mL and 830 mL in Group A, B and C respectively (p = 0.71). Transfusion rates of red blood cells were not statistically different (Group A 56%, B 64% & C 62% ; p = 0.747). In multivariate analysis, female gender, older age, and preoperative clopidogrel intake (stopped 5 days prior to surgery) were associated with higher transfusion rates.

Conclusion : In elective first time coronary artery bypass graft patients who had no aspirin or clopidogrel intake 5 days prior to surgery, the use of enoxaparin up to 12 hours prior to skin incision does not increase the risk of post-op bleeding.

Keywords : enoxaparin, coronary artery bypass, postoperative hemorrhage

RÉSUMÉ • Contexte: Les héparines de bas poids moléculaire remplacent dans la pratique l’héparine non fractionnée avant la chirurgie cardiaque. Cette étude examine les indicateurs hémorragiques postopératoires chez les patients ayant reçu de l’énoxaparine et subi un pontage coronarien électif isolé pour la première fois. Méthodes : 125 patients consécutifs ayant subi cette procédure entre 2009 et 2011 dans un centre tertiaire ont été examinés et divisés en trois groupes: groupe A (n = 50) ont reçu la dernière dose d’énoxaparine entre 12 et 24 h avant la chirurgie, groupe B (n = 25) ont reçu la dernière dose avant 24 h, et le groupe C (n = 50) n’ont pas reçu d’énoxaparine. Les indicateurs de saignements peropératoires et les taux de transfusion ont été comparés. Résultats : Les caractéristiques des patients préopératoires étaient comparables entre les trois groupes. Pas de décès per opératoires et pas de retour au bloc opératoire pour hémorragie majeure ou autre raison quelconque. Les indicateurs de saignements postopératoires étaient similaires dans les trois groupes. Le drainage thoracique moyen à 24 heures postopératoires était de 880 ml, 695 ml et 830 ml dans les groupes A, B et C respectivement (p = 0,71). Les taux de transfusion de globules rouges n’étaient pas statistiquement différents (groupe A 56%, B 64% et C 62%, p = 0,747). Une analyse multivariée a montré que le sexe féminin, l’âge, et le clopidogrel en préopératoire (arrêté 5 jours avant la chirurgie) ont été associés à des taux plus élevés de transfusion.

Conclusion : Chez les patients opérés d’un pontage coronarien électif pour la première fois et qui n’avaient pas pris d’aspirine ou de clopidogrel 5 jours avant la chirurgie, l’utilisation de l’énoxaparine jusqu’à 12 heures avant l’incision de la peau n’augmente pas le risque d’hémorragie postopératoire.

INTRODUCTION

heparins (LMWH), particularly enoxaparin, became more popular, replacing UFH in many indications and many centers around the world. In fact, enoxaparin has a higher bioavailability, is easily administered, and has more predictable dose-response characteristics with no required laboratory monitoring. Furthermore, enoxaparin has been shown to be more effective than UFH in preventing coronary events in patient with ACS [4-6].

LMWHs duration of activity is longer than that of UFH and only partially neutralized by protamine sulfate [6-7], with a potential risk of increased bleeding when used around the time of a coronary artery bypass graft (CABG) surgery.

In this paper, we describe our experience with the use of enoxaparin prior to CABG, and its effect on bleeding

Unfractionated heparin (UFH) plays a major role as antithrombotic agent in the treatment of acute coronary syndrome (ACS) [1-3]. However, its use is associated with an unpredictable anticoagulant effect requiring frequent blood testing to adjust the dose, a tendency to rebound and a risk of thrombocytopenia. Thus, low molecular weight Departments of Cardiothoracic Surgery1, Cardiac Surgery Anesthesia3, Cardiology4, St Georges Hospital-University of Balamand Medical Center, Beirut, Lebanon.

2 Faculty of Medicine & Medical Sciences, University of Balamand, Beirut, Lebanon.

Correspondence: Jihad Irani, MD. email: jihad.irani@balamand.edu.lb

Lebanese Medical Journal 2015 • Volume 63 (4) 185

in the postoperative (post-op) phase in general and according to its stopping time preoperatively.

MATERIAL AND METHODS

We retrospectively reviewed consecutive patients who underwent elective first time CABG at our tertiary center between 2009 and 2011. The study was approved by the Institutional Review Board (IRB) at the University of Balamand.

We included all first time isolated CABG patients and excluded those who had hematologic diseases, elevated creatinine (Cr) levels (Cr > 1.2), those on heparin and those who were on anti-platelet therapy in the last five preoperative (pre-op) days. Patients with elevated creatinine were excluded since, according to the manufacturer, enoxaparin associated risk of bleeding is increased with the degree of renal impairment.

We divided eligible patients into three groups: Group A received enoxaparin until 12 to 24 hours before surgery, Group B received the last dose of enoxaparin more than 24 hours before surgery and Group C consisted of patients who did not receive enoxaparin at all (control). The dose of enoxaparin given was 1 mg/kg twice a day. The enoxaparin used in our center was Lovenox® (Sanofi-Aventis, Canada).

We collected the following data on all eligible patients: baseline hematologic characteristics, creatinine level, duration of enoxaparin treatment, time between the last enoxaparin dose and surgery and pre-op use of oral anti-platelets agents (aspirin, clopidogrel). Data regarding the CABG procedure, that was undertaken by the same senior surgical team, included the duration of cardiopulmonary bypass (CPB), number of grafts, activated clotting time (ACT) and the volume of blood and blood products transfused during the operation. Hematologic and transfusion data collected included perioperative hematocrit (Hct) measurement as well as the quantity of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets administered intraoperatively and during the first 72 hours after surgery.

All CABG procedures were performed by the same surgical team, including the general anesthesia, radial artery cannulation, median sternotomy, central cannulation, non-pulsatile CPB with moderate systemic hypothermia (32-33°C) and antegrade and retrograde cold blood cardioplegia. All patients received tranexamic acid 10 mg/kg at induction of the general anesthesia and then 250 mg on CPB. Anticoagulation was established by a standard dose of UFH (4 mg/kg) via the central line.

Additional UFH was given in order to maintain an ACT greater than 480 sec. After the discontinuation of bypass support, UFH was reversed by administration of 1 mg protamine per 100 U of UFH to achieve an ACT of 130140 sec. The cardiopulmonary bypass prime was 1.55 L: 0.5 L of sodium bicarbonate 1.4%, 0.5 L of Haes sterile 6% (Fresenius Kabi, India), 0.5 L of Ringer (Taj pharmaceuticals, India) and 0.05 L of albumin 20%.

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In post-op, we collected the chest tube output for the first 24 and 48 hours in addition to the amount of blood products administration in the first 72 hours. All chest tubes were removed systematically on day 2 post-op.

Patients were given PRBC to keep their Hct level above 25%. FFP was given for fibrinogen levels below 100 or for an international normalized ratio (INR) more than 1.7. Platelets were given for platelet count below 50000.

Post-op hematologic characteristics were also recorded.

Statistical Analysis At first, we used means, medians and standard deviations (SD) to describe our quantitative data, and proportions to describe our qualitative data. We used traditional statistical tests to compare between variables, Student t-test, ANOVA for normally distributed variables and Mann-Whitney and Kruskall-Wallis tests when appropriate. We used chi-square test to compare qualitative data, and Fisher exact test when appropriate. We ran a logistic regression model to analyze the factors associated with the outcome variable ‘need for PRBC transfusion’, and we included in the model all the variables that were associated to this outcome in the bivariate analysis, in addition to the variable ‘group belonging’. Model calibration was assessed using Hosmer-Lemeshow test. The c-statistic was calculated as a measure of discrimination.

All p-values below 0.05 were considered statistically significant. We used SPSS v16.0 and MedCalc v 12.3 for statistical analysis.

166 patients undergoing isolated CABG

Excluded

29 patients (Cr > 1.2)

Included

125 patients

5 patients (UFH used within 12 hours of the surgery)

3 patients Redo surgery

3 patients Off pump CABG

1 patient (History of coagulopathy

before surgery)

FIGURE 1 Total number of patients included and excluded in the study

M. ABI GHANEM et al. – Preoperative enoxaparin in CABG and bleeding

RESULTS

Among 166 patients who had the procedure between June 2009 and October 2011, 125 met our selection criteria (Figure 1).

We analyzed the data on all 125 patients. Collected patients’ demographics (such as age, sex, etc.) were identical and equally distributed between the three groups (Table I). The average age of the studied sample was 65.8 years. Most of our patients were male (80%).

Base-line hematocrit, platelets count, creatinine levels, and diabetic status were comparable between the different groups. The prothrombin time (PT) and partial

thromboplastin time (PTT) were similar, as well as the average bypass time. The pre-op ACT was slightly more elevated in the Group A compared to Group B (mean 146 vs. 139, p = 0.010 post-hoc analysis).

Seventy-five patients (60%) received one or more unit of PRBC during the observed period. Only 17 patients (13.6%) needed FFP, and 10 patients (8%) needed platelet transfusion. In order to estimate the severity of bleeding, we analyzed the “need for PRBC transfusion” as an outcome variable. In the three groups, the need for PRBC transfusion was 56% in Group A (28 patients), 64% in Group B (16 patients) and 62% in Group C (31 patients) (p = 0.747; Table II).

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There were no significant differences in PRBC transfusion nor in chest tube drainage post-op among the three groups (Table II), (Figure 2).

The following factors were significantly associated with receiving more PRBC: being a female, older age and having taken clopidogrel in pre-op independently of what group they belong to (Table III). Eighty-eight percent of female patients needed a transfusion versus 53% of male patients (p = 0.001). The mean age of patients receiving PRBC transfusion was 68 years compared to a mean of 62 years in those who did not receive any PRBC transfusion (p < 0.001). Of those patients who were on clopidogrel in pre-op (26 patients - stopped 5 days pre-op on average), 85% needed a PRBC transfusion compared to 53% of those who never had clopidogrel (p = 0.004).

After performing a logistic regression analysis, including in the model the following variables: sex, age, aspirin receipt in pre-op, clopidogrel in pre-op, pre-op Hct and UFH in per-op (Table IV), the factors ‘age’, ‘sex’ and ‘prior use of clopidogrel’ remained statistically associated with the outcome ‘need for PRBC’.

When examining drains’ output of the first 24 hours post-op, the following factors were found to be associated with a higher output: number of bypasses (more than two grafts) and being a male (Table V).

DISCUSSION

Anticoagulation has been considered to be the cornerstone of the management of ACS [1]. Since the 1970’s, UFH was shown to benefit patients with acute myocardial infarction by exerting an activity against factor Xa and thrombin [1-2].

New formulation of LMWH, which have a greater activity against Xa, have been used in treating ACS [6].

In contrast to UFH, these molecules produce more predictable anticoagulation response, have a better bioavailability and do not require laboratory monitoring [6]. enoxaparin, which is a LMWH, has shown to be superior to UFH in the treatment of ACS, however its long

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Units of PRBC received per group None

enox 12-24h

1-2 units

enox > 24h

3-4 units

5 units and more

None

Group

FIGURE 2. Amount of PRBC transfused per group

duration of activity and its partial neutralization by protamine have raised concerns regarding bleeding complications in patients undergoing CABG treated by LMWH prior to surgery [6-7].

According to the latest guidelines concerning perioperative management of antithrombotic therapy published by the American College of Chest Physicians (ACCP) in 2012 [8], it is suggested continuing aspirin around the time of surgery in patients requiring CABG instead of stopping it 7 to 10 days before, and administering the last dose of LMWH 24 hours before surgery instead of 12 hours before. Those recommendations are grade 2C which means very weak recommendations with low-quality evidence; that’s why those recommendations remain a sug-

M. ABI GHANEM et al. – Preoperative enoxaparin in CABG and bleeding

gestion and other alternatives may be equally reasonable.

In order to elucidate this matter, many reports studied the incidence of bleeding complications in patients undergoing CABG treated prior to surgery by LMWH. Some of these studies showed no significant risk of bleeding in those patients compared to subjects receiving UFH [9-10]. In fact, Renda et al. found that transfusional requirements of blood and plasma was similar in patients receiving either UFH or LMWH (stopped 12 hours prior to surgery) but their study had sample size limitation [9]. Medalion et al. found also that administration of enoxaparin more than 8 hours before surgery did not increase bleeding or products’ transfusion rate [10].

However, these findings contrast with what Jones et al. found: a significant increase in incidence of re-exploration for post-op bleeding in a group of patient receiving enoxaparin [11]. Their study was done on a small size of patients who had some significant differences in the baseline characteristics between the two groups in relation to age, sex and type of surgery. It showed a lack of correlation between blood products usage and increased risk of surgi-

cal re-operation, and failed to describe any temporal relationship between the last dose of enoxaparin and post-op bleeding. The increased risk of bleeding and mediastinal re-exploration in a group treated by LMWH was also mentioned by two studies: a study by Myhre et al. [12] in 2004 and a study by McDonald et al. [13] in 2005. Kincaid et al. showed also that the preoperative use of enoxaparin less than 12 hours before CABG is associated with lower postop hemoglobin values and higher rates of transfusion when compared to continuous use of UFH [14].

In our study, we showed that the use of enoxaparin in pre-CABG does not affect some bleeding parameters,

M. ABI GHANEM et al. – Preoperative enoxaparin in CABG and bleeding

Lebanese Medical Journal 2015 • Volume 63 (4) 189

when stopped earlier than 12 hours prior to the surgery.

Enoxaparin is usually administered twice daily and since our patients had all elective surgery, we stopped enoxaparin at two different intervals prior to surgery. In one of the groups, enoxaparin was stopped 12 hours prior to surgery while in the other it was stopped 24 hours prior to surgery. We found that whether using enoxaparin and stopping it late (12-24 h prior) or early (24 h prior) did not affect bleeding parameters (tube drainage and transfusion rate) in comparison to the controls. Our series showed lower bleeding rates in general and that could be related to the use of tranexamic acid.

All patients who received enoxaparin did not have pre-op higher PT, PTT or ACT levels than the control group. There is no data in the literature about heparin resistance and pre-op use of enoxaparin.

The heparin use on bypass in this study was similar between all groups (p = 0.258; Table I). This implies absence of any heparin resistance, even though it is documented in the literature in around 26% of the cases [15]. Based on our findings, administering enoxaparin up to 12 hours prior to surgery appears safe.

The findings that the number of bypasses grafts and being a male increase chest tube drainage is interesting but not related to the use of enoxaparin (Table V).

On the other hand a multivariate analysis showed that female gender, age and administration of clopidogrel more than five days prior to surgery increase the need for transfusion. This also is not related to the use of enoxaparin, even though they are important findings and need to be affirmed in larger studies.

The fact that being of female gender was an indicator of increased need for transfusion with however lower absolute amounts of chest tube drainage is intriguing, but can be explained when looking to their smaller body surface area (BSA). In fact the female patients had a lower mean BSA (1.75) than male patients (1.91) and this may explain the higher transfusion rate in them even though they had lower chest tube drainage.

Our study has its own limitations; it is a one-center retrospective study, reflecting the practice of one group which might affect the generalizability of the findings.

The sample size is relatively small and that might affect the ability to detect differences that really exist (type-2 error). Large multicenter studies would be required in order to shed more lights on this issue.

CONCLUSION

In elective first time CABG patients who had no aspirin or clopidogrel intake five days prior to surgery, the use of enoxaparin up to 12 hours prior to skin incision is safe and does not increase the risk of bleeding postoperatively or the transfusion rate.

However, the use of clopidogrel (more than five days prior to surgery), age and being a female may predict a higher transfusion rate.

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REFERENCES 1. Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet 1981; 1: 1225-8.

2. Théroux P, Ouimet H, McCans J et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11.

3. Oler A, Whooley MA, Oler J et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis.

JAMA 1996; 276: 811-15.

4. Antman EM, McCabe CH, Gurfinkel EP et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999 Oct 12; 100 (15): 1593-601.

5. Goodman SG, Cohen M, Bigonzi F et al. Randomized trial of low molecular weight heparin (Enoxaparin) versus unfractionated heparin for unstable coronary artery disease: One-year results of the ESSENCE study. J Am Coll Cardiol 2000; 36: 693-8.

6. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.

7. Holst J, Lindblad B, Bergqvist D et al. Protamine neutralization of intravenous and subcutaneous low-molecularweight heparin (tinzaparin, logiparin). An experimental investigation in healthy volunteers. Blood Coagulation & Fibrinolysis 1994; 5: 795-803.

8. Douketis JD, Spyropoulos AC, Spencer FA et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2 suppl): e326S-e350S. 9. Renda G, Di Pillo R, D’Alleva A et al. Surgical bleeding after pre-operative unfractionated heparin and low molecular weight heparin for coronary bypass surgery.

Haematologica 2007; 92: 366-73.

10. Medalion B, Frenkel G, Patachenko P et al. Preoperative use of enoxaparin is not a risk factor for postoperative bleeding after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003 Dec; 126 (6): 1875-9.

11. Jones HU, Muhlestein JB, Jones KW et al. Preoperative use of enoxaparin compared with unfractionated heparin increases the incidence of re-exploration for postoperative bleeding after open-heart surgery in patients who present with an acute coronary syndrome: clinical investigation and reports. Circulation 2002 Sep 24; 106 (12 Suppl 1): I19-I22.

12. Myhre U, Stenseth R, Karevold A et al. Bleeding following coronary surgery after preoperative low-molecular-weight heparin. Asian Cardiovasc Thorac Ann 2004; 12: 3-6.

13. McDonald SB, Renna M, Spitznagel EL et al. Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients.

J Cardiothorac Vasc Anesth 2005; 19: 4-10.

14. Kincaid EH, Monroe ML, Saliba DL et al. Effects of preoperative enoxaparin versus unfractionated heparin on bleeding indices in patients undergoing coronary artery bypass grafting. Ann Thorac Surg 2003; 76: 124-8.

15. Ranucci M, Isgro G, Cazzaniga A et al. Predictors for heparin resistance in patients undergoing coronary artery bypass grafting. Perfusion 1999; 14: 437-42.

M. ABI GHANEM et al. – Preoperative enoxaparin in CABG and bleeding

ARTICLE ORIGINAL / ORIGINAL ARTICLE PROFIL GÉRIATRIQUE selon l’INSTRUMENT IDENTIFICATION SYSTÉMATIQUE des AÎNÉS à RISQUE (ISAR) au SERVICE des URGENCES d’un CENTRE HOSPITALIER UNIVERSITAIRE http://www.lebanesemedicaljournal.org/articles/63-4/original4.pdf 1

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Rita EL-HAYECK , Rafic BADDOURA , Patricia FADEL , Amine WEHBÉ , Antoine ZOGHBY , Marc BERTHEL El-Hayeck R, Baddoura R, Fadel P, Wehbé A, Zoghby A, Berthel M. Profil gériatrique selon l’instrument Identification systématique des aînés à risque (ISAR) au service des urgences d’un centre hospitalier universitaire. J Med Liban 2015 ; 63 (4) : 191-197.

El-Hayeck R, Baddoura R, Fadel P, Wehbé A, Zoghby A, Berthel M. [Geriatric profile according to the Identification of Seniors At Risk (ISAR) tool in the emergency department in a teaching hospital]. J Med Liban 2015 ; 63 (4) :) : 191-197.

RÉSUMÉ • Contexte : Avec l’augmentation prévisible du nombre des personnes âgées au Liban, il est important de mettre en place des services adaptés à leurs besoins spécifiques. Le questionnaire Identification of Seniors At Risk (ISAR) permet d’identifier, aux urgences, les personnes âgées fragiles à risque d’évènements défavorables et susceptibles de bénéficier d’une prise en charge gériatrique spécifique.

Objectifs : i) Évaluer le profil gériatrique selon le score ISAR ; ii) corréler le score ISAR aux suites deux mois après l’accueil aux urgences. Méthodologie : Étude prospective sur deux mois : aux urgences du centre hospitalier universitaire de l’Hôtel-Dieu de France, nous avons interrogé 273 personnes âgées de 70 ans et plus (ou l’aidant de la personne en question) en utilisant le questionnaire ISAR. Un suivi par téléphone a été fait deux mois plus tard. Résultats : La prévalence de sujets avec un score ISAR ≥ 2 et donc susceptibles de bénéficier de la mise en place d’un service de gériatrie est de 70,7% (IC 95% : 64,9-76,0). Les sujets âgés reçus aux urgences avec un score ISAR ≥ 2 sont plus à risque d’être hospitalisés (51,6%) que les sujets de même âge et sexe avec un score ISAR < 2 (36,9%) (p = 0,034). Au bout de 2 mois de suivi, le risque de réadmission à l’hôpital et le risque de décès étaient significativement associés au score ISAR (p = 0,0005) Conclusion : Le pourcentage de personnes âgées susceptibles de bénéficier d’une prise en charge par une filière gériatrique spécialisée dès leur accueil aux urgences d’un centre hospitalier universitaire est significativement élevé [70,7% (IC 95% : 64,9-76,0)].

Mots-clés : personnes âgées, services des urgences, dépistage, services sanitaires gériatriques, Liban

ABSTRACT • Background : With the anticipated increase in the number of elderly people in Lebanon, it is important to develop services tailored to their specific needs. The Identification of Seniors At Risk (ISAR) tool identifies, in emergency setting, frail elderly people at risk of adverse outcomes, who are more likely to benefit from a geriatric approach.

Objectives : i) Assess the geriatric profile according to ISAR score ; ii) correlate the score to outcomes two months after Emergency Department (ED) visit. Methods : A twomonth prospective study : at the ED of Hôtel-Dieu de France Hospital, we interviewed 273 people aged 70 years and older (or their caregiver) using the ISAR tool. Telephone follow-up was done two months later. Results : The prevalence of subjects with ISAR score ≥ 2 and thus likely to benefit from the establishment of a geriatric service is 70.7% (95% CI : 64.9-76.0). Elderly patients admitted to ED with ISAR score ≥ 2 are more likely to be hospitalized (51.6%) than subjects of the same age and sex with ISAR score < 2 (36.9%) (p = 0.034). After two months of follow-up, the risk of hospital readmission and the risk of death was significantly associated with the ISAR score (p = 0.0005) Conclusion : The percentage of elderly people likely to benefit from specialized geriatric care network upon admission to the ED of a university hospital is significantly high [70.7% (95% CI: 64.9-76 .0)].

INTRODUCTION

Parmi les personnes âgées fragiles, le risque de déclin fonctionnel lié à une hospitalisation est augmenté, probablement autant par la rupture de l’équilibre global que par la pathologie même qui motive la prise en charge hospitalière [1-2]. L’inadéquation entre le profil de fragilité 1

Département de Gériatrie, Faculté de Médecine, Université Saint-Joseph, Beyrouth, Liban.

2 Service de Rhumatologie, Centre hospitalier universitaire HôtelDieu de France (CHU-HDF), Beyrouth, Liban.

3 Service des Urgences, CHU-HDF. 4 Pôle de Gériatrie, Hôpitaux Universitaires de Strasbourg, France.

Correspondance : Dr Rita El-Hayeck. e-mail : rita.elhayeck@usj.edu.lb

et les structures traditionnelles de l’hôpital d’une part, et la méconnaissance des indicateurs de ce profil d’autre part, exposent la population âgée aux risques de pertes de capacités fonctionnelles, de placement en institution et de réadmissions à l’hôpital [3-5].

Ces risques peuvent être infléchis favorablement si, dès l’admission, les indicateurs de ces risques sont pris en compte et que des interventions ciblées selon le modèle de l’évaluation gériatrique standardisée sont mises en œuvre durant le séjour avec une planification proactive de la sortie [6-10].

C’est avec cette conception de soins que les services spécialisés en gériatrie, appelés aussi unités de court séjour gériatrique (UCSG), ont été mis en place dans plusieurs pays depuis plus de 30 ans [11].

La principale compétence des unités de gériatrie se trouve dans la capacité de l’équipe hospitalière pluridisciplinaire à répondre à trois défis : – La prise en charge de la polypathologie, en quoi elle Journal Médical Libanais 2015 • Volume 63 (4) 191

se rapproche de sa sœur aînée, la médecine interne, mais se distingue des spécialités médicales d’organe.

– Le repérage des fragilités par la démarche validée dans la littérature internationale de l’évaluation gériatrique standardisée [8, 12-13].

– La capacité à préserver voire à améliorer les capacités fonctionnelles, ce qui permet de réduire l’entrée en institution et favorise ainsi le maintien à domicile des patients âgés [12-13].

Au Liban, sur l’ensemble du territoire, seulement deux UCSG ont été mises en place jusqu’à cette date [14]. Actuellement, la plupart des patients âgés fragiles sont encore admis dans des services d’hospitalisation traditionnels.

Les projections démographiques montrent que d’ici 2035, la proportion des personnes âgées de 65 ans et plus va doubler, passant de 7,3% à 14% [15]. Il est donc important de mettre en place des UCSG adaptées aux besoins spécifiques et prévisibles de cette tranche d’âge ; mais ce qui est encore plus pertinent c’est de bien cibler la clientèle gériatrique qui bénéficiera le plus de ces unités afin d’utiliser à bon escient nos ressources sanitaires [14].

Dans cette perspective, l’utilisation du questionnaire Identification of Seniors At Risk (ISAR) permet d’identifier, aux urgences, les personnes âgées fragiles à risque d’évènements défavorables et susceptibles de bénéficier d’une prise en charge gériatrique [16-18]. Le questionnaire ISAR comprend six items (Tableau I) évaluant la présence de facteurs de risque prédictifs d’évènements défavorables tels que : hospitalisation, déclin fonctionnel, entrée en institutions, voire réadmissions aux urgences à brève échéance [18]. Un patient est considéré à risque de subir un événement défavorable lorsqu’il a plus de 2 réponses positives avec une sensibilité de 73% et une spécificité de 51% [18-19].

D’autres instruments de dépistage existent tels que le Triage Risk Screening Tool (TRST) [20], l’Hospital Admission Risk Profile (HARP), et le Care Complexity Prediction Instrument (CCPI) [21]. Cependant, deux études ont démontré que le test ISAR performe mieux que le TRST lorsqu’il a été appliqué dans des services d’urgences belges et canadiens [22-23]. Une étude

comparant les trois instruments HARP, CCPI et ISAR a démontré la supériorité prédictive de ce dernier sur le risque de déclin fonctionnel [23]. D’autres études ont également montré les bonnes performances du test ISAR dans différents contextes de soins [17-19, 22, 24]. De plus le test ISAR est le plus facile à administrer [25].

Dans la perspective de création d’une UCSG à l’HôtelDieu de France qui est le Centre hospitalier universitaire (CHU) de l’Université St Joseph (USJ), et pour répondre à la question « Quel est le nombre de patients âgés qui nécessiteraient une prise en charge par une filière gériatrique ? », cette étude a été mise en place. Elle avait donc pour objectifs : – Évaluer le profil gériatrique selon le score ISAR parmi les personnes âgées qui se présentent aux urgences de l’Hôtel-Dieu de France.

Estimer la prévalence des personnes âgées ayant un – score ≥ 2 .

– Identifier des facteurs de risque potentiels d’avoir un score ISAR ≥ 2.

– Corréler le score ISAR aux suites après l’accueil aux urgences.

MATÉRIELS ET MÉTHODES

La population étudiée incluait l’ensemble des personnes âgées de 70 ans et plus qui se sont présentées aux urgences de l’Hôtel-Dieu de France, pendant un mois, du 4 juin au 4 juillet 2012.

Le patient, ou un membre de sa famille qui l’accompagnait, a été interrogé aux urgences par les internes de septième année de Médecine, avec le questionnaire ISAR. Les personnes qui n’ont pas pu être interrogées aux urgences, ont été rappelées dans leur chambre durant les deux premiers jours de leur admission. Les données collectées comprenaient outre les items du score ISAR : l’âge, le sexe, l’existence d’une couverture médicale, l’admission ou non à l’hôpital et, en cas d’admission, dans quel service hospitalier le sujet avait été admis.

Pour les personnes qui n’ont pas été admises à l’HDF, elles ont été rappelées à domicile deux mois plus tard durant la période du 1er septembre au 24 octobre 2012.

TABLEAU I QUESTIONNAIRE ISAR *

QUESTIONS 1. Avant cette admission aux urgences, aviez-vous besoin d’aide à domicile ?

2. Depuis le début des symptômes qui vous ont amené aux urgences, avez-vous eu besoin de plus d’aide à domicile ?

3. Avez-vous été hospitalisé pour 1 ou plusieurs jours ces 6 derniers mois ?

4. Dans la vie quotidienne souffrez-vous de problèmes de vue ?

5. Dans la vie quotidienne souffrez-vous de problèmes de mémoire ?

6. Prenez-vous plus de 3 médicaments par jour ?

Oui / Non Oui / Non Oui / Non Oui / Non Oui / Non Oui / Non

* Questionnaire de dépistage des patients âgés à risque d’évènements indésirables.

Un patient est considéré à risque d’évènement indésirable (déclin fonctionnel, réadmission) avec plus de 2 réponses positives.

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R. EL-HAYECK et al. – Utilité de l’instrument ISAR dans les soins gériatriques

Le questionnaire utilisé comprenait les informations suivantes : âge, sexe, score ISAR, système de couverture médicale, si le patient a regagné son domicile ou s’il a été transféré dans un autre hôpital et dans ce dernier cas pourquoi et dans quel service il a été admis, et finalement l’état du malade deux mois après sa présentation aux urgences.

L’analyse statistique a été réalisée avec le logiciel STATA version 9. L’hypothèse d’une association entre un score ISAR ≥ 2 et des facteurs de risque potentiels a été testée par un χ2 pour l’analyse univariée et logistique pour une analyse multivariée. Le degré de signification statistique est de 5%. Les différentes estimations sont calculées avec leur intervalle de confiance à 95%.

TABLEAU II POURCENTAGE DE SUJETS BÉNÉFICIANT D’UN TIERS PAYANT PAR CATÉGORIE

Tiers payant

RÉSULTATS

Effectif

Fréquence

Pas de réponse Assurance privée CNSS Assurance privée + CNSS Mutuelle des fonctionnaires de l’État Armée Payant ordinaire Caisse des Français à l’étranger Autres

8 84 49 17 31 8 36 7 33

2,9% 30,8% 17,9% 6,2% 11,4% 2,9% 13,2% 2,6% 12,1%

Total

273

100,0%

CNSS: Caisse Nationale de Sécurité Sociale

Du 4 juin au 4 juillet 2012, 2575 consultations ont été réalisées aux urgences parmi lesquelles 374 concernaient des personnes âgées de 70 et plus, soit une prévalence de 14,5% de l’effectif total des consultations aux urgences (Figure 1). Ces 374 consultations correspondaient effectivement à 355 sujets car certaines personnes se sont présentées aux urgences à plusieurs reprises durant cette même période.

Caractéristiques sociodémographiques de la population étudiée Il y avait 184 hommes soit 51,8% de l’effectif, et 171 femmes soit 48,2% de l’effectif (IC 95% : 42,9-53,5%).

L’âge maximal était de 96 ans avec une médiane de 78 ans et une moyenne (DS = 6,1) de 79 ans. Pas de différence significative entre hommes (79,1) et femmes (79,0). Des 355 personnes reçues aux urgences, 181 (50,9%) ont été hospitalisées à l’HDF. Nous avons pu interroger 128 personnes hospitalisées (soit 70,7% de ceux qui ont été hospitalisés à l’HDF). Pour le reste : 22 personnes ont été

admises aux soins intensifs et n’ont pas pu être interrogées, et pour les 31 qui restaient les causes étaient multiples : refus de participation, troubles de l’acuité auditive, départ de l’hôpital avant de les interroger.

Des 174 personnes qui n’ont pas été hospitalisées, nous avons pu en appeler 145 (soit 83,3%).

Pour le reste : • 14 : pas de réponses après plusieurs appels • 8 : faux numéros de téléphone • 3 : refus de répondre • 3 : ligne occupée après plusieurs tentatives • 1 : en voyage) (Figure 1).

Douze personnes ont été transférées dans un autre hôpital (10/12 à cause de faute de place) lorsqu’elles ont quitté les urgences de l’HDF. Au total, sur les 273 personnes que nous avons pu interroger, nous avons eu les résultats suivants : Bénéfices d’un tiers payant 86,8% des personnes interrogées bénéficiaient d’un tiers payant (Tableau II).

2575 personnes admises aux urgences 355 personnes âgées de 70 ans et plus

181 personnes hospitalisées

174 personnes non hospitalisées

22 : admises aux soins intensifs 31 : refus de participation, départ de l’hôpital avant de les interroger…

128 personnes interrogées

29 : pas de réponse, faux numéros, occupé, refus de répondre...

145 personnes interrogées FIGURE 1. Population étudiée

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Journal Médical Libanais 2015 • Volume 63 (4) 193

78,5

80

Prévalence des sujets avec un score ISAR ≥ 2 et donc susceptibles de bénéficier de la mise en place d’une UCSG Parmi l’ensemble des 273 personnes interrogées, le nombre de sujets avec un score ISAR ≥ 2 était de 193 soit une prévalence de 70,7% (IC 95% : 64,9-76,0).

La prévalence était de 67,9% (IC 95% : 59,3-75,9) parmi les femmes et de 77,1% (IC 95% : 68,9-83,9) parmi les hommes ; (p = 0,094).

Parmi les personnes qui ont été hospitalisées à l’HDF, le taux de prévalence était de 77,3% versus 64,8% parmi les personnes non hospitalisées à l’HDF.

% de “oui”

70 60 46,6

50 40

46,2

35,7

30

22.1

24.8

20

Corrélation entre le score ISAR et l’âge Le score ISAR augmentait significativement avec l’âge : le χ2 de tendance est de 10,26 avec un p de 0,00136 ; la fréquence de sujets ayant un score ISAR ≥ 2 augmentait aussi avec l’âge. (Tableau III).

Plus de 3 médicaments

Troubles de mémoire

Troubles visuels

Antécédents d’hospitalisation

Plus d’aide

0

Aide à domicile

10

Comparaison entre hospitalisés et non hospitalisés • La moyenne (DS) d’âge des sujets hospitalisés est 80,2 (6,2) ans versus 77,9 (5,7) parmi les sujets non hospitalisés ; la différence est statistiquement significative (p = 0,0003).

FIGURE 2. Pourcentage de réponses « oui » à chacune des questions du score ISAR

24,81

Répartition des personnes hospitalisées à l’HDF selon les services d’admission à l’hôpital La proportion de sujets hospitalisés est de 50,9% (IC 95% : 45,7%-56,3%) parmi l’ensemble des sujets reçus aux urgences ; elle est de 49,2% parmi les hommes versus 54,1% parmi les femmes, différence statistiquement non significative. (p = 0,35) 71% des personnes âgées admises à l’HDF ont été hospitalisées dans des services de médecine, 14% dans des services de chirurgie et 15% dans des services de soins intensifs.

25

%

21,43

20,3

20

18,05

15

10 7,14

6,02

Pourcentage de réponses « oui » aux questions du score ISAR (cf. Figure 2)

5 2,26

Distribution du score ISAR dans la population étudiée (cf. Figure 3) Le score ISAR varie entre 0 et 6 avec une médiane de 2 et une moyenne de 2,5 (DS = 1,5). Pas de différence significative entre hommes (2,5) et femmes (2,6) (p = 0,8).

0

0

1

2

3

4

5

6

FIGURE 3. Distribution en pourcentage du score ISAR dans la population étudiée.

TABLEAU III DISTRIBUTION EN NOMBRE ABSOLU (%) DU SCORE ISAR ET FRÉQUENCE DES SUJETS AYANT UN SCORE ≥ 2 PAR TRANCHE D’ÂGE DE 5 ANS

AGE

Score ISAR

0

1

2

3

4

5

6

% Score ISAR ≥ 2

[70-75[

6 (8,3%)

18 (25%)

15 (20,8%)

15 (20,8%)

14 (19,4%)

4 (5,5%)

0

66,7%

[75-80[

6 (7,4%)

15 (18,5%)

26 (32,1%)

20 (24,7%)

10 (12,3%)

3 (3,7%)

1 (1,2%)

74,1%

[80-85[

2 (3,3%)

16 (26,7%)

18 (30%)

6 (10%)

11 (18,3%)

4 (6,7%)

3 (5%)

70,0%

[85-90[

2 (5,4%)

6 (16,2%)

5 (13,5%)

9 (24,3%)

10 (27%)

4 (10,8%)

1 (2,7%)

78,4%

0

2 (13,3%)

2 (13,3%)

3 (20%)

3 (20%)

4 (26,7%)

1 (6,6%)

86,7%

90+

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TABLEAU IV

• Le score ISAR des sujets hospitalisés est 2,8 (1,4)

CORRÉLATION ENTRE LE SCORE ISAR ET LE RISQUE D’HOSPITALISATION LORS DE L’ACCUEIL AUX URGENCES

versus 2,3 (1,5) parmi les sujets non hospitalisés ; la différence est également statistiquement significative (p = 0,01).

• Le score ISAR était significativement lié à la probabilité d’hospitalisation, en ajustant sur l’âge et le sexe ; OR (IC 95%) : 1,21 (1,01-1,44) ; p = 0,035 (Tableau IV).

Comparaison des sujets ayant un score ISAR ≥ 2 avec ceux ayant un score ISAR < 2 Il n’y a pas de différence significative entre les deux groupes selon l’âge, le sexe, le système de couverture médicale. Par contre, ceux ayant un score ISAR ≥ 2 sont plus à risque d’être hospitalisés puisque le pourcentage de sujets hospitalisés parmi ceux avec un ISAR < 2 est de 36,9% versus 51,6% pour un ISAR ≥ 2 ; p = 0.034.

Suivi au bout de 2 mois • Parmi les 170 sujets non hospitalisés, 145 sujets ont pu être réévalués deux mois plus tard : 29% ont été réadmis plus tard à l’hôpital, 6% sont décédés et 64,8% sont dans un état stationnaire.

• Le score ISAR est significativement lié à chacune de ces trois éventualités ; le score ISAR moyen est de 1,9 (1,3) parmi ceux dont l’état reste stationnaire, 2,9 (1,6) parmi ceux qui sont réadmis à l’hôpital et 3,2 (0,5) parmi ceux qui décèdent dans les deux mois qui suivent leur arrivée aux urgences. La différence ainsi observée entre les trois groupes est statistiquement significative (p = 0,0005) DISCUSSION

Notre étude a montré que les personnes âgées de 70 ans et plus constituent 14,5% de l’effectif total des admis aux urgences. Les données américaines montrent un taux moyen de 18% pour les personnes âgées de 65 ans et plus (allant de 11% à 23%) [26]. Les données italiennes sont similaires avec des taux de 21% en moyenne [27-28].

Dans la plupart de ces pays ce taux est en train d’augmenter due au vieillissement de la population [26-28].

Dans notre étude, 51% des personnes âgées qui se sont présentées aux urgences ont nécessité une hospitalisation. Par rapport aux sujets jeunes, les personnes âgées utilisent les services des urgences pour des problèmes plus urgents [29], nécessitent plus de ressources, et plus d’admissions hospitalières (30-50% vs 12% chez les jeunes) [30]. Les personnes âgées sont aussi plus à risque de visites à répétition aux urgences, de réhospitalisation, d’entrée en institutions, de déclin fonctionnel et de mortalité après une visite aux urgences [30].

Le questionnaire ISAR a été développé pour identifier les personnes âgées le plus à risque d’évolution défavorable [18]. Il a été démontré qu’il performe bien dans les services des urgences [17-19, 22, 24].

C’est la première étude libanaise qui étudie le profil de fragilité selon le score ISAR chez les personnes âgées

Variable

OR (IC 95%)

P

Age

1,05 (1,01-1,09)

0,035

Sexe

1,85 (1,12-3,04)

0,016

ISAR

1,21 (1,01-1,44)

0,035

qui se présentent aux urgences d’un CHU. Les résultats d’une étude récente faite en GrandeBretagne sont assez proches de la nôtre puisque 39% avaient besoin d’aide à domicile (versus 35,7% dans notre étude), 25% des problèmes visuels (versus 22% dans notre étude), 18% avaient des problèmes de mémoire (24,8% dans notre étude), 45% (46,2% dans notre étude) ont des antécédents d’hospitalisation dans les six mois précédents, 78% (78,5% dans notre étude) prenaient plus de 3 médicaments/jour. Par contre, beaucoup plus de personnes dans notre étude ont eu besoin de plus d’aide à domicile depuis le début des symptômes ayant motivé le recours aux urgences (46% versus 25% dans l’étude anglaise) [31].

La prévalence du score ISAR ≥ 2 dans notre échantillon est de 70,7%. Ce chiffre est assez proche d’une autre étude récente faite en Italie qui a montré une prévalence de 68%. Cette étude ayant pris en considération les sujets âgés à partir de l’âge de 65 ans alors que dans notre étude c’était à partir de 70 ans, mais la moyenne d’âge de l’étude italienne est supérieure à notre échantillon (81,7 ans vs 79 ans). C’est pour cela, sachant que la prévalence du score ISAR > 2 augmente avec l’âge, que nous avons trouvé une prévalence assez proche de l’étude italienne [32].

Dans l’étude faite en Grande-Bretagne consacrée comme la nôtre aux sujets âgés de 70 ans et plus, 69% avaient un score ISAR ≥ 2 [31], ce qui est assez proche de nos résultats.

Donc, selon notre étude, plus des 2/3 des patients âgés de plus de 70 ans qui se présentent aux urgences nécessitent une évaluation gériatrique standardisée et davantage, plus des 3/4, parmi ceux qui sont hospitalisés.

Il est illusoire d’admettre tous ces patients dans une unité de court séjour gériatrique surtout que 30% ont été admis directement en chirurgie ou en soins intensifs.

Mais ce qui est évident, c’est que ce sont des patients qui, à défaut d’être admis dans une UCSG, peuvent au moins profiter de la consultation d’une équipe mobile de gériatrie.

Notre étude a démontré que les personnes qui se présentent aux urgences avec un score ISAR ≥ 2 ont un OR de 1,21 d’être hospitalisés. Ces résultats sont en accord avec d’autres études qui ont aussi démontré un OR de 2,68 [32] ou de 3,38 pour le risque d’hospitalisation [33]. Notre étude a aussi démontré qu’un score ISAR élevé est relié à un risque plus élevé de mortalité. Ce qui est en accord avec plusieurs autres études [18, 25, 30, 32].

Presque tous les patients avaient un régime d’assurance-maladie ce qui ne représente pas vraiment l’en-

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Journal Médical Libanais 2015 • Volume 63 (4) 195

semble de la population âgée libanaise où seulement près de 59% bénéficient d’une couverture médicale [34].

Il y a donc un biais de sélection car le CHU est un hôpital privé et ceux qui n’ont pas d’assurance se dirigent plutôt vers les hôpitaux publics. Donc, il est difficile d’extrapoler les résultats à l’ensemble des services d’urgence.

Les patients hospitalisés n’ont pas été interrogés dans un deuxième temps pour évaluer leur état deux mois plus tard, à l’instar de ce qu’a été fait avec les sujets retournant à domicile.

Nous n’avons pas évalué la corrélation entre le score ISAR et le risque de déclin fonctionnel mais ceci pourra faire l’objet d’études ultérieures. Comme il sera intéressant d’étendre cette étude à d’autres services d’urgence de manière à avoir une population représentative de l’ensemble du pays et de pouvoir ainsi estimer approximativement la charge potentielle de soins gériatriques au niveau national.

CONCLUSION

10.

11.

12.

13.

14.

15.

Bien que la littérature scientifique ait démontré l’existence de plusieurs outils de dépistage des personnes âgées fragiles aux urgences qui sont à risque d’évolution défavorable, ces outils ne sont pas encore utilisés dans les différents services d’urgence au Liban. L’identification des personnes âgées à risque d’évolution défavorable n’est que la première étape d’une prise en charge gériatrique adaptée qui peut être réalisée soit dans un service de court séjour gériatrique, soit par une équipe mobile de gériatrie auprès des différents services hospitaliers.

org/unpd/wpp/index.htm

16.

17.

18.

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Journal Médical Libanais 2015 • Volume 63 (4) 197

ARTICLE ORIGINAL / ORIGINAL ARTICLE FALSE AND TRUE ACUTE RHEUMATIC FEVER A Lebanese Experience http://www.lebanesemedicaljournal.org/articles/63-4/original5.pdf 1,2

1,2

3

Najwa JAWHAR , Imad CHAMI , Zakhia SALIBA , Ghassan CHEHAB

1,2,3

Jawhar N, Chami I, Saliba Z, Chehab G. False and true acute rheumatic fever: a Lebanese experience. J Med Liban 2015 ; 63 (4) : 198-202.

Jawhar N, Chami I, Saliba Z, Chehab G. Rhumatisme articulaire aigu, vrai ou faux ? Étude libanaise. J Med Liban 2015 ; 63 (4) : 198-202.

ABSTRACT • Objectives : The main aim of this study is to evaluate the significance of several clinical and laboratory findings presented by a large number of pediatric patients who were suspected to have acute rheumatic fever (ARF) by physicians who ordered echocardiogram for confirmation and for avoiding overuse of unnecessary antibiotics. These suspecting reasons include elevated ASO titers and recurrent tonsillitis. Another aim is to stress the role of Doppler echocardiogram in confirming the diagnosis of ARF by detecting rheumatic heart disease (RHD) in suspected cases. Materials and methods : 401 patients were registered in the National Registry of the Pediatric and Congenital Heart Disease (RNCPC) from April 1, 2002 until the end of March 2013 as suspected cases of ARF. The clinical reasons that brought suspicion are discussed and evaluated in accordance to modified Jones criteria. The patients are distributed into two groups : 1) confirmed ARF and 2) different diagnosis.

All patients underwent echocardiogram. Patients came from different geographic areas and were referred by a variety of physicians. Results : 48 patients out of 401 suspected cases turned to have confirmed ARF (12%). In this group, the predominant suspecting reasons are reported as heart murmur in 29/48 (60.4%), arthritis in 28/48 (58.3%), arthralgia with reduced physical activity in 15/48 (31%) and chorea in 5/48 (10%). In the different diagnosis group with a high ASO titer 174/353 (49.3%), isolated arthralgia 91/353 (25.8%) and combined elevated ASO with arthralgia in 44/353 (12.5%) were the predominant suspecting reasons. Doppler echocardiography could detect 38/48 cases of active carditis and subclinical carditis (SCC). Conclusion : Heart murmur, arthritis, arthralgia with reduced physical activity and chorea are the main clinical reasons that lead to suspicion in the ARF group.

High ASO titers, arthralgia, and combination of high ASO titers with arthralgia are the main presenting symptoms in the group with a different diagnosis. We concluded that elevated ASO titer and normal ESR with arthralgia not reducing physical activity can exclude ARF. Doppler echocardiography is found to be a gold standard key to confirm acute rheumatic heart disease and ARF. Keywords : rheumatic fever, acute rheumatic fever, rheumatic heart disease, subclinical carditis, RNCPC

RÉSUMÉ • Objectifs : L’objectif principal de cette étude est d’évaluer l’importance de plusieurs signes cliniques et biologiques présentés par un grand nombre de patients en pédiatrie conduisant les médecins à suspecter un rhumatisme articulaire aigu (RAA) et demander une échocardiographie visant à confirmer le diagnostic. Ces raisons comprennent des taux élevés d’ASO et une amygdalite récurrente qui mènent habituellement à la surconsommation d’antibiotiques. Un autre objectif est de souligner le rôle de l’échocardiographie pour confirmer le diagnostic de RAA en détectant la cardite rhumatismale (CR) dans les cas suspects.

Matériels et méthodes : 401 cas présumés de RAA ont été enregistrés au Registre national de cardiologie pédiatrique et congénitale du 1er avril 2002 à fin mars 2013. Les raisons cliniques qui mènent à la suspicion sont examinées et évaluées selon les critères de Jones modifiés. Les patients sont classés en deux groupes: 1) RAA confirmé et 2) autre diagnostic. Tous les patients, venus de différentes régions géographiques du Liban et adressés par une variété de médecins, ont bénéficié d’une échocardiographie. Résultats: Sur un total de 401 cas suspects, le diagnostic de RAA a été confirmé chez 48 patients (12%). Dans ce groupe, les raisons principales faisant soupçonner le diagnostic sont : souffle cardiaque : 29/48 (60,4%); arthrite : 28/48 (58,3%); arthralgie avec réduction de l’activité physique : 15/48 (31%) et chorée : 5/48 (10%). Dans le groupe ayant reçu un diagnostic différent, un taux d’ASO élevé 174/353 (49,3%), arthralgie isolée 91/353 (25,8%) et ASO élevé avec arthralgies dans 44/353 (12,5%) sont les raisons prédominantes de soupçon. L’échocardiographie Doppler a pu détecter 38/48 cas de cardite active et cardite infraclinique (CIC). Conclusion: Souffle cardiaque, arthrite, arthralgie avec activité physique réduite et chorée sont les principales raisons cliniques qui mènent à soupçonner le RAA. Des taux élevés d’ASO et/ou arthralgie ont été les principales raisons observées dans le groupe ayant reçu un diagnostic différent. Nous avons conclu qu’un taux d’ASO élevé et une vitesse de sédimentation normale avec arthralgies et une activité physique normale peuvent exclure ce diagnostic. L’échocardiographie Doppler est l’examen-clé pour confirmer la cardite rhumatismale, CIC en particulier, et donc le RAA.

1

Department of Pediatrics, Faculty of Medical Sciences, Lebanese University, Greater Beirut, Lebanon.

Department of Pediatrics, Sahel General Hospital, Beirut South Suburb, Lebanon.

3 CHU Hôtel-Dieu de France, Beirut, Lebanon.

Correspondence : Najwa Jawhar, MD. e-mail : najwa.jawhar2@gmail.com 2

198 Lebanese Medical Journal 2015 • Volume 63 (4)

INTRODUCTION

Acute rheumatic fever (ARF) is a post streptococcal serious inflammatory illness due to its significant morbidity and cardiovascular death. It is associated with active carditis and rheumatic heart disease (RHD) manifested as subclinical carditis (SCC). RHD is reported to cause 200,000-250,000 premature deaths every year in devel-

oping countries [1].WHO report in Geneva 2004 states that the incidence of ARF is directly related to socioeconomic risks that are mostly: poverty, overcrowding, and limited access to medical centers and that ARF is one of the major problems in large cities of the third world.

WHO also claims that the prevalence of ARF is decreasing in developed countries while it is endemic in most developing countries [2]. The annual incidence in USA approximates 1 in 83 people or < 1 % [3]. In developing countries, the incidence is 100-200 times greater than that in developed countries [4]. In general, the worldwide prevalence approximates 19 per 100,000 populations ranging between 5-51 per 100,000 people. There are few data about the incidence of rhumatic fever (RF) and its complications in the Middle East countries. Extrapolated statistics – not based on country specific data sources and only estimates having very limited relevance to the actual incidence – are reported as 45,326 warnings in Lebanon. This is claimed by US Census Bureau, Population Estimates 2004. Besides, studies about RF in Lebanon are very limited. A Lebanese epidemiological survey reported in a prospective study from 1999 to year 2005 states that rheumatic heart disease was the most common acquired heart disease in children [5]. Comparatively the mean annual incidence of ARF in Kuwait is reported as 23 per 100,000 people and is 11.2 per 100,000 in Qatar, while it approximates 51 per 100,000 in India [6]. In Egypt, a field study on school children shows the prevalence of rheumatic fever and rheumatic heart disease per 1000 is 1.3 and 1.2 respectively [7].

ARF being associated with heart problems remains a substantial global health issue especially in developing countries. This is emphasized through many studies including one reported by Dr Bitar et al. which was done on 91 patients hospitalized in a tertiary hospital in Beirut.

This study revealed carditis in 93% of cases, congestive heart disease in 44%, arthralgia in 55% and fever in 62% [8]. Thus, early diagnosis and management is needed, based on evaluation of clinical, laboratory and echocardiography findings in collaboration with Jones criteria that are stated by the American Academy of Pediatrics (AAP) in 1992 and most recently updated in 2002 “modified Jones criteria” [9]. Elevated ASO titers and recurrent tonsillitis are recognized by many physicians as warning reasons to suspect ARF. In fact, elevated ASO titers denote group A streptococcal infection rather than ARF. According to “modified Jones criteria,’’ diagnosis of ARF does not require serologic evidence of recent group A strep infection, but documented strep infection through a positive throat culture and that elevated ASO titers are considered as minor criteria [9].

This study deals with patients coming from different geographic regions presenting with clinical and laboratory manifestations that made physicians suspect ARF, so they referred these patients and confirmed their diagnosis by echocardiogram. We studied these different clinical and lab criteria in the group of patients who turned to have ARF (true diagnosis) and in the group who turned

to have a different diagnosis. The role of elevated ASO titers and repeated tonsillitis and its relevance to the diagnosis of ARF in our cases are also evaluated. In addition, we aim to evaluate the role of Doppler echocardiogram as a key tool for the diagnosis of ARF in the form of rheumatic carditis or subclinical carditis.

MATERIELS AND METHODS

The subjects of the retrospective study are children 5 to 16 years old who were suspected to have ARF and automatically referred to the National Registry of the Pediatric & Congenital Heart Disease (RNCPC*), to undergo echocardiogram for confirming the disease. This registry is a private sector controlled and organized by a group of paediatric cardiologists. Children less than 5 years are not included because ARF is reported as rare in this age group. Physicians who referred the suspected patients are pediatricians, cardiologists, rheumatologists and general practitioners. The geographic locations where our patients were living are specified. The duration of the study covered a period of 11 years from April 1st, 2002, until the end of March 2013.

The 401 patients are classified into 2 groups: the first group proved to have true ARF based on clinical and laboratory criteria that coincide with Jones criteria, complemented with echocardiography findings. The second group proved to have a different diagnosis since they had nonconforming echocardiography and lack of fulfillment to Jones criteria. Clinical and lab reasons are discussed and evaluated in all patients to estimate the significance of each criterion to diagnose ARF. All patients underwent Doppler echocardiography to identify if heart problems are present, whether active carditis or subclinical carditis or other diagnosis. The role of Doppler echocardiography is stressed and evaluated.

RESULTS

Reviewing the clinical manifestations and echocardiography findings of the heart in 401 suspected patients revealed true ARF diagnosis in 48/401 patients (12%) with a mean age of 7.7 years ranging between 7.2-16.8 years.

Their distribution according to gender is M:F 1.3:1. On the other hand, patients with a diagnosis different from RF are 353/401 (88%), aged 1.7-15.2 yrs range with a mean of 7.6 years and distributed as M:F 1.2:1. Unlike the patients with true diagnosis these patients do not fulfill Jones criteria and their Doppler echocardiogram turned to be non suggestive of ARF (Table I).

TABLE I DISTRIBUTION of CASES in RELATION to GENDER and AGE Number Different diagnosis ARF Total

353 (88%) 48 (12%)

Male Female

Age (years)*

209 27

7.6 (1.7-15.2) 7.7 (7.2-16.8)

144 21

401 236 165 7.6 (1.7-15.2) * Average and extremes ARF: acute rheumatic fever

*RNCPC: The National Registry of the Pediatric and Congenital Heart Disease of the Society of Cardiology in Lebanon, created in May 1999, Lebanese Order of Physicians. This registry is a private sector controlled and organized by a group of private pediatric cardiologists.

Physicians who referred suspected RF patients were mostly pediatricians. They referred 351/401 patients out of which 45/351 proved to have the disease (11.2%). The remaining 50/401 suspected patients were referred by other physicians: • 19/50 by cardiologists and only one turned to have RF • 17/50 by rheumatologists out of which one proved to have RF • 14/50 by general practitioners and again one turned to have ARF (Table II).

The geographic distribution of the suspected patients shows • 275 patients living in Beirut and its south suburbs region • 41 in Mount Lebanon • 52 in the Bekaa • 13 in the North and • 21 in the South. The 48 ARF cases are geographically distributed as follows: • 27 (56.2%) living in Beirut and its south suburbs region • 7 (14.58%) in Mount Lebanon • 7 (14.58%) in the Bekaa • 5 (10.4%) in the North • and 2 (4%) in the South. These numbers show that the majority of our ARF patients are living in Beirut and its south suburbs region (56.2%) (Table III).

The clinical and lab findings that mostly concerned physicians and made them suspect ARF and request a Doppler echocardiography are evaluated. In the group of ARF patients they are: • heart murmur in 29/48 patients (60.4%) • arthritis in 28/48 (58.3%) • arthralgia with reduced physical activity in 15/48 patients (31%) • chorea is evident in 5/48 patients (10%) and • prolonged fever in only 2/48 patients (4%). Recurrent tonsillitis, elevated ASO titers with or without arthralgia are not evident in the 48 ARF patients. Only 3 patients of the ARF group were documented to have positive throat culture of strep group A and were given penicillin G as prophylaxis (Table IV).

Other findings in the ARF group include elevated ESR in 42 patients (87.5%), fever in 37 cases (77%) and PR prolongation in 7 cases (15%). (Table V).

To summarize: heart murmur, arthritis, arthralgia with reduced physical activity and chorea are found to be the most predominant clinical reasons of suspicion in the ARF group (Table IV). Also, elevated ESR and fever are additional complementary reasons.

On the other hand, the suspected clinical and lab reasons that are predominant in the group with a different diagnosis include: • heart murmur in 16 out of 353 patients (4.6%) • arthritis in 28/353 (7.9%) and • arthralgia not altering physical activity in 91/353 (25.8%)). Recurrent tonsillitis is evident in 12/353 (3.4%), elevated ASO titers as an isolated finding and ASO associated with arthralgia are detected in 174/353 and in 44/353, (49.3%) and (12.5%) respectively. So, the major sus-

TABLE II DISTRIBUTION of REFERRED PATIENTS in RELATION to REFERRING PHYSICIANS

ARF

Number (%)

Different diagnostic

Total

306 (87.2%) 18 (95%) 16 (94%) 13 (93%)

351 19 17 14

Pediatricians 45 (11.2%) Cardiologists 1 (5%) Rheumatologists 1 (6%) General practitioners 1 (7%)

*87.5% of total cases were referred by pediatricians & 12.5% by other physicians.

pecting reasons in this group are listed in decreasing order: elevated ASO titers (49.3%), arthralgia (25.8%), elevated ASO combined with arthralgia (12.5%), arthritis (7.9%), heart murmur (4.6%) and recurrent tonsillitis (3.4%). (Table IV).

Carditis is diagnosed by echocardiography in 38/48 cases (79%) in the ARF Group. These cases are distributed as clinical carditis in 22/48 cases (46%), subclinical carditis in 16/48 (33%), mitral regurgitation (MR) in 26/38 (68%), and MR combined with aortic regurgitation in 12/38 (32%) of cases (Table V).

DISCUSSION

The diagnosis of ARF is based on fulfillment to modified Jones criteria complemented by Doppler echocardiography. The files of 401 suspected patients are retrospectively reviewed and 48 patients out of the 401 suspected cases found to have true ARF diagnosis (12%).

The remaining 353/401 (88%) suspected patients were complaining of a different diagnosis since their clinical findings do not comply with Jones criteria and their echocardiograms are either normal or suggest another disease such as congenital heart disease or acquired heart disease as Kawasaki. Both groups show male predominance and nearly the same average age at presentation.

Pediatricians are the predominant physicians who referred most of the suspected cases, 351 patients out of 401 (87.5%). The remaining physicians referred 50/401 suspected cases (12.5%).

Regarding clinical findings, the cardiac murmur is presented in 60.4% of the ARF group and in 16/353 (4.6%) patients with a different diagnosis. This proves that cardiac murmur is an important finding that brings suspicion and mostly suggests carditis or subclinical valvular heart disease and thus echocardiography is needed for confirmation. On the other hand, the murmur in the second group (patients with a different diagnosis)

TABLE III GEOGRAPHIC DISTRIBUTION

Beirut + Southern Suburbs Acute Rheumatic Fever Different diagnosis TOTAL

27 (9.8%) 248 (90.2%) 275

200 Lebanese Medical Journal 2015 • Volume 63 (4)

Mount-Lebanon 7 (17%) 34 (83%) 41

Bekaa Number (%) 7 (13%) 45 (87%) 52

North 5 (39%) 8 (61%) 13

South

Total

2 (10%) 19 (90%)

48 (12%) 353 (88%)

21

401

N. JAWHAR et al. – Rheumatic fever in Lebanon

TABLE IV CLINICAL & LABORATORY FINDINGS that MAKE PHYSICIANS SUSPECT ACUTE RHEUMATIC FEVER in PATIENTS

Reason for referring to pediatric cardiologist Heart murmur Arthritis Arthralgia Chorea Prolonged fever Recurrent tonsillitis Parental anxiety Elevated ASO Elevated ASO + arthralgia

Number of ARF patients (48) N % 29 60.4 28 58.3 15 31 5 10 2 4 0 0 0 0 0 0 0 0

Different diagnosis (353) N % 16 4.6 28 7.9 91 25.8 0 0 5 1.4 12 3.4 7 2 174 49.3 44 12.5

may have a different etiology: a functional murmur or a sign of a congenital heart disease. So, echocardiography is needed, supplemented with clinical, lab and auscultatory findings for differentiation and for the diagnosis of rheumatic heart disease [10].

Arthritis is detected in 28/48 (58.3%) patients of the ARF group and in 28/353 (7.9%) patients of the group with a different disease. Arthritis is an important clinical criterion especially in the acute phase of ARF and it implies a first Doppler echocardiogram in children. Besides, arthritis is a significant major criterion in correlation to Jones criteria [11-12]. Arthritis in the group of patients with a different diagnosis may have a different etiology such as viral or bacterial infection or a connective tissue disease.

Arthralgia as an isolated entity is detected in 15/48 cases (31%) in the ARF group and in 91/353 (25.8%) in the group of patients with a different diagnosis. Arthralgia in ARF patients is more often associated with reduced physical activity. Arthralgia associated with elevated ASO titer is not found in our ARF group, while it is present in 44/353 patients of the second group (12.5%), indicating that arthralgia could be a symptom of infection as viral infection, bacterial infection as Streptococcus group A, systemic disease or a connective tissue disease.

According to our series we can estimate that arthralgia alone is not a significant index of suspicion that does not require echocardiography.

ASO titers were done 2-4 weeks after the onset of symptoms. They were not elevated in any of the ARF group, while elevated titers with or without arthralgia presented in 44/353 (12.5%) and 174/353 (49.3%) patients of the group of different disease respectively. Thus, in our series, ASO titer is found to be a poor reason to suspect ARF. This is supported by the WHO report 2003 in Geneva claiming that ASO titer is more an evidence of group A streptococcal infection and is becoming a weak indicator to confirm ARF. It is also reported that elevated titers may be coincidental [13-14]. ASO titer is claimed to be elevated in many inflammatory diseases [15]. This explains the N. JAWHAR et al. â&#x20AC;&#x201C; Rheumatic fever in Lebanon

elevated ASO titers in the group with a different diagnosis.

Elia et al. evaluated ASO titers in patients with and without ARF living in areas with high or low incidence of RF. They concluded that non rheumatic patients living in an area with high incidence of RF did show elevated ASO titers. This reflects more correctly a high prevalence of strep infections [16]. It is worth to mention here, that many physicians are still considering elevated ASO titers a warning sign to suspect ARF, thus leading to over diagnosis. Regarding our series, elevated ASO titers alone are not a significant reason to perform echocardiography.

This is supported by the modified Jones criteria that consider elevated ASO is no more required as a serologic evidence of recent strep infection [9, 17].

Chorea is evident in 5 patients of our ARF group, 5/48 i.e. (10%). The presence of chorea alone is enough for diagnosis and Doppler echocardiogram is not a must except if carditis is suspected [11].

Recurrent tonsillitis is detected in 12/353 (3.4%) of suspected patients who turned to have a different diagnosis, and not found in any of our ARF group. Strep infection is not documented as a cause of tonsillitis by throat culture in our patients. Recurrent tonsillitis may result from strep infection and any viral or bacterial infection other than strep [11]. The important issue here is that recurrent streptococcal tonsillitis is common in developing countries and may lead to damage and complications in cardiac valves that may pass unnoticed [6,18].

Prolonged fever is found in 2/48 patients of the ARF group (4%) and in 5/353 cases (1.4%) of the group of different diagnosis. It is a significant reason to suspect ARF in the presence of other criteria that comply with Jones criteria [4]. Increased erythrocyte sedimentation TABLE V CRITERIA FOUND in the GROUP of CHILDREN with ACR

(Normal ESR in 3 patients with chorea, and 3 diagnosed few weeks after the onset of the disease based on the medical history, laboratory tests and evidence of carditis.)

MAJOR CRITERIA

Carditis Total Clinical Subclinical Mitral regurgitation [MR] MR + Aortic regurgitation Arthritis Erythema Chorea Nodules

Number

%

38 22 16 26 12 28 6 5 1

79 46 33 68 32 58.3 12.5 10.5 2

42 37 15 7

87.5 77 31 15

MINOR CRITERIA

Elevated ESR Fever Arthralgia PR prolongation

ACR: acute rheumatic fever ESR: erythrocyte sedimentation rate PR: interval between P & R in EKG

Lebanese Medical Journal 2015 â&#x20AC;˘ Volume 63 (4) 201

rate (ESR) in this study, is detected in 42/48 cases (87.5%) in the group of confirmed RF mainly in the acute phase of the disease and in the presence of carditis and arthritis. Normal ESR is reported in 3 patients with chorea and in 3 patients who were diagnosed few weeks after the onset of the disease (Table V). ESR is elevated in 156/353 (44%) patients of the group with a different diagnosis indicating a different inflammatory disease.

The application of the findings of our patients to Jones criteria is shown in (Table V).

The role of Doppler echocardiography appeared to be an essential key tool for the diagnosis of rheumatic carditis and subclinical carditis (SCC) based on important clinical criteria as heart murmur and arthritis. Echocardiography could detect 38/48 cases of total carditis (79%) distributed as mentioned before in (Table V). This reflects that echocardiography is very needed to confirm the diagnosis of rheumatic carditis and its long term complications as SCC [18-19]. In general, studies state that the prevalence of rheumatic heart disease is much higher, around 10 times more diagnosed by echocardiogram v/s clinical screening [18]. Performing the first echocardiogram in children is important to the diagnosis of clinical and subclinical rheumatic carditis especially that during the past two decades, the presentation of RF has changed markedly from that of an acute illness to a more subtle subacute form that is frequently missed.

CONCLUSION

• The prevalence rate in our limited study is 12% but this does not reflect the prevalence rate in Lebanon.

• Heart murmur, arthritis and arthralgia reducing physical activity are the predominant clinical reasons to suspect ARF and thus to refer patients to Doppler echocardiography.

• Recurrent tonsillitis is found to have no value in suspecting and diagnosing RF, especially if strep infection is not documented.

• Elevated ASO titers, according to our series, proved to have a weak predictive value to suspect ARF and thus to do Doppler echocardiogram.

• Elevated ASO titers with normal ESR and with arthralgia not reducing physical activity can exclude ARF. • Doppler echocardiography is the most reliable key for the diagnosis of rheumatic carditis and rheumatic heart disease in children.

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17. Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert KA. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2009 Mar 24; 119 (11): 1541-51.

18. Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever: a systematic review. Int J Cardiol 2007 Jun 25; 119 (1): 54-8.

19. Marijon E, Ou P, Celermajer DS et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007; 357 (5): 470-6.

20. Rheumatic fever in the new Millenium pediatrics, by guest Alyaa Kotby, April 16, 2014, Aapublications.org

N. JAWHAR et al. – Rheumatic fever in Lebanon

ARTICLE ORIGINAL / ORIGINAL ARTICLE NASALANCE SCORES IN LEBANESE ENGLISH-SPEAKING ADULTS USING NASOMETRIC ANALYSIS http://www.lebanesemedicaljournal.org/articles/63-4/original6.pdf 1

1

2

2

Abdul Latif HAMDAN , Georges ZIADE , Jad JABBOUR , Gebran KHNEIZER , Issa KUTKUT

2

Hamdan AL, Ziade G, Jabbour J, Khneizer G, Kutkut I. Nasalance scores in Lebanese English-speaking adults using nasometric analysis. J Med Liban 2015 ; 63 (4) : 203-208.

Hamdan AL, Ziade G, Jabbour J, Khneizer G, Kutkut I. Scores de nasalance pour adultes libanais de langue anglaise utilisant l’analyse nasométrique. J Med Liban 2015 ; 63 (4) : 203-208.

ABSTRACT • Objective : To obtain normative data for nasalance scores in Middle Eastern English-speaking adult population. Design : Cross-sectional study. Participants : A total of 102 subjects were recruited in the study, 26 were excluded, thus, 77 Middle Eastern English-speaking adults (mean age = 23.77 ± 4.295 ; 39 males, 38 females) with normal speech and no hearing problems participated in the study. Interventions : Using Nasometer II 6450, nasalance scores were obtained for each participant’s readings of 3 passages : Zoo and Rainbow passages and nasal sentences. Main outcome measures : Mean nasalance score, standard deviation and range.

Results : Mean nasalance scores for Zoo passage, Rainbow passage and nasal sentences were 25.21 ± 11.07, 34.04 ± 9.30 and 41.29 ± 9.87 respectively. Mean scores didn’t differ significantly between males and females, though scores for the Zoo passage were slightly higher among males (26.51 ± 11.66) than females (23.87 ± 10.42). In within-session reliability testing, 86% of retests for all three passages fell within 5 nasalance points of the previous test. In across-session reliability testing, 93% of retests for all 3 passages were within 5 points of initial test. Conclusions and Relevance: This study provides normative data for nasalance scores among Middle-Eastern adults, which can help make nasometer and determination of nasalance more clinically useful in this population.

Keywords: nasalance, nasality, nasometer, Middle-East

RÉSUMÉ • Objectif : Obtenir des données normatives pour les scores de nasalance dans la population adulte anglophone du Moyen-Orient. Protocole : Étude transversale. Participants : Sur un total de 102 sujets recrutés, 26 ont été exclus ; 77 adultes anglophones du Moyen-Orient (âge moyen = 23,77 ± 4.295 ; 39 hommes, 38 femmes), ayant un discours normal et sans problèmes auditifs, ont participé à l’étude. Interventions: On a demandé aux participants de lire 3 passages chacun: les passages Zoo et Rainbow et des phrases nasales; les scores de nasalance ont été obtenus avec un Nasometer II 6450.

Principaux critères de jugement: le score de nasalance, l’écart type et la gamme. Résultats : Les scores de nasalance pour les passages Zoo, Rainbow et les phrases nasales étaient de 25,21 ± 11,07, 34,04 ± 9,30 et 41,29 ± 9,87 respectivement.

Les scores moyens ne diffèrent pas significativement entre hommes et femmes, bien que les scores pour le passage Zoo aient été légèrement plus élevés chez les hommes (26,51 ± 11,66) que chez les femmes (23,87 ± 10,42). Les tests de fiabilité menés dans la même session ont montré que 86% des nouveaux essais pour les trois passages se trouvaient à presque 5 points de nasalance de l’essai précédent. Dans les tests de fiabilité entre sessions, 93% des nouveaux essais pour les trois passages se trouvaient à moins de 5 points du test initial.

Conclusions et pertinence: Cette étude fournit des données normatives pour les scores de nasalance pour les adultes du Moyen-Orient, ce qui peut aider à rendre le nasomètre et la détermination de nasalance plus utile cliniquement dans cette population.

INTRODUCTION

Speech has several acoustic and aerodynamic measures that relate to velopharyngeal function, among which is nasality. The assessment of nasality has traditionally been a perceptual task performed by speech language pathologists. The reliability of these perceptual ratings has always been subject to criticism in view of the diversity in the rating scales used and the presence of confounding factors in speech that may mask the perception of nasality [1-4].

Thus, despite the extensive information provided by the speech therapists in the evaluation of patients with velopharyngeal incompetence and the relative validity of such information, the need for other assessment tools has risen.

From American University of Beirut Medical Center, Lebanon, 1 Department of Otolaryngology, 2Medical student.

Correspondence: Abdul Latif Hamdan, MD. AUB-Medical Center, P.O.Box 110236, Beirut. Lebanon. e-mail: ah77@aub.edu.lb

Nasal endoscopy and videofluoroscopy have been used as alternative or complementary diagnostic tests. However, both are rather invasive and one entails exposure to radiation therapy. The nasometer, a microcomputer-based instrument devised by Kay Pentax to measure nasalance and calculate a nasalance score [5], has been commonly used as a noninvasive, reliable and objective device to measure the extent of nasality [6-8]. The primary function of the nasometer is to provide a quantitative measure related to perceived hypernasality. The term nasalance is often used to reflect the ratio of nasal acoustic energy to nasal-plusoral acoustic energy in speech. The consensus remains that nasalance can be used as a reliable supplement in the evaluation of velopharyngeal competence. This is in view of the results of extensive studies on the validity of the device that have shown a high correspondence between the perceptual judgments of nasality and the nasalance scores [3,9-10].

Lebanese Medical Journal 2015 • Volume 63 (4) 203

In order for the nasometer to have clinical usefulness, normative data on normal speakers’ nasalance scores is needed for reference. Normative data on nasalance have been published for white Americans, African Americans [11], Australian English-speaking children [12], Irish children [13], American English-speaking children [4], Canadian children [14], Puerto Rican Spanish-speaking women [15], Dutch children [16], and many others.

These studies have indicated that nasalance scores vary across languages and dialects [7], these could be language-specific, material-specific or dialect-specific. Differences in mean nasalance scores between the different languages and dialects were attributed to the usage of different vowels, oral and nasal consonants across languages [14,17] further substantiating that normative nasalance scores for each region and language are needed.

So far, no study has examined the nasalance scores in English-speaking Lebanese adults. The purpose of this study is to obtain normative nasalance data for a large group of normal English-speaking Lebanese adults knowing that dialectal variations have an effect on mean nasalance scores. The standard speech stimuli: the Zoo passage, the Rainbow passage and nasal sentences will be used. It is not the purpose of this study to provide language specific material or stimuli or to look at the effect of language on nasalance scores.

After informed consent was obtained and basic demographic information (age, gender, and history of smoking and reflux) recorded for each participant, the headgear was placed using previously described techniques [20]. The participant was then asked to read the Zoo passage, Rainbow passage, and nasal sentences, in that order, one time each. All testing was carried out by one of two researchers, following the same protocol, in a quiet room, where only the participant and researcher were present.

MATERIALS AND METHODS

RESULTS

Participants A total of 102 subjects were recruited in the study, 26 were excluded, therefore, 77 English-speaking Lebanese adult volunteers were enrolled in the study after having read and signed the informed consent approved by the Institutional Review Board at the American University of Beirut Medical Center (AUBMC) in Lebanon. Exclusion criteria included history of hearing loss, recent upper respiratory tract infection, and history of nasal or velopharyngeal surgery. The data were collected over a course of two months at the “Hamdan Voice Unit” at the AUBMC.

Demographic Data A total of 102 participants were recruited, however 26 subjects were excluded because they didn’t fit the study’s inclusion criteria, a total of 77 participants were thus included in the final analysis.

The mean age was 23.77 ± 4.295 years old, with a range from 19 to 40. Thirty-nine participants were males, and 38 females, with no significant difference in age between the two groups (males: 23.41 ± 2.704, females: 24.13 ± 5.418; p = 0.46). Fourteen participants (18.2%) were smokers and 14 (18.2%) reported having reflux (Table I).

Materials and Procedures Three reading passages originally described by Fletcher [18] and utilized in most clinical and nonclinical studies on nasalance [7,11,19] were used in this study: 1) the Zoo passage, which contains no nasal consonants, 2) the Rainbow passage, in which the occurrence of phonemes is similar to their occurrence in conversational speech, and 3) a set of nasal sentences loaded with nasal consonants.

The Nasometer II 6450 from Kay Elemetrics [5] was used for data collection and analysis. As previously described, this computer-based system includes headgear that contains two microphones, one on either side of a separator plate, which allows for distinct determination of nasal and oral contributions in speech [7]. The same device, computer, and headgear were used for all subjects. Prior to each testing session, the nasometer was calibrated according to the manufacturer’s instructions.

204 Lebanese Medical Journal 2015 • Volume 63 (4)

Data Analysis Mean, minimum, and maximum nasalance scores for each passage for each participant were computed using the “Calculate” function available in the Nasometer 6450 software package. Descriptive analysis was used to report the mean nasalance scores, standard deviations and range for each stimulus. Unpaired t-tests and ANOVA were used to assess differences across studies and between genders within this study.

Seven participants were randomly selected for reliability testing at a later stage. This involved following the same procedures as the initial test, but with each passage being read twice. The comparison was made by comparing the means of the two readings in the second session to the corresponding value collected in the initial session. This allowed for comparisons both within and across sessions.

TABLE I DEMOGRAPHIC INFORMATION for STUDY POPULATION (N = 77)

Age Mean ± SD Minimum Maximum

23.77 ± 4.295 19 40 Gender

Male Female

39 (50.6%) 38 (49.4%) Smoking

Yes No

14 (18.7%) 61 (81.3%) Reflux

Yes No

14 (18.7%) 61 (81.3%)

A.L. HAMDAN et al. – Nasalance scores in Lebanese English-speaking adults

TABLE II NASALANCE SCORES of the THREE PASSAGES for the TOTAL STUDY POPULATION

Zoo Passage

Rainbow Passage

Nasal Passage

Mean value ± SD [Range]

Overall population (N = 77)

25.21 ± 11.07 [9-49]

34.04 ± 9.30 [14-56]

41.29 ± 9.87 [20-73]

Males (N = 39)

26.51 ± 11.66 [9-49]

34.05 ± 10.46 [14-56]

41.21 ± 12.08 [20-73]

Females (N = 38)

23.87 ± 10.42 [9-43]

34.03 ± 10.08 [24-48]

41.37 ± 7.08 [32-55]

SD: standard deviation

Nasal Values The group mean nasalance scores for the Zoo passage, Rainbow passage and nasal sentences were 25.21 ± 11.07, 34.04 ± 9.30 and 41.29 ± 9.87, respectively. As expected, the mean nasalance score was highest for the nasal sentences and lowest for the Zoo passage. For the Zoo passage, the mean nasalance score was slightly higher in males compared to females (26.51 ± 11.66 vs. 23.87 ± 10.42), but the difference was not significant (p = 0.30).

For the Rainbow passage and nasal sentences, the mean nasalance scores were comparable for the male and female groups (Table II).

DISCUSSION

Multiple instruments have been used to estimate or compute the extent of nasalance in normal English-speaking adults and children. These instruments and techniques have also been relied upon for the evaluation of hypernasality and hyponasality in subjects with velopharyngeal incompetence or cleft palate deformity. Since its introduction in 1986, the nasometer has been used as a research tool and as a noninvasive method for assessing nasal resonance related to velopharyngeal insufficiency [8,21] and nasal obstruction [22]. A nasalance score reflects the dispersion of nasal acoustic energy in the overall vocal tract. Its perceptual correlate is the perceived nasality in speech.

Several studies have evaluated the relationship between perceptual ratings of nasality and nasalance using correlation analysis and sensitivity and specificity measures. The correlation between nasalance and nasality has varied between 0.02 and 0.82 [8]. This range in variability has been attributed to differences in methodology related to variations in speech stimuli, rating scales and number of listeners. Speech stimuli loaded with nasal consonants tend to increase the correlation between perceptual rating and hyponasality whereas speech stimuli devoid of nasal consonants increase the correlation with hypernasality. Several studies indicate that nasalance scores vary across languages and dialects [17], an observation that mandates the presence of separate normative data to be used as cutoffs for what is normal and what is

Reliability Test The difference in the mean nasalance scores within sessions and between sessions varied with the reading stimuli.

For within-session variability, at least 86% of retests for all three passages were < 5 nasalance points different from the initial test. In the case of the Zoo passage and Rainbow passage, there was one outlier participant representing the remaining 14% whose retest was 8 nasalance points different for the Zoo passage and 7 points different for the Rainbow passage.

For across-session variability, at least 93% of retests for all three passages were < 5 nasalance points different, again with one test representing the remaining 7% in the case of the Rainbow passage and nasal sentences.

For the Zoo passage, 100% of the retests resulted in a difference in mean nasalance score within 5 nasalance points (Table III).

TABLE III CUMULATIVE FREQUENCIES in PERCENT of EACH of the SEVEN SUBJECTS' REPEATED READINGS WITHIN SESSION (7 MEASUREMENTS) and ACROSS SESSIONS (14 MEASUREMENTS).

Difference (Nasalance points) <1 <2 <3 <4 <5 < 6 <7 <8 < 9

Zoo Passage Within session 0 43 71 71 86 86 86 86 100

Rainbow Passage

Nasal Passage

Across sessions

Within session

Across sessions

Within session

Across sessions

7 36 57 79 100

0 14 71 86 86 86 86 100

14 43 64 79 93 93 93 100

14 57 71 71 100

14 29 79 86 93 93 100

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Lebanese Medical Journal 2015 • Volume 63 (4) 205

abnormal in different cultures, languages and even for speakers of the same language in different regions. The usage of pre-existing normative data derived primarily from Western countries may be misleading in the assessment and management of patients with nasalance problems in other contexts. Thus, having normative data for a given language or at least foreign-English-speaking individuals is necessary in order to better evaluate and manage speakers with resonance disorders. Very few studies have looked at the effect of dialect on nasalance scores in English-speaking adults [17]. Most of the studies have been done in North America. Dalston et al. reported different cutoff scores in different regions of North America [17]. Speakers of American English have been reported to have significant differences in their nasalance scores across different geographic regions in the United States [7]. Another study showed no significant differences between white and African American men in the mean nasalance scores for the Zoo passage [11]. The normative scores for the Zoo passage, Rainbow passage, and nasal sentences have been reported as 11.25 ± 5.63, 31.47 ± 6.65, and 59.55 ± 7.96, respectively, for American English-speaking adults [7]. In other English-speaking countries, Van Doorn and Purcell have reported normative data for Australian English-speaking children, and found that mean nasalance scores on the Zoo passage were 2 points lower in their population compared to American English-speaking children [12]. Sweeney et al. examined a group of Irish-speaking children and report-

ed the normative scores for the total speech sample, high pressure consonant sentences, low-pressure consonant sentences and nasal consonant sentences to be 26%, 14%, 16% and 51%, respectively, with no significant differences among genders [13].

In our study, the mean nasalance score for the Rainbow passage was comparable to the scores reported in the literature for different English dialects, whereas scores for the Zoo passage and nasal sentences were quite different from the results of other studies. For the Rainbow passage, the nasalance score in English-speaking Lebanese adults (34.04 ± 9.30) was well within the range of 31.69 ± 5.47 to 35.2 ± 4.7 reported for Canadian adults [19] and American adults from various regions [7]. For the Zoo passage, the results differed by 4-12 points in comparison to the normative data reported for American EnglishSpeaking adults from different regions [7], by almost 7 points in comparison to White Americans and 8 points compared to African Americans [11]. All differences for this passage were statistically significant, (p = 0.032 for study population compared to Mid-Atlantic U.S. adults, the group with the closest value). For the nasal sentences, the nasalance score was markedly lower than those reported by other studies (16-19 points). Similarly, all differences were statistically significant (p < 0.0001 for study population compared to any other group). Table IV displays the mean nasalance scores obtained in this study alongside with those from readings of the same passages in previously published studies [7,11-12,19].

TABLE IV NASALANCE SCORES of the THREE PASSAGES for the STUDY POPULATION - FOREIGN ENGLISH-SPEAKING LEBANESE ADULTS, SEVERAL ENGLISH SPEAKING ADULT POPULATIONS in the U.S. and CANADA, and AUSTRALIAN CHILDREN

Population Lebanon, Adults

N

Mean age ± SD [Range]

77 (39 M;38 F)

23.77 ± 4.295 [19-40]

Zoo Passage

Rainbow Passage

Nasal Passage

25.21 ± 11.07

34.04 ± 9.30

41.29 ± 9.87

*Mid-Western U.S., Adults1

148

15 ± 6

35 ± 5

62 ± 6

*Mid-Atlantic U.S., Adults1

148

21 ± 5

39 ± 6

65 ± 5

*Southern U.S., Adults1

148

13 ± 7

34 ± 6

61 ± 6

*Ontario, Canada, Adults1

148

12 ± 6

36 ± 7

61 ± 7

African American Adults2

80 (40 M;40 F) 80 (40 M;40 F) 76 (25 M;51 F) 245 (122 M;123 F)

White American Adults2 Toronto, Ontario, Adults3 Australian Children4

23.2 ± 5.33

17.05 ± 5.2

57.74 ± 5.3

23.2 ± 5.33

18.24 ± 4.2

60.89 ± 6.6

26.5 ± 5.8

13.45 ± 5.9

6.5 ± 1.5

13.1 ± 5.9

31.69 ± 5.47

57.9 ± 6.69 59.6 ± 8.1

For all the *subjects as one group, the mean age was 33.07 years with a range of 16.17-63.33 and the male (M) to female (F)ratio: 56 males and 92 females.

1 Seaver et al., 1991, using Nasometer 6200. 2Mayo et al., 1996, using Nasometer 6200. 3Bressman, 2005, using Nasometer 6200.

4 Van Doorn & Purcell, 1998, using Nasometer 6200.

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A.L. HAMDAN et al. – Nasalance scores in Lebanese English-speaking adults

The significant differences in nasalance scores for the Zoo passage and nasal sentences may be attributed to several factors. First and foremost is the known difference in vowels and consonants across different dialects in English, as previously discussed. This provide the most reasonable explanation for why mean nasalance scores in this Lebanese English-speaking population showed such a smaller range (i.e. were significantly higher for the Zoo passage and significantly lower for the nasal sentences) compared to other English dialects. A second potential factor is the difference in the mean age group in the reported studies.

Mean age in the studies by Seaver et al. (1991), Bressman (2005) and Van Doorn and Purcell (1998) [7,12,19] were all significantly different from the mean age in this study (Table IV). The possible effect of such differences is unclear. Trindade et al. (1997) found that children, compared to adults, had significantly lower nasalance scores for non-nasal passages [23]. At the same time, other studies that have compared adults and children have found no significant differences in nasalance scores between the two groups [4,7], concluding that factors such as language or dialect more directly influence nasalance than does age [13]. A third potential effect relates to the nasometer used; the Nasometer 6450 was used in this study while the version used in all comparison studies was the Nasometer 6200. In a comparison of the Nasometer 6400 series and Nasometer 6200 series, Watterson et al. (2005) found that the former tends to yield slightly higher means than the latter [19]. This difference was statistically significant, but probably due mostly to within-participant performance inconsistency and variation in headgear placement [19].

While this machine variation might help explain some of the discrepancy in our findings related to the Zoo passage, we would have anticipated such an (elevating) effect for all three passages. Aside from the variations of mean nasalance scores in relation to language- and dialect-specific stimuli, gender may have an impact as well. Gender’s effect has been attributed to physiological differences, among other methodological discrepancies [24-25].

Whether female speakers have significantly higher nasalance scores than male counterparts has been an issue of debate, with no clear consensus on whether such a difference exists or if it is significant [7,23,26]. Many authors have indicated that women have higher nasalance scores for language-specific stimulus material [7,26]. These differences were more pronounced on passages containing nasal consonants, as reported by Van Lierde et al. (2001) [26] and Seaver et al. (1991) [7]. Others have reported the opposite, indicating that men have higher mean nasalance scores than women [24,27]. Even when statistically significant differences in the mean nasalance scores were present between genders, these were in the range of only 2 scalar points and thus carry little clinical significance. Reflecting the equivocal literature, there was no considerable difference based on gender in our study. Scores were roughly equal between males and females for the Rainbow passage and the nasal sentences, and there was a slight but insignificant difference (p = 0.3) for the Zoo passage.

CONCLUSIONS

This study helps fill a gap in clinical knowledge by providing normative data for nasalance scores in a Lebanese English-speaking population. Our data can subsequently be employed to direct the use of then nasometer as a clinical assessment tool in this population. Compared to normative data from other English-speaking populations, the overall range of mean nasalance scores in this population was smaller, with significantly higher values for the Zoo passage and significantly lower values for the nasal sentences. This is most likely due to differences in vowels and oral and nasal consonants across different dialects.

No significant difference in nasalance scores was found between males and females. Similar studies could be done in the future in order to corroborate our study findings in the Middle East population.

ACKNOWLEDGMENTS

This manuscript has no actual or potential conflict of interest.

Please note that Dr. Abdul Latif Hamdan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

REFERENCES 1. Bradford LJ, Brooks AR, Shelton RL Jr. Clinical judgment of hyper-nasality in cleft palate children. Cleft Palate J 1964; 1: 329-35.

2. Fletcher SG. Theory and instrumentation for quantitative measurement of nasality. Cleft Palate J 1970; 7: 601-9.

3. Fletcher SG. “Nasalance” vs. listener judgements of nasality. Cleft Palate J 1976; 13: 31-44.

4. Fletcher SG, Adams LE, McCucheon MJ. Cleft palate speech assessment through oral-nasal acoustic measures.

In: Bzoch KR, ed. Communicative Disorders Related to Cleft Lip and Palate. Boston: Little, Brown 1989: 24657.

5. Kay Elemetrics. Nasometer II Model 6450 Instruction Manual. Lincoln Park, NJ: Kay Elemetrics, 1994.

6. Dalston RM, Warren DW, Dalston ET. A preliminary investigation concerning the use of nasometry in indentifying patients with hyponasality and/or nasal airway impairment. J Speech Hearing Res 1991a; 34: 11-18.

7. Seaver EJ, Dalston RM, Leeper HA, Adams LE. A study of nasometric values for normal nasal resonance. J Speech Hear Res 1991; 34: 715-21.

8. Nellis JL, Nieman GS, Lehman JA. Comparison of nasometer and listener judgments of nasality in the assessment of velopharyngeal functions after pharyngeal flap surgery. Cleft Palate Craniofac J 1992; 29: 157-63.

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10. Hardin MA, Van Demark DR, Morris HL, Payne MM. Corrrespondence between nasalance scores and listener judgments of hypernasality and hyponasality. Cleft

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Van Doorn J, Purcell A. Nasalance levels in the speech of normal Australian children. Cleft Palate Craniofac J 1998; 35: 287-92.

Sweeney T, Sell D, O’Regan M. Nasalance scores for normal-speaking Irish children. Cleft Palate Craniofac J 2004; 41: 168-74.

Leeper HA, Rochet AP, Mackay IRA. Characteristics of nasalance in Canadian speakers of English and French. International Conference on Spoken Language Processing, Banff, Alberta, Canada, October 1992: 49-52. Abstract.

Anderson RT. Nasometric values for normal Spanishspeaking females: a preliminary report. Cleft Palate Craniofac J 1996; 33: 333-6.

Van der Heijden P, Hobbel HH, Van der Laan BF, KorstenMeijer AG, Goorhuis-Brouwer SM. Nasometry normative data for young Dutch children. Int J Pediatr Otorhinolaryngol 2011; 75: 420-4.

Dalston RM, Neiman GS, Gonzalez-Landa G. Nasometric sensitivity and specificity: a cross-dialect and crossculture study. Cleft Palate Craniofac J 1993; 30: 285-91.

Fletcher SG: Diagnosing Speech Disorders from Cleft Palate, New York: Grune and Stratton, 1978: 92-157.

Bressman T. Comparison of nasalance scores obtained with the Nasometer, the NasalView, and the OroNasal System. Cleft Palate Craniofac J 2005; 42: 423-33.

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Watterson T, Lewis K, Brancamp T. Comparison of nasalance scores obtained with the Nasometer 6200 and the Nasometer II 6400. Cleft Palate Craniofac J 2005; 42: 574-9.

Dalston RM, Warren DW, Dalston ET. Use of nasometry as a diagnostic tool for identifying patients with velopharyngeal impairment. Cleft Palate Craniofac J 1991b; 28: 184-9.

Dalston RM, Warren DW, Dalston ET. The identification of nasal obstruction through clinical judgments of hyponasality and nasometric assessment of speech acoustics.

Am J Orthod Dentofac Orthop 1991c; 34: 11-18.

Trindade IEK, Genero KF, Dalston RM. Nasalance scores of normal Brazilian Portuguese speakers. Braz J Dysmorphol Speech Hear Disord 1997; 1: 23-34.

Litzaw LL, Dalston RM. The effect of gender upon nasalance scores among normal adult speakers. J Commun Disord 1992; 25: 55-64.

Zajac D, Lutz R, Mayo R. Microphone sensitivity as a source of variation in nasalance scores. J Speech Hear Res 1996; 39: 1228-31.

Van Lierde KM, Wuyts FL, De Bodt M, Van Cauwenberge P. Nasometric values for normal nasal resonance in the speech of young Flemish adults. Cleft Palate Craniofac J 2001; 38: 112-18.

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A.L. HAMDAN et al. – Nasalance scores in Lebanese English-speaking adults

ARTICLE ORIGINAL / ORIGINAL ARTICLE FORMANT CHARACTERISTICS OF ENGLISH-SPEAKING LEBANESE MEN http://www.lebanesemedicaljournal.org/articles/63-4/original7.pdf 1

1

2

3

Abdul Latif HAMDAN , Georges ZIADE , Zeid AL-ZAGHAL , Dollen TABRI , Solara SINNO 2 3 2 Rami SAADE , Jad JABBOUR , Jihad NASSAR

3

Hamdan AL, Ziade G, Al-Zaghal Z, Tabri D, Sinno S, Saade R, Jabbour J, Nassar J. Formant characteristics of English-speaking Lebanese men. J Med Liban 2015 ; 63 (4) : 209-212.

Hamdan AL, Ziade G, Al-Zaghal Z, Tabri D, Sinno S, Saade R, Jabbour J, Nassar J. Caractéristiques des formants d’hommes libanais anglophones. J Med Liban 2015 ; 63 (4) : 209-212.

ABSTRACT • Objective : To report the formant characteristics of English-speaking Lebanese men during steady prolongation of vowels /a/ and /i/. Design : Cross-sectional study involving volunteer participants. Participants : Fifty healthy English-speaking males with a mean age of 32 ± 4.027 years and a range of 42 years (18-60). Materials and Methods : A total of 50 healthy males between the age of 18 and 60 were recruited for the study. Each subject was asked to phonate a sustained /a/ and /i/ sound at a comfortable pitch and intensity level. Measures were made in real-time and formant frequencies across F1, F2, F3 and F4 were determined using the Real-time Spectrogram VP 3950 (Kay Elemetrics, New Jersey). Main outcome measures : The formant frequencies across F1, F2, F3 and F4 were recorded. Results: For the vowel /a/, the mean values of F1, F2, F3 and F4 were 622.86 ± 61.293 Hz, 1264 ± 78.602 Hz, 2610.90 ± 206.359 Hz and 3483.56 ± 206.833 Hz, respectively. For the vowel /i/, the corresponding values were 378.88 ± 51.825 Hz, 2210.34 ± 124.077 Hz, 2847 ± 168.770 Hz and 3576.82 ± 242.760 Hz, respectively. Conclusion: Formant characteristics vary among cultures and ethnic groups.

Keywords : formant characteristics, vowel, male

RÉSUMÉ • Objectifs : Signaler les caractéristiques des formants d’hommes libanais anglophones au cours de la prolongation stable des voyelles /a/ et /i/. Protocole : Étude transversale. Participants: Cinquante hommes anglophones avec un âge moyen de 32 ± 4,027 ans et un éventail de 42 ans (18-60). Interventions : Il a été demandé à chaque sujet de vocaliser les voyelles /a/ et /i/ et de les soutenir pour une certaine durée avec un ton et un niveau d’intensité confortables. Les fréquences en temps réel ont été enregistrées, et les formants à travers F1, F2, F3 et F4 ont été déterminés et ce en utilisant le spectrogramme en temps réel VP 3950 (Kay Elemetrics, New Jersey). Principaux critères de jugement : Les fréquences des formants à travers F1, F2, F3 et F4 ont été enregistrées. Résultats : Pour la voyelle /a/, les valeurs moyennes de F1, F2, F3 et F4 étaient 622,86 ± 61,293 Hz, 1264 ± 78,602 Hz, 2610,90 ± 206,359 Hz et 3483,56 ± 206,833 Hz, respectivement. Pour la voyelle /i/, les valeurs correspondantes étaient de 378,88 ± 51,825 Hz, 2210,34 ± 124,077 Hz, 2847 ± 168,770 Hz et 3576,82 ± 242,760 Hz, respectivement. Conclusion : Les caractéristiques des formants varient selon les cultures et les groupes ethniques.

INTRODUCTION

different morphological features of the speakers [2].

Because formants are affected by the shape and configuration of the vocal tract and since these are under the influence of genetic and cultural differences, we anticipate that groups of different languages, cultures and ethnicities to have different acoustics in terms of frequencies and formant characteristics [3-5]. Yet listeners in general and speech language pathologists in particular build a perceptual evaluation of what is abnormal based on their inherent understanding and knowledge of what is a normal voice and what is deviant from a normal voice, a judgment that is mostly founded on normative data collected invariably from Western population. Other factors that might affect their judgment are their own culture and manner in communication [6].

With the presence of empirical data in the literature demonstrating some differences in the spectral measurements and speaking frequencies across different cultures and ethnicities, and with the assumption that vowels may not consistently carry acoustic data in a universal fashion, we elected in this study to report the formant characteristics of English-speaking Lebanese men during steady prolongation of vowels /a/ and /i/.

The human’s voice perceptual quality has many perspectives. It is, not only, an indicator of health and sickness, but also carries information on the speaker’s identity, culture, language, dialect and intellectual status [1]. As a means of communication, the acoustic perceptual qualities of the speaking voice are influenced by race, language, intonation and cultural effects. As such, these seem to be major variables in determining the speaking frequencies and carry differences in the vocal characteristics as well.

The cross-linguistic differences in the acoustic parameters of the speaking voice, namely the formant frequencies and their dispersion, have been attributed not only to the cross-cultural differences in patterns of stressing and intonation while speaking, but also to the Departments of 1Otolaryngology, 2Otolaryngology-Head & Neck Surgery, 3Medical student, American University of Beirut Medical Center, Lebanon.

Correspondence: Abdul Latif Hamdan, MD. AUB - Medical Center, P.O.Box 110236. Beirut. Lebanon. e-mail: ah77@aub.edu.lb

Lebanese Medical Journal 2015 • Volume 63 (4) 209

MATERIALS AND METHODS

TABLE I DEMOGRAPHIC DATA

Participants A total of 50 healthy males between the age of 18 and 60 were recruited for the study. Subjects with recent history of upper respiratory tract infection, laryngeal manipulation or surgery, or history of chronic disease known to affect the voice were excluded from the study. All subjects were informed about the study, which was approved by the Institution Review Board of the American University of Beirut, Lebanon.

Data Collection and Analysis After having read and signed the consent form, each subject was seated in a quiet room in front of a unidirectional condenser microphone at a constant mouth-tomicrophone distance of 10 cm. Each subject was asked to phonate a sustained /a/ and /i/ sound at a comfortable pitch and intensity level. Measures were made in realtime, and formant frequencies across F1, F2, F3 and F4 were determined using the Real-time Spectrogram VP 3950 (Kay Elemetrics). The Sono Match module, using the Real-Time FFT window, was used to confirm the results obtained by the Real-Time Spectrogram. The cursor was placed at the centermost point of the steady-state formant band when looking at the spectrogram.

The mean, standard deviation (SD) and range values were derived for all variables. Outliers were detected by the means of a box-plot. Statistical analyses were carried out with SPSS (Version 17). Statistical significance was set at p-value < 0.05.

RESULTS

Demographic Data All subjects were males with a mean age of 32 ± 4.027 years and a range of (18-60 years). The mean weight and height were 80.684 ± 13.01 Kg and 179.84 ± 7.147 cm, respectively (Table I).

Formant Frequencies of Vowels /a/ and/i/ For the vowel /a/, the mean values and ranges of F1, F2, F3 and F4 were 622.86 ± 61.293 Hz (403-735), 1264.16 ± 78.602 Hz (1067-1446), 2610.90 ± 206.359 Hz (2110-3153) and 3483.56 ± 206.833 Hz (3035-3841), respectively.

For the vowel /i/, the corresponding values were

Mean value ± SD [Range] 32.0 ± 4.027

Age (years)

[18-60] 179.84 ± 7.147

Height (cm)

[163-196] 80.684 ± 13.0181

Weight (kg)

[59.1-123.4]

378.88 ± 51.825 Hz (285-474), 2210.34 ± 124.077 Hz (1897-3134), 2847.52 ± 168.770 Hz (2537-3177) and 3576.82 ± 242.760 Hz (2533-4149), respectively (Table II).

DISCUSSION

A review of the literature revealed numerous reports demonstrating that listeners can invariably identify the speaker’s age, gender and dialect when the required speaking tasks and duration of voice sample are controlled [7]. Likewise, racial and phonetic characteristics of the speaker could be identified with good reliability during steady vowel prolongations [7-10].

These perceptual evaluations have been substantiated by other acoustic studies documenting the differences in fundamental frequencies and formant values among various ethnic groups. In a study by Andrianopolus et al., fundamental frequency (F0) and formant frequencies characteristics during sustained vowels varied in relation to race and gender [11-12]. Along the same line of thought, Altenberg and Ferrand have reported higher mean speaking fundamental frequency (SF0) during connected speech in English-speaking Russian females when speaking English and Russian compared to the mean SF0 of the monolingual English-speaking control group [13]. Similarly, there has been numerous reports showing no consensus regarding the presence of significant differences in the acoustic values between native and English-speaking adults [14-15]. In comparison to Americans, it appears that for the vowel /a/, the second formant F2 is consistently lower in the English-speaking Lebanese men whereas formant F3 is rather comparable

TABLE II FORMANT FREQUENCIES of VOWELS / a / and / i /

Mean value ± SD [Range] (Hz) Vowel /a/ Vowel /i/

F1

F2

F3

F4

622.86 ± 61.293

1264.16 ± 78.602

2610.90 ± 206.359

3483.56 ± 206.833

[403-735]

[1067-1446]

[2110-3153]

[3035-3841]

378.88 ± 51.825

2210.34 ± 124.077

2847.52 ± 168.770

3576.82 ± 242.760

[285-474]

[1897-3134]

[2537-3177]

[2533-4149]

210 Lebanese Medical Journal 2015 • Volume 63 (4)

A.L. HAMDAN et al. – Formant characteristics of Lebanese men

[16-17]. According to Hillenbrand et al. [16] formant F1 is lower in Americans compared to English-speaking Lebanese men, whereas based on Lee et al. study F1 is higher [18]. Likewise for the vowel /i/, F1 is consistently higher and F2 and F3 are consistently lower in Englishspeaking Lebanese men compared to Americans, even though the differences are not significant [16-17]. Several explanations can be proposed to account for the crosslingual differences in speakers’ formant frequencies. These include vocal tract configurations and linguistic factors.

The intrinsic relationship between vocal tract configuration and formant frequencies has been clearly confirmed in the literature [19]. Initially due to the limitations of imaging studies the focus was on the vocal tract length but more recent studies using acoustic reflection and magnetic resonance imaging have helped in further dissecting the relationship between the two [2].

Vowel formant frequencies are one of many frequently used acoustic parameters for the analysis of a speaker’s speech signal. They are also intimately related to the shape and configuration of the vocal tract which again varies with culture, language, dialect and other genetic and social factors. By altering the shape of the vocal tract, we can change the desired frequencies of vibration or the preferred resonating frequencies, known as formants. These are also affected by the position of the tongue, with F1 for instance being lower when the tongue is at the roof of the mouth, whereas F2 is more related to the frontness and backness of the highest part of the tongue [19]. F3 seems to be more important in determining the phonemic quality of a speech sound, and F4 and F5 reflect more the quality of voice. Aside from the inherent factors such as race, culture and other physiological factors that are major determinants of our vocal frequencies, are the acquired pathological changes and/ or the surgical induced alterations in the vocal tract. The effect of vocal tract alterations on voice has been reported by numerous studies investigating formant characteristics in subjects undergoing surgery of upper aerodigestive system. Reports on formants frequencies following partial laryngectomy, glossectomies, tonsillectomies, palatal surgeries and other interventions [20-22], substantiate further the intrinsic relationship between vocal tract configuration and voice.

In order to draw objective conclusions on what is normal or abnormal, non-biased formant frequency analysis among groups of different cultures, ethnicities and native languages must be taken into consideration.

The results of our study clearly indicate that there are differences in formant characteristics between Englishspeaking Lebanese men and Americans for the vowels /a/ and /i/. These differences must be considered in the analysis of normal and/or pathological voice samples.

This study carries certain limitations. One is the limited number of vowels examined; it would have been more informative to have the formant characteristics of the remaining vowels as well. Second is the fact that our data is limited to men only.

A.L. HAMDAN et al. – Formant characteristics of Lebanese Men

CONCLUSION

Formant characteristics vary among cultures and ethnic groups. The cross-ethnic and cross-cultural variations ought to be taken into consideration by speech language pathologists. The formant frequencies of English-speaking Lebanese men vary in comparison to Americans.

Examining the differences between formant frequencies of vowels /a/, /i/ and /u/ of trilingual English-, Frenchand Arabic-speaking subjects compared to monolingual Arabic-speaking subjects will be the core investigation of the future study.

ACKNOWLEDGMENTS

This manuscript has no actual or potential conflict of interest.

Please note that Dr. Abdul Latif Hamdan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis REFERENCES 1. Titze IE. Workshop on Acoustic Voice Analysis.

Summary Statement. Iowa City, IA: National Center for Voice and Speech. Wendell Johnson Speech & Hearing Center, University of Iowa; 1995. Accessed from http: //tsvoice.net84.net/media/sumstat.pdf on Nov 13, 2013.

2. Xue SA, Hao GJ, Mayo R. Volumetric measurements of vocal tracts for male speakers from different races. Clin Linguist Phon 2006; 20 (9): 691-702.

3. Titze IE. Physiologic and acoustic differences between male and female voices. J Acoust Soc Am 1989; 85: 1699-707.

4. Majewski W, Hollien H, Zalewski J. Speaking fundamental frequency of Polish adult males. Phonetica 1972; 25:119-25.

5. Hudson Al, Holbrook A. A study of the reading fundamental frequency of young black adults. J Speech Lang Res 1981; 24: 197-201.

6. Aronson A. Introduction to clinical voice disorders. In: Aronson, editor. Clinical Voice Disorders. New York, NY: Thieme, 1990: 1-9.

7. Lass NJ, Tecca JE, Mancuso RA, Black WI. The effect of phonetic complexity on speaker race and sex identifications. J Phonet 1979; 7: 105-18.

8. Peterson GE, Barney HL. Control methods used in a study of vowels. J Acoust Soc Am 1952; 24: 175-84.

9. Bricker PD, Pruzanski S. Effects of stimulus content and duration on talker identification. J Acoust Soc Am 1966; 40:1442-9.

10. Assmann PF, Neary TM, Hogan JT. Vowel identification: orthographic, perceptual, and acoustic aspects. J Acoust Soc Am 1982; 71: 975-89.

11. Andrianopoulos MV, Darrow KN, Chen J. Multimodal standardization of voice among four multicultural populations: Fundamental frequency and spectral characteristics. J Voice 2001; 15 (2):194-219.

12. Andrianopoulos MV, Darrow KN, Chen J. Multimodal standardization of voice among four multicultural popu-

Lebanese Medical Journal 2015 • Volume 63 (4) 211

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Altenberg EP, Ferrand CT. Perception of individuals with voice disorders by monolingual English, bilingual Cantonese-English, and bilingual Russian-English women.

J Speech Lang Hear Res 2006; 49 (4): 879-87.

Walton JH, Orlikoff RF. Speaker race identification from acoustic cues in the vocal signal. J Speech Hear Res 1994; 37: 738-45.

Mayo R, Manning WH. Vocal tract characteristics of African-American and European-American adult males.

Tex J Audiol Speech Pathol 1994; 20: 33-6.

Hillenbrand J, Getty LA, Clark MJ, Wheeler K. Acoustic characteristics of American English vowels. J Acoust Soc Am 1995; 97 (5 Pt 1): 3099-111.

Alotaibi YA, Husain A. Formant based analysis of spoken Arabic vowels. Lecture Notes in Computer Science 2009; 5707: 162-9.

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Oliveira Barrichelo VM, Heuer RJ, Dean CM, Sataloff RT. Comparison of singer’s formant, speaker’s ring, and LTA spectrum among classical singers and untrained normal speakers. J Voice 2001; 15 (3): 344-50.

Lee S, Potamianos A, Narayanan S. Acoustics of children’s speech: Developmental changes of temporal and spectral parameters. J Acoustic Soc Am 1999; 105 (3): 1455-68.

Kazi R, Prasad VM, Kanagalingam J et al. Analysis of formant frequencies in patients with oral or oropharyngeal cancers treated by glossectomy. Int J Lang Commun Disord 2007; 42 (5): 521-32.

Ilk HG, Erogul O, Satar B, Ozkaptan Y. Effects of tonsillectomy on speech spectrum. J Voice 2002; 16 (4): 580-6.

Akpinar ME, Kocak I, Gurpinar B, Esen HE. Effects of soft palate implants on acoustic characteristics of voice and articulation. J Voice 2011; 25 (3): 381-6.

A.L. HAMDAN et al. – Formant characteristics of Lebanese men

MISE AU POINT/ IN-DEPTH REVIEW TOWARDS DEVELOPING A SUSTAINABLE FACULTY DEVELOPMENT PROGRAM An Initiative of an American Medical School in Lebanon http://www.lebanesemedicaljournal.org/articles/63-4/review1.pdf 1

1

Boushra RAHAL , Nabil MANSOUR , Ghazi ZAATARI

1,2

Rahal B, Mansour N, Zaatari G. Towards developing a sustainable faculty development program: An initiative of an American medical school in Lebanon. J Med Liban 2015 ; 63 (4) : 213-217.

Rahal B, Mansour N, Zaatari G. Vers l’élaboration d’un programme de développement durable pour les membres de la faculté: Une initiative d’une faculté de médecine américaine au Liban. J Med Liban 2015 ; 63 (4) : 213-217.

ABSTRACT • Introduction and Objectives : The American University of Beirut Faculty of Medicine (AUB-FM) strategy is to develop faculty members (fm) skills by sponsoring local and international scientific activities has been in place for over three decades, and remains dependent on individuals’ efforts.

In 2011-2012, Faculty Development Program (FDP) was introduced to develop faculty leadership, business skills in medicine, fulfill personal and professional goals, followed by a five-year plan to cover five themes: Management/Leadership, Marketing, Finance, Strategic Planning and Communications with the purpose of integrating these themes in medical practice. Methods: A survey was sent to all departments at AUBFM in 2011 to assess needs and determine themes. Nine workshops were conducted, followed by post-workshop evaluation.

Results: 117 fm responded to needs assessment surveys.

Respondents had on average 15 years in clinical practice, 50% with extensive to moderate administrative experience; 71% assumed administrative responsibilities at least once, 56% in leadership positions. Faculty attendance dropped midway from 69 to 19, although workshops were rated very good to excellent. Discussion: Although faculty were interested in FDP, the drop in attendance might be attributed to: challenges to achieve personal and professional goals while struggling to fulfill their roles, satisfy promotion requirements and generate their income. Recommendations: FDP has to be aligned with FM strategic goals and faculty objectives, be complimentary to a faculty mentoring program, provide rewards, and be supported by a faculty progression tool.

Keywords : faculty development, mentoring, career growth, faculty progression

RÉSUMÉ • Introduction et objectifs : À l’Université américaine de Beyrouth la stratégie de la Faculté de médecine (AUB-FM) réside dans le développement des compétences des membres de la faculté (fm) en sponsorisant des activités scientifiques locales et internationales ; mise en place depuis plus de trois décennies, elle reste corrélée aux efforts individuels. En 2011-2012, le Programme de développement de la faculté (PDF) a été introduit pour développer le leadership de la faculté, les compétences relatives aux affaires en médecine et pour réaliser des objectifs personnels et professionnels. Le PDF a été suivi par un plan quinquennal englobant les thèmes suivants: gestion/leadership, commercialisation, finances, planification et communications stratégiques dans le but d'intégrer ces thèmes en médecine. Méthodes : Un questionnaire a été envoyé à tous les départements de la FM en 2011 pour évaluer les besoins et déterminer les thèmes. Neuf ateliers ont été organisés.puis évalués par les participants. Résultats : 117 fm ont répondu à des enquêtes d’évaluation des besoins. Les répondants ont en moyenne 15 années de pratique clinique, 50% avec une expérience comprise entre vaste et modérée en administration; 71% ont assumé des responsabilités administratives au moins une fois et 56% ont occupé des postes de leadership. La présence fm a chuté de 69 à 19, bien que les ateliers aient été jugés très bons ou excellents. Discussion : Bien que les professeurs aient été intéressés par le PDF, la chute de la présence pourrait être attribuée à des défis visant à atteindre des objectifs personnels et professionnels tout en s’efforçant d’assumer leurs rôles, de satisfaire aux exigences de promotion et de créer leurs revenus. Recommandations : Le PDF doit être en ligne avec les buts et les objectifs de la faculté de médecine, complémenter le programme de mentorat en vigueur, offrir des récompenses et disposer d’un outil de progression de faculté.

INTRODUCTION AND OBJECTIVES

Developing academic physicians is one of the major challenges for healthcare centers and physicians at the same time. Healthcare centers are interested in developing academic healthcare professionals to improve quality care to patients and quality teaching and training to medical students and postgraduate trainees; whereas 1

Faculty Affairs Office, Faculty of Medicine and Medical 2 Center, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon.

Correspondence: Boushra Rahal, MPH, EMBA Nabil Mansour, MSc e-mail: br02@aub.edu.lb & nm08@aub.edu.lb

academic physicians are required to fulfill multifaceted roles in teaching, research, clinical, and administrative services, and hence, it is essential for them to improve their skills in these four main areas. In this respect, it was suggested that it is important for academicians to keep their growth and productivity at all career levels, in spite of their challenges in maintaining a well-balanced role in research, teaching and service responsibilities [1]. On the other hand, it is argued that the three traditional roles of academic physicians are competing with each other, considering the dominant compensation structure that adds pressure on physicians to earn their own income,

Lebanese Medical Journal 2015 • Vol 63 (4) 213

and whether they can still fulfill their traditional triple role successfully [2]. It was also stressed that mentoring was important in developing the career of future academic physicians. The latter argument was supported by a group of researchers who reported several disadvantages that academic physicians suffer for not having proper mentorship or “academic parenting,” such as lower salaries and scholarly productivity, and the time spent on learning things, compared to their peers who had mentors [3].

Physicians who opt to pursue career in academic medicine face obstacles in achieving their new goals, mainly because their training prepared them to be medical doctors, but not tutors or researchers [4]. This notion alludes to certain gaps and needs that could hinder the establishment of a successful academic career by the physicians, which might be bridged by proper mentorship. Successful mentoring depends however, on the skills of the mentors and mentees, as well as on the institutional supporting environment [5], and on finding a qualified mentor [6].

It is the strategy of the American University of Beirut Faculty of Medicine (AUB-FM) to develop faculty skills through continuing education by sponsoring local activities, and funding the attendance of an international meeting for all faculty members. Such initiative has been in place for over three decades and remains dependent on individuals’ efforts. To promote these initiatives further, and in an attempt to bridge the gaps of skills required by academic physicians to accomplish their multiple roles, AUB-FM introduced in 2011-2012 a yearround Faculty Development Program (FDP) [7], aiming

to develop the leadership and business skills in medicine, and to help them fulfilling their personal and professional goals at once.

The purpose of this study is to evaluate the FDP initiative and its impact on the attendees, and to conclude a lesson from this experience as a step towards establishing a sustainable faculty development or mentorship program at AUB-FM. METHODS

An online survey was sent to all faculty members in the 19 academic and clinical departments at AUB-FM in 2011 to assess needs and determine themes (See Annex).

Nine workshops were conducted covering business in medicine topics: • How to financially manage your practice • Selection and Appraisal of personnel • Type of corporation: What’s in it for you? • Leadership in Medicine • Financial Investments and Liability • How to position yourself in a competitive practice • Business Planning • Strategic Financial Management and • Conflict Management and Resolution. These workshops were also opened to senior administrators and residents. Post workshop evaluation survey was sent to the attendees. IRB approval is not required for this study.

RESULTS

Out of 296 faculty members, 117 responded to the first survey of needs assessment at the Faculty of Medicine. Distribution of respondents by department is shown in Table I.

TABLE I DISTRIBUTION of RESPONDENTS by DEPARTMENT

Total Number of Faculty Members

Number of Respondents

% of Respondents by Department

% of Respondents by Department from Total Number of Respondents

Anesthesiology Biochemistry & Molecular Genetics Dermatology Diagnoslic Radiology Emergency Medicine Family Medicine Anatomy, Cell Biology & Physiology Internal Medicine Experimental Pathology, Inmunology & Microbiology Obstetrics & Gynecology Ophthalmology Otolaryngology, Head & Neck Surgery Pathology & Laboratory Medicine Pediatrics & Adolescent Medicine Pharmacology & Therapeutics Psychiatry Radiation Oncology Surgery

16 4 10 8 4 16 12 71

7 2 7 6 4 16 5 31

44% 50% 70% 75% 100% 100% 42% 44%

6% 2% 6% 5% 3% 14% 4% 26%

4

2

50%

2%

17 13 14 16 28 4 4 5 50

7 7 8 3 1 0 4 2 5

41% 54% 57% 19% 4% 0% 100% 40% 10%

6% 6% 7% 3% 1% 0% 3% 2% 4%

TOTAL

296

117

40%

100%

DEPARTMENT

The respondents were characterized by having an average of 15 years in clinical practice, 50% had an extensive to moderate administrative experience, and 71% of them had assumed administrative responsibilities at least once, 56% of which in leadership positions. The distribution of respondents by rank is shown in Figure 1.

The results of the needs assessment survey revealed the interest and need of faculty members to developing skills in the following areas: leadership, strategic planning, marketing, financial management, recruitment & selection and conflict management. The topics of workshops were selected and conducted according to the results of the needs assessment.

Overall, the attendance per workshop ranged from 69

to a minimum of 19. On average, the faculty attendance was the highest compared to residents and administrators.

However, the attendance of faculty dropped midway through almost after the sixth workshop out of nine, as shown in Figure 2.

DISCUSSION

Developing faculty members and physicians is one of the main goals of medical centers, which provides a better career management and decrease physicians overturn [8]. It was reported that for healthcare centers to grow, academic physicians should be developed and retained [9].

Past Administrative Experience

Professorial Rank 13%

13%

34%

37%

26%

30%

27%

20%

FIGURE 1. Percent distribution of respondents by academic rank.

Faculty member

How to Financially Manage Your Practice

Selection and Appraisal of Personnel

Type of Corporation: What’s in it for you?

Resident

Leadership in Medicine

Administrator

Financial Investments and Liability

How to position Yourself in a Competitive Practice

Total

Business Planning

Strategic Financial Management

Conflict Management and Resolution

FIGURE 2. Attendants of the workshops by category of attendees.

B. RAHAL et al. – Towards developing a sustainable faculty development program

Lebanese Medical Journal 2015 • Vol 63 (4) 215

The workshops conducted took into consideration the adult learning framework [10-11] that divides the gap and needs at both organizational and individual levels.

The topics were selected according to the choice of faculty members themselves and their needs. However, the workshop attendance declined gradually mostly among junior faculty, while the topics and lecturers were rated “very good” to “excellent.”

Although faculty were genuinely interested in FDP, as verified by the needs assessment and program evaluation, this drop in attendance might be attributed to one or more of the factors highlighted below, to be further investigated: A. Academic physicians are expected to dedicate 80% of their time and effort in clinical care and teaching with the remaining 20% of their time to conduct research and be engaged in different administrative duties. This structure seems to be challenging for them to satisfy their multifaceted roles and expectations, and yet attend to their personal development and career progression.

B. Promotion requirements are demanding and add another burden to academic physicians, which require excellence in two areas per academic track to be achieved within six years in rank: teaching, research, clinical and administrative services.

C. Compensation structure is the major burden over and above the previous two challenges. Physicians are expected to generate two-third of their income through clinical practice, which confirms the conclusions of a group of researchers [2] that physicians are pressured to earn their own income and fulfill the expectations with limited resources and time.

Therefore organizational support should be offered in terms of resources, information and individual [11].

Accordingly, these academic physicians are challenged to achieve personal and professional goals, while they are struggling to fulfill their roles. Our findings are in agreement with that highlighted by Garand et al. [1] that it is crucial for academicians to maintain their growth and productivity at all career levels, in spite of their challenges in maintaining a well-balanced academic and clinical role. Concurrently, Borges et al. [2], and Milner et al. [12] concluded that pursuing a career in academic medicine is challenging, mainly in the absence of institutional support, mentoring and development program. Moreover, the research findings of Kashiwagi et al. [13] and Gray et al. [14], support the importance of mentoring junior academic physicians and developing their skills, although the forms and goals of such programs vary from one academic center to another.

RECOMMENDATIONS

To ensure sustainability, commitment and success, we recommend that the Faculty Development Program has to be: • Aligned with the institutional strategic goals as well 216 Lebanese Medical Journal 2015 • Volume 63 (4)

as the academic physicians’ objectives.

Complimentary to a well-structured and institution• alized faculty mentoring program, specifically targeting junior academic physicians.

• Provide protected time and academic rewards and recognitions that would ensure continuous growth and development.

• Supported by a faculty progression tool for continuous monitoring of junior faculty academic progress [1].

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2. Borges NJ, Navarro AM, Grover A, Hoban JD. How, when, and why do physicians choose careers in academic medicine? A literature review. Academic Medicine 2010; 85 (4): 680-6.

3. Jackson VA, Palepu A, Szalacha L, Caswell C, Carr PL, Inui T. “Having the right chemistry”: A qualitative study of mentoring in academic medicine. Academic Medicine 2003; 78 (3): 328-34.

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7. American University of Beirut, http://www.aub.edu.lb/ FM/FAO/FD/Pages/purpose.aspx. Retrieved on December 20, 2013.

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9. Thorndyke LE, Gusic ME, George JH, Quillen DA, Milner RJ. Empowering junior faculty: Penn State’s faculty development and mentoring program. Academic Medicine 2006; 81 (7): 668-73.

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11. Chevalier RD. When did ADDIE become addie?

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12. Milner RJ, Gusic ME, Thorndyke LE. Perspective: toward a competency framework for faculty. Academic Medicine 2011; 86 (10): 1204-10.

13. Kashiwagi DT, Varkey P, Cook DA. Mentoring programs for physicians in academic medicine: A systematic review. Academic Medicine 2013; 88 (7): 1029-37.

14. Gray J, Armstrong P. Academic health leadership: Looking to the future. Proceedings of a workshop held at the Canadian Institute of Academic Medicine meeting Quebec, Que., Canada, Apr. 25 and 26, 2003. Clinical and Investigative Medicine 2003; 26 (6): 315-26.

B. RAHAL et al. – Towards developing a sustainable faculty development program

ANNEX ONLINE SURVEY DISTRIBUTED TO ALL FACULTY MEMBERS AT AUB-FACULTY OF MEDICINE

B. RAHAL et al. – Towards developing a sustainable faculty development program

Lebanese Medical Journal 2015 • Vol 63 (4) 217

MISE AU POINT / IN-DEPTH REVIEW MANAGEMENT OF METASTATIC COLORECTAL CANCER Current Treatments and New Therapies http://www.lebanesemedicaljournal.org/articles/63-4/review2.pdf 1-2

4

5

4

Anna-Maria HENAINE , Georges CHAHINE , Pascale SALAMEH , Edouard ELIAS , Marcel MASSOUD 1-2 1,2,3 2,6 Daniel HARTMANN , Gilles AULAGNER , Xavier ARMOIRY

4

Henaine A-M, Chahine G, Salameh P, Élias E, Massoud M, Hartmann D, Aulagner G, Armoiry X. Management of metastatic colorectal cancer: Current treatments and new therapies.

J Med Liban 2015 ; 63 (4) : 218-227.

Henaine A-M, Chahine G, Salameh P, Élias E, Massoud M, Hartmann D, Aulagner G, Armoiry X. Prise en charge du cancer colorectal métastatique : Traitements standards et nouveautés thérapeutiques. J Med Liban 2015 ; 63 (4) : 218-227.

ABSTRACT • Colorectal cancer represents 8% of metastatic cancers. For decades, the gold standard therapy has been infusional chemotherapy with 5-Fluorouracil (5-FU) associated to folinic acid. The discovery of irinotecan, oxaliplatin and oral forms of 5-FU in the nineties is considered a milestone in the treatment of this disease. Since 2004, targeted therapy with monoclonal antibodies including anti-EGFR and angiogenesis inhibitors showed superiority in terms of mortality compared to conventional therapy. Metastatic colorectal cancer, however, remains an incurable disease. We present the current treatments of metastatic colorectal cancer, the clinical development of these emerging treatments, and their position in the Lebanese health care system.

Keywords: metastatic colorectal cancer, chemotherapy, monoclonal antibodies

RÉSUMÉ • Le cancer colorectal représente 8% des cas de cancers métastatiques. Pendant des décennies, la chimiothérapie associant le 5-Fluorouracil (5-FU) et l’acide folinique a constitué le traitement conventionnel de référence. L’arrivée de l’irinotécan, de l’oxaliplatine et des formes orales de 5-FU au cours des années 90 a été considérée comme une grande avancée thérapeutique. À partir de 2004, la thérapie ciblée, avec les anticorps monoclonaux visant les récepteurs EGF et l’angiogenèse (VEGF), a permis un bénéfice en termes de survie même si le cancer colorectal métastatique reste, à ce jour, incurable. Nous présentons la prise en charge actuelle du cancer colorectal métastatique, le développement clinique de ces traitements émergents et leur positionnement dans le système de santé libanais.

LIST OF ABBREVIATIONS 5-FU : 5-Fluorouracil 5-FULV : 5-Fluorouracil/Leucovorin APC : Protein coding ASPECCT : A Study of Panitumumab Efficacy and safety Compared to Cetuximab Trial BRAF : V-Raf murine sarcoma viral oncogene homolog B1 CORRECT : Regorafenib monotherapy for previously treated metastatic colorectal cancer CRC : ColoRectal Cancer CRYSTAL : Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer CYP3A4 : Cytochrome P DNA : DeoxyriboNucleic Acid EGF : Epidermal Growth Factor EGFR : Epidermal Growth Factor Receptor FGFR : Fibroblast Growth Factor Receptor FIRE : Trial comparing Cetuximab and bevacizumab FOLFIRI : 5-FULV + Irinotecan FOLFOX : 5-FULV + Oxaliplatin FOLFOXIRI : 5-FULV + Oxaliplatin + Irinotecan GSK3B : Glycogen Synthase Kinase 3B HER : Human Epithelial Growth Factor Receptor Ig : Immunoglobulin KRAS : Kirsten RAt Sarcoma 2 viral oncogene homolog MAPK : Mitogen Activated Protein Kinase 1

mCRC : metastatic colorectal cancer NRAS : Neuroblastoma RAS viral oncogene homolog OPUS : Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer OR : Overall response ORR : Overall response rate OS : Overall survival PDGF : Platelet Derived Growth Factor PEAK : A Randomized, Multicenter Phase II Study of Panitumumab + Modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab + mFOLFOX6 in Patients With Previously Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer PFD : Progression free disease PFS : Progression free survival PI3K/Akt : Phosphoinositide 3-kinase PIGF : Placental growth factor PRIME : Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy RR : Response rate UGT1A : UDP-glucuronosyltransferase 1A VEGF : Vascular Endothelial Growth Factor VEGFR : Vascular Endothelial Growth Factor Receptor VELOUR : Phase III study of aflibercept and FOLFIRI in patients with metastatic colorectal cancer after failure of an oxaliplatin regimen.

WT : Wild

2 Université de Lyon, Claude Bernard Lyon 1, Lyon, France.

UMR CNRS 5510 MATEIS, Lyon, France Hospices Civils de Lyon, Groupement Hospitalier Est, Service pharmaceutique, Bron, France.

4 Hôtel-Dieu de France (Beyrouth) & Hôpital Notre-Dame de Secours (Byblos), Liban.

5 Université libanaise, Laboratoire clinique et épidémiologique, Faculté de Pharmacie, Hadath, Liban.

6 Hospices civils de Lyon, Cellule Innovation/Délégation à la Recherche Clinique et à l’Innovation, Av. du Doyen Lépine, France.

Correspondence : Anna Maria HENAINE, PharmD. UMR CNRS 5510 MATEIS. 8 Avenue Rockefeller. 69373 Lyon. France. e-mail : annamaria.henaine@gmail.com 3

218 Lebanese Medical Journal 2015 • Volume 63 (4)

BACKGROUND

Metastatic colorectal cancer (mCRC) is a major cause of morbidity and mortality throughout the world. It is the fourth most common cancer diagnosed in the U.S. and the second leading cause of cancer death in 2014. In Lebanon, colorectal cancer is the third leading cause of death from cancer and the most common cancer both sex combined [1-2]. In 2012, according to national cancer statistics, the number of eligible new cases diagnosed in the hospital system was 2035, 979 men and 1056 women [3].

About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder.

The remaining 25% of patients have a family history of CRC suggesting a hereditary contribution, common exposures among family members, or a combination of both.

Numerous factors are found important in the development of CRC including high risk luminal environment, inflammation, as well as lifestyle factors such as diet, tobacco and alcohol consumption. In recent years, focus has turned towards the genetics and molecular biology of CRC and several interesting and promising correlations and pathways have been discovered. The major genetic pathways of CRC are the chromosome instability pathway representing the pathway of sporadic CRC through the KRAS, APC and p53 mutations, and the microsatellite instability pathway of hereditary non-polyposis through mutations in mismatch repair genes [4].

Metastases are observed in 40-60% of cases of CRC of which 25% are synchronous. Among patients without metastases at diagnosis, the risk of metachronous is 3040% [5]. Without any treatment, patients with mCRC have a median survival of seven months.

In some cases, the metastases reveal the cancer (precessive metastases) whose primary site is not known and should be identified. Approximately 30-50% of CRC patients develop liver metastases, responsible alone for two thirds of the deaths. Being able to consider their resection is a major challenge since the resection significantly improves the survival of patients. The extra-hepatic locations are rare and of poor prognosis.

Currently, a multitude of clinical evidences have shed a new light on the issues such as the selection and duration of therapy, the associations with targeted agents and treatments tailored towards the clinic and molecular factors. Moreover, knowledge of prognostic and predictive biomarkers such as mutation in KRAS, NRAS, and BRAF, is of growing interest to allow a better selection of drugs and treatment strategies.

The aim of this paper is to review the updates to the management of mCRC. THERAPEUTIC STRATEGIES in the TREATMENT of mCRC

The objectives of the management of patients with mCRC are generally palliative rather than curative, with the exception of a small proportion of patients with resectable liver metastases and controllable by radiofreA.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

quency (or cryotherapy) or locoregional treatment by direct injection of radioactive spheres [6].

Recent advances in chemotherapy regimens have increased the median overall survival (OS) from 6 months to over 30 months through the targeted therapy and double or triple combination protocols [7].

The three active agents for mCRC, known as conventional chemotherapy, are fluoropyrimidines (5-FU or its oral prodrug), irinotecan and oxaliplatin. The associations FOLFOX/XELOX and FOLFIRI are commonly used in the Lebanese hospitals [8] with no evidence from literature of differences between both regimens in terms of OS [9]. Triple associations such as FOLFOXIRI induce a median OS without disease progression with greater response rate than FOLFIRI regimen, but are associated with a poor safety profile [10]. In fact, the FOLFOXIRI has been compared to FOLFIRI in two randomized clinical trials in unresectable patients: in both studies, FOLFOXIRI led to an increased in R0 secondary resection rates: 6% vs 15% (p = 0.033) in the Gruppo Oncologico Nord Ovest (GONO) trial and 4% vs 10% (p = 0.08) in the Gastrointestinal Committee of the Hellenic Oncology Research Group (HORG) trial. In a follow-up study of the GONO trial, the 5-year survival rate was higher in the group receiving FOLFOXIRI (15% vs 8%) with a median OS of 23.4% vs 16.7% month (p = 0.026) [11-13].

The addition of targeted therapies to these four cytotoxic regimens has shown better outcomes in the majority of cases. However, the best strategy sequence and the respective roles of each combination are still debated.

PRINCIPAL AGENTS USED in the TREATMENT of mCRC

Table I summarizes the principal drugs used to treat mCRC. Cytotoxic chemotherapy drugs Cytotoxic drugs induce acute cell death (necrosis), programmed cell death (apoptosis), growth arrest or differentiation. Many antineoplasic drugs have multiple actions on the cell: 5-FU is activated to 5-fluorodeoxyuridylate, which, in the presence of a reduced folate co-factor, inhibits the enzyme thymidylate synthase. This blocks the production of thymidine phosphate which is required for DNA synthesis. The 5-fluorodeoxyuridylate may also be fraudulently incorporated into DNA causing a form of DNA damage [14].

Capecitabine is an orally bioavailable 5-FU prodrug that undergoes sequential hydrolysis and deamination reactions in the liver to produce 5’-deoxy-5-fluorouridine. It is converted to 5-FU by thymidine phosphorylase (also known as platelet-derived growth factor). As this enzyme is abundant in tumor tissue there is some tumor specificity in the patient’s exposure to 5-FU. The adverse effects, such as hand and foot syndrome, of capecitabine resemble those of 5-FU when given by protracted infusion.

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TABLE I SUMMARY of APPROVED THERAPIES for METASTATIC COLORECTAL CANCER in LEBANON Drug

Class

CHEMOTHERAPY 5-Fluorouracil (5-FU®) Capecitabine (Xeloda®)

Antimetabolite (pyrimidine antagonist) Antimetabolite (pyrimidine antagonist)

IV PO

Oxaliplatine (Eloxatine®)

Alkylating agent (Platinum compound)

IV

Irinotecan (Campto®) TARGETED AGENTS Cetuximab (Erbitux®) Panitumumab (Vectibix®) Bevacizumab (Avastin®) Aflibercept (Zaltrap®)

Topoisomerase inhibitor

IV

Monoclonal antibody (IgG1 chimeric) Monoclonal antibody (fully human) Monoclonal antibody (recombinant humanized) Recombinant fusion protein

IV IV IV IV

Regorafenib (Stivarga®)

Tyrosine kinase inhibitor

PO

Ig: immunoglobulin

MAPK: mitogen-activated protein kinase

Other oral 5-FU prodrugs (e.g. S-1, UFT) have been the subject of extensive clinical trials [15].

These are mostly combinations of 5-FU prodrugs with uracil, which is an inhibitor of dihydropyrimidine dehydrogenase, a ubiquitous enzyme that rapidly degrades 5-FU. Oxaliplatin is a diaminocyclohexane platinum derivative and a bifunctional alkylator capable of reacting with adjacent guanine residues in DNA. It provides either intra- or inter-strand DNA cross-links, which interfere with DNA processing.

Oxaliplatin was evaluated as the first line metastatic combination with 5-FULV (FOLFOX4). Three trials showed a significant improvement in the objective response and a progression-free survival, but no significant difference in term of OS [16]. The two limiting toxicities of FOLFOX4 were neutropenia and the specific reversible sensory neuropathy of oxaliplatin. The results of the OPTIMOX 1 study [17] showed that a “stop and go” approach using oxaliplatin free-interval resulted in a decrease in neurotoxicity without affecting the OS. Therefore, the panel recommends adjusting the schedule/ timing of the administration of this drug as a means of limiting this adverse effect. The current clinical data are insufficient to support the routine use of calcium/ magnesium infusions to prevent the oxaliplatin related neurotoxicity.

Irinotecan is a topoisomerase I inhibitor used to treat several solid tumor types, especially in combination with other chemotherapeutic agents in the treatment of mCRC. Inhibition of topoisomerase I by irinotecan and its active metabolite, SN-38, prevents re-ligation of single stranded DNA breaks induced during DNA synthesis phase of cellular replication. Cell death ultimately occurs. Adverse effects include severe diarrhea, myelosuppression and neutropenia, likely induced by inefficient metabolism and

220 Lebanese Medical Journal 2015 • Volume 63 (4)

Mode of administration

PI3K/Akt: phosphoinositide 3-kinase

Pathway

DNA / RNA damage DNA / RNA damage DNA / RNA damage (nonspecific cell cycle) DNA damage PI3K / Akt, MAPK PI3K / Akt, MAPK Angiogenesis Angiogenesis Angiogenesis, oncogenesis tumor microenvironment IV: intravenous

PO: per os

excretion of SN-38, which undergoes glucuronidation primarily in the liver by UGT1A prior to excretion through the kidneys. UGT1A locus is alternatively spliced to produce nine isoenzymes and the UGT1A1 isoform is solely responsible for the phase II metabolism of bilirubin, numerous endogenous hormones and pharmacologic compounds, including irinotecan. Thus, genetic variation in UGT1A correlates with adverse events caused by irinotecan toxicity [18].

Evidence indicates that, at relatively high irinotecan level (> 250 mg/m2), patients who are homozygous for the UGT1A1*28 variant experience a greater risk of clinically important neutropenia, especially with particular chemotherapy agents/oxaliplatin [19]. That’s why it is reasonable to determine the UGT1A genetic background to assist in toxicity management. Unfortunately, this molecular testing is not present in our Lebanese hospitals to date.

Irinotecan is also an inhibitor of acetyl cholinesterase and patients may experience an acute onset of cholinergiclike symptoms including lacrimation, sweating, abdominal cramping and diarrhea.

Irinotecan, in combination with fluorouracil (FOLFIRI), in the second-line, is considered a good standard in the palliative treatment of mCRC. Several studies [20-21] have shown a significant increase in the response rate, PFS and OS with FOLFIRI compared to 5-FULV alone.

MODULATORS of the TARGETED BIOLOGICAL RESPONSE

As observed in a retrospective cohort study conducted in Lebanese hospitals [8], approximately 75% of patients with mCRC receive a biological agent during their treatment course targeting one of two main pathways: the EGFR cascade and the VEGF signaling.

A.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

FGFR:fibroblast growth factor receptor PDGFR: platelet-derived growth factor receptor PIGF: placental growth factor VEGF: vascular endothelial growth factor VEGFR: vascular endothelial growth factor receptor FOLFIRI: 5-FULV/Irinotecan mCRC: metastatic colorectal cancer RPLS: reversible posterior leukoencephalopathy syndrome CBC: complete blood count

SUMMARY of the ANTIANGIOGENIC DRUGS CURRENTLY APPROVED for mCRC TREATMENT: BEVACIZUMAB, AFLIBERCEPT & REGORAFENIB Bevacizumab Aflibercept Regorafenib Approval date 2004 August 2012 September 2012 Registration in Lebanon 2006 2014 2014 Genentech Inc., South San Francisco, CA, USA Sanofi-Aventis, Bridgewater, NJ, USA Bayer AG, Leverkusen, Germany Origin Multikinase inhibitor against VEGFR1, VEGFR2, VEGFR3, PDGFR-β, FGFR1, TIE2, KIT, RET VEGFR decoy binding VEGF-A,VEGF-B & PIGF Mechanism of action Targets VEGF-A (only) as well as a signal transduction inhibitor of the RAF/MEK/ERK pathway Extracellular Intracellular Extracellular / Intracellular Extracellular 3rd line mCRC as single agent, in refractory/ st nd nd Indication 1 /2 line mCRC + combination chemotherapy 2 line in mCRC + FOLFIRI progressive disease 5-10 mg/kg IV every 2 weeks in combination with 4 mg/kg IV every 2 weeks in combination with 160 mg daily for 21 days of an every 28 d cycle Dosing FOLFOX or FOLFIRI FOLFIRI Hypertension, proteinuria, thromboembolism, Hypertension, proteinuria, diarrhea, bone marrow Hypertension, asthenia, gastrointestinal Common & classically gastrointestinal perforation (rare), suppression (neutropenia), delay wound healing, perforation (rare), hemorrhage, hand-foot syndrome, side effects fistula, RPLS, thromboembolism rash, hepatotoxicity, RPLS hemorrhage, delay wound healing, RPLS Arterial & venous thromboembolism, Wound healing impairment, hemorrhage, Hepatotoxicity (rare), RPLS, dehydration, Black box warnings gastrointestinal perforation (rare) cardiac disease hypertension, wound healing impairment.

Blood pressure, liver functions, electrolytes Renal function, proteinuria, blood pressure, Renal function, CBC, infection, proteinuria, (if diarrhea), INR (if the patient is taking warfarin), Monitoring parameters blood pressure, bleeding, dehydration bleeding callous in the hands or feet TABLE II

A.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

Triggering cell death via cancer-directed immunotherapy or immunomodulation with the aim to overcome major mechanisms of immune resistance is a newly arising field [22-23]. We will discuss the major approaches and current therapies in the treatment of mCRC. Inhibitors of angiogenesis Angiogenesis is a central mechanism in human CRC development and growth [24]. In particular, VEGF is closely associated with the induction of neovascularization in human colon cancer and is one of the most important endogenous ligands of receptors present on the endothelial cell plasma membrane; it’s binding leads to intracellular signaling and, ultimately, gene transcription that promotes endothelial proliferation, migration, and tube formation of endothelial cells resulting in tumor growth and metastasis.

Given the crucial importance of neoangiogenesis in mCRC, anti-VEGF pathway therapies have been intensively investigated. The monoclonal antibody bevacizumab is the first antiangiogenic agent to be approved in mCRC treatment, because of response rate and survival benefit [25-26].

The three antiangiogenic agents available within Lebanese hospitals are presented in Table II. Bevacizumab is a recombinant humanized IgG1 monoclonal antibody (7% murine) directed against VEGF-A. After showing its efficacy in several murine xenograft models of human tumors, bevacizumab alone or in combination with other cytotoxic agents, was shown to be well tolerated in phase I trials apart from some side effects such as thromboembolic events, bleeding, hypertension and proteinuria.

The association of bevacizumab with 5-FU increased the OS (12.9 months for FOLFOX4/bevacizumab vs 10.8 months for FOLFOX4 alone) and the disease free progression (DFP) significantly (7.3 months vs 4.7 months respectively). In November 2012, bevacizumab was approved in combination with chemotherapy based on fluoropyrimidine, irinotecan or oxaliplatin for the treatment of mCRC disease. This approval allows the patients, who received first-line treatment with bevacizumab plus irinotecan-based chemotherapy or with oxaliplatin, to continue receiving bevacizumab plus other chemotherapy based on oxaliplatin or irinotecan as second-line treatment after progression of the disease. In the Lebanese hospitals, the practice is to preferably use the protocol FOLFOX-Bevacizumab as first-line [8].

Aflibercept also known as VEGF Trap, is a fully human soluble recombinant protein composed of extracellular domains from both VEGFR-1 and VEGFR-2 fused to the Fc (a) region of human IgG1 [27]. It was designed to act as a decoy VEGF receptor, binding VEGF-A, VEGF-B, and PlGF, subsequently preventing their interactions with VEGFR-1 and VEGFR-2 [28-29].

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Aflibercept was studied in combination with FOLFIRI in a prospective, randomized, double-blind, multicenter, study on patients with mCRC previously treated with an oxaliplatin-based chemotherapy regimen. Patients were randomized either to FOLFIRI plus aflibercept (4 mg/kg intravenously every 2 weeks) or FOLFIRI plus placebo.

The aflibercept arm showed significant improvement in the primary endpoint of OS (13.50 months vs 12.06 months). PFS and ORR were also increased (6.90 months vs 4.67 months and 19.8% vs 11.1% respectively). In subgroup analyses of patients with or without priorbevacizumab regimen, PFS was significantly improved in both. OS was significantly improved in the bevacizumab-naïve subset, but did not achieve significance in the prior-bevacizumab subset.

Based on these results, the FDA approved, on August 2012, the use of aflibercept in combination with FOLFIRI for the treatment of patients with mCRC that is resistant to or that has progressed after an oxaliplatincontaining regimen. Both antiangiogenic-associated and chemotherapy-related adverse effects were seen with greater incidence in the aflibercept arm (83.5% of grade 3 or 4 adverse events). The antiangiogenic toxicities described were hypertension, hemorrhage, and arterial and venous thromboembolism, diarrhea, and asthenia.

Regorafenib is an oral small-molecule multikinase inhibitor, inhibiting multiple oncogenic kinases, PDGF, FGFR and VEGFR-1. Its mechanism is not clearly understood, but studies have shown that it induces expression of PUMA, p53 target and critical mediator of apoptosis in colorectal cells after inhibition of ERK and activation of GSK3B through the cascade of NF-kB [30-31].

Regorafenib was approved for the treatment of mCRC patients previously treated with fluoropyrimidine, oxaliplatin, or irinotecan-based chemotherapy regimens, with prior anti-VEGF and/or anti-EGFR (KRAS wild) therapies. Regorafenib was evaluated in the Phase III CORRECT trial [32] on patients with mCRC who had progressed during or within three months after the above therapies. Patients on the study were randomized to receive either regorafenib (160 mg/day/21 days) or placebo.

Treatment with regorafenib was associated with a modest but significant increase in survival (6.4 months vs 5.0 months). The CORRECT trial showed a survival benefit with regorafenib in an extensively treated patient population, also about 40% of patients achieved disease stabilization. Adverse events associated with regorafenib are hand-foot skin reaction, fatigue, diarrhea, mucositis, dysphonia, weight loss, infection, hypertension (impaired angiogenesis). Hepatotoxicity (sometimes fatal), increased incidence of hemorrhage, myocardial ischemia, infarction, reversible post leukoencephalopathy syndrome, gastrointestinal perforation and fistula are rare and should be closely monitored.

The bioavailability of regorafenib is 69% after oral administration in tablet form. Absorption is dependent on the fat content of a meal (better with low-fat diet). It

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is metabolized by CYP3A4 and UGT1A9 to two active metabolites (M-2 & M-5) and is excreted primarily by the feces [33].

Regorafenib may interact strongly with CYP3A4 inducers (rifampin, phenytoin, and carbamazepine), CYP3A4 inhibitors (ketoconazole, voriconazole, grapefruit juice, clarithromycin, itraconazole) and substrates of UGT1A1 (irinotecan) [34].

EGFR (epidermal growth factor receptor) inhibitors EGFR is a transmembrane cell surface glycoprotein and a member of the human epithelial growth factor receptor (HER) family of tyrosine kinases. Binding of ligands to the EGFR leads to homodimerization or heterodimerization of HER family members and results in autophosphorylation of intracellular tyrosine residues, initiating several key cell-signaling pathways including RAS/RAF/MAPK axis, involved in cell proliferation and PI3K/AKT pathway, involved in cell survival and motility. Binding to EGFR enhances processes critical to tumor growth and progression such as angiogenesis, apoptosis inhibition, tumor invasiveness and metastatic spread [35]. RAS is one of the most important molecules in the signaling pathway downstream of the EGFR. Three human RAS genes have been identified: HRAS, KRAS and NRAS. Since the activation of the EGFR leads to activation of KRAS, it was hypothesized that mutations in signaling pathway downstream of the EGFR may result in receptor independent pathway activation that renders the tumors unresponsive to EGFR blockage at the cell surface.

Mutations in KRAS codons 12 and 13 (exon 2) are present in 35-45% of CRC with high concordance between primary and metastatic lesions and have been established as predictors of lack of response to antiEGFR treatment. Consequently, KRAS exon 2 mutation testing is widely implemented for selection of patients with wild-type mCRC for anti-EGFR treatment. A moderate response rate of 40-60%, also in KRAS exon wild-type tumors, has motivated assessment of the predictive role of additional alterations, primarily within the RAS-RAF-MAPK and PI3KAKT-mTOR pathways. Additional mutations in KRAS as well as NRAS (effector binding domains identical to KRAS and present in 10% of mutations) have been suggested to infer resistance to anti-EGFR therapies and the European label for panitumumab treatment was recently modified to require testing also for KRAS mutations outside of exon 2 and for NRAS mutations. The added treatment predictive value of mutation in BRAF (principal effector of KRAS and present in 8% of mutations), PIK3CA and PTEN is more uncertain [36]. According to the most current data, the BRAF biomarker is deemed to be a negative predictive biomarker as well as a prognostic biomarker.

The BRAF and KRAS status must be determined to be wild-type to produce a positive response to antiEGFR therapies.

A.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

Figure 1 shows the important role of the BRAF & KRAS status in the response of anti-EGFR drugs.

Testing is based on lesions with greater than 50% tumor.

This is a tumor percentage that can be easily obtained from an untreated primary lesion or a well-defined metastasis without treatment or extensive inflammatory infiltrate. It is estimated that 20% of patients present with metastatic disease, so mutation testing based on a primary lesion is not always feasible. Although most studies have found that metastases maintain the mutation profile of the primary lesion in more than 90% of cases, 54-60% discordance may arise for technical reasons or, rarely, because of metastases from separate primaries. For this reason, it is preferable to test the metastases rather than the primary tumor, if possible, because itâ&#x20AC;&#x2122;s the former that is being treated by the EGFR targeted therapy.

Two monoclonal antibodies that block EGFR signaling and prevent endogenous receptor activating ligands are currently approved for the treatment of mCRC: cetuximab and panitumumab. The efficacy of these drugs is limited to patients with wild-type (non-mutated) KRAS (KRAS WT) (cetuximab) and non-mutated RAS (panitumumab) tumors.

A multitude of recent clinical trials have indicated that expanded RAS testing is more effective than traditional KRAS testing for patients with CRC. As a result of these findings, the number of patients with CRC who are eligible for EGFR inhibitors has been reduced to approximately 40% [37].

Cetuximab is a recombinant human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the EGFR on both normal and tumor cells, and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor-Îą. The recommended dose of cetuximab, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose administered as a 120-minute IV infusion. The recommended weekly maintenance dose is 250 mg/m2 infused over 60 minutes. WT KRAS status is required for initiation of treatment with cetuximab but further studies also show that WT RAS status (mutations at exons 2, 3 and 4 of KRAS, NRAS and BRAF) is mandatory prior to initiation of treatment with cetuximab using a validated method of analysis, newly applied in Lebanon.

The addition of cetuximab improved the resection rate of initially unresectable, liver-limited, KRAS WT mCRC Monoclonal antibodies (cetuximab or panitumumab)

EGF

EGFR

WT KRAS/ WT BRAF

MUT KRAS / MUT BRAF

EGFR signaling pathways

NUCLEUS KRAS BRAF CELL CYCLE PROGRESSION

MEK ERK

Response to drug following the status of KRAS and/or BRAF non mutated (WT): cell proliferation, survival, invasion & metastases are blocked Effect of monoclonal anti-EGFR antibodies

When the status of KRAS and/or BRAF are mutated (MT), the cell cycle progression continues: cell proliferation, survival, invasion & metastases Nuclear cellular abnormally increased

FIGURE 1 KRAS (Kirsten rat sarcoma viral oncogene homolog) / BRAF (V-Raf murine sarcoma viral oncogene homolog B1): mutations and anti-EGFR therapy in mCRC. Anti-EGFR drugs block receptor signals thus preventing downstream events such as KRAS or BRAF mediated effects.

when compared with the corresponding chemotherapy regimen alone. The efficacy of cetuximab was derived from two randomized controlled trials. The CRYSTAL study is a phase III, multicenter, open-label randomized controlled trial, which compared cetuximab in combination with FOLFIRI with FOLFIRI alone. The OPUS study trial is a phase II, multicenter, open-label randomized controlled trial, which compared cetuximab in combination with FOLFOX4 with FOLFOX4 alone [38-39].

The results of the CRYSTAL trial for the KRAS WT subgroup showed a statistically significant increase in PFS with cetuximab in combination with FOLFIRI (9.9 months vs 8.7 months). The OPUS trial also showed a statistically significant increase in PFS with a median PFS of 7.7 months for cetuximab in combination with FOLFOX compared with 7.2 months for FOLFOX alone. The RR was also improved: 60.7% in the cetuximab + FOLFOX vs 37.0% FOLFOX alone. The OPUS trial included 30.5% patients with additional RAS mutations; those in the cetuximab + FOLFOX arm had inferior survival, PFS and objective RR than those assigned to receive FOLFOX alone. Safety evaluations showed no new findings attributable to cetuximab when comparing WT and mutated RAS populations: the inferior outcome was due to lack of efficacy in combination with the known toxicity profile.

As a result, some evidence of WT RAS status and of KRAS (and NRAS) is required before initiating treatment with cetuximab and that this drug is contraindicated in case of mCRC with mutant RAS or unknown RAS status.

The most serious adverse reactions observed in clinical trials of cetuximab, alone or in combination with irinotecan, were infusion reactions, dermatologic toxicity (acneiform rash), interstitial lung disease, fever, sepsis, renal dysfunction, pulmonary embolism, dehydration and diarrhea.

Panitumumab is a fully humanized IgG2 monoclonal antibody that binds to the extracellular domain of the EGFR of both tumor and normal cells with high affinity.

By competing with endogenous ligand binding, panitumumab inhibits receptor phosphorylation and activation of EGFR associated cell signaling [40]. This also results in down regulation of EGF receptors through receptor internalization, induction of apoptosis, autophagy and inhibition of angiogenesis. Panitumumab was approved for use by the FDA in September 2006 but registered in Lebanon since 2014. It is administered intravenously at a recommended dosing schedule of 6 mg/kg once every 2 weeks. The elimination half-life of panitumumab is approximately 7 days, longer than cetuximab where the half-life is 4 days, providing the rationale for the weekly schedule of cetuximab versus the alternate weekly administration schedule for panitumumab. It also has dual clearance mechanisms. Specific clearance of panitumumab involves binding to EGFR, internalization into the cell and degradation in lysosomes.

The evidence to support the use of panitumumab in the first-line treatment setting comes from the PRIME study (phase III trial) and two phase II trials [41-44]. The 224 Lebanese Medical Journal 2015 • Volume 63 (4)

PRIME trial randomized untreated patients with mCRC to FOLFOX chemotherapy and panitumumab versus FOLFOX chemotherapy. The results of the study are shown in table III. Patients with WT KRAS mCRC who reported grades 2 to 4 skin toxicities (rash, acneiform dermatitis, pruritus, dry skin, skin fissures or erythema), diarrhea and electrolytes deficiencies (hypokalemia) had longer PFS and OS as well as ORR. The development of skin toxicity is an early clinical indicator of the panitumumab regimen’s efficacy. This updated analysis confirms the value of adding panitumumab to FOLFOX in the firstline treatment of patients whose tumors are determined to be WT KRAS. Because crossover to an EGFR-targeted monoclonal antibody after progression on FOLFOX was permitted, potential survival differences may be attenuated related to panitumumab. PRIME also confirms that patients whose tumors are KRAS-mutated should not be treated with panitumumab. The recently completed PEAK study (also panitumumab in first-line treatment but phase II trial) is the first head-to-head analysis of FOLFOX combined with either panitumumab or bevacizumab in KRAS WT mCRC (Table III).

The use of panitumumab in second-line treatment of KRAS WT mCRC comes from two large phase III randomized trials, and two single-arm phase II trials (Table III).

To summarize, the addition of a biological agent to a chemotherapy backbone containing oxaliplatin or irinotecan may increase the number of patients potentially eligible for resection and improve outcomes.

COMPARATIVE DATA BETWEEN mCRC TARGETED THERAPIES

The ASPECCT trial is an open-labeled, randomized, phase III trial designed to compare the effects of panitumumab and cetuximab for monotherapy of chemorefractory patients with KRAS WT tumors. The ORR was 22% for the panitumumab arm compared to 19.8% for the cetuximab arm. The PFS was 4.1 months in patients treated with panitumumab versus 4.4 months in patients treated with cetuximab. The study met its primary endpoint, demonstrating that panitumumab was non-inferior to cetuximab for OS (10.4 months vs 10 months). Therefore, based on these results and those from other previous trials, there is no therapeutic preference in clinical practice for using cetuximab versus panitumumab either as monotherapy or in combination with chemotherapy in naïve or chemorefractory mCRC. Treatment selection is an art more than an algorithm.

The first step is to take into account the goal of therapy and the toxicity profile that the patient is willing to live with.

The use of anti-EGFR antibody treatment in combination with chemotherapy in earlier lines of treatment is a less common and more complex issue. For RAS WT patients the optimal targeted agent in first-line therapy remains undefined with the addition of either bevacizumab or an anti-EGFR antibody supported by multiple phase III A.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

TABLE III PROGRESSION-FREE SURVIVAL and OVERALL SURVIVAL in FIRST & SECOND TRIALS of PANITUMUMAB [46] TRIALS

KRAS status

Treatment regimen (control)

PFS (months)

Hazard ratio

Median OS (month)

Hazard ratio

ORR

FOLFOX4 + P (FOLFOX4) FOLFOX4 + P (FOLFOX4)

9.6 8.0 7.3 8.8

0.8*

23.9 19.7 15.5 19.3

0.83

55% 48% 40% 40%

KRAS WT

FOLFOX + P FOLFOX + Bev

10.9 10.1

0.87

Not reached 25.4

0.72

58% 54%

KRAS WT

FOLFIRI + P FOLFIRI FOLFIRI + P FOLFIRI

5.9 3.9 5.0 4.9

0.73*

14.0 12.5 11.8 11.1

0.85 0.94

35% 10% 13% 14%

IrPan Irinotecan FOLFIRI + P FOLFIRI + Bev

NR NR 7.7 9.2

10.4 10.9 18.0 21.4

1.01

34%* 12% 32% 19%

First line PRIME (N = 1183)

KRAS WT KRAS MT

PEAK (N = 285)

1.29*

1.24

Second line (N = 1186) Peeters et al.

KRAS MT PICCOLO (N = 460) SPIRITT (N = 182)

KRAS WT KRAS WT

0.85

0.78* 1.01

1.06

CI: 95% confidence interval PFS: progression-free survival OS: overall survival ORR: objective response rate N: number of patients KRAS: Kirsten rat sarcoma gene FOLFOX: infusional 5-Fluorouracil/folinic acid/oxaliplatin P: panitumumab MT: mutated WT: wild-type (nonmutated) Bev: bevacizumab FOLFIRI: infusional 5-Fluorouracil/folinic acid/irinotecan IrPan: irinotecan/panitumumab NR: not reported * p < 0.05

trials. Several factors may lead the clinician to prefer an anti-EGFR antibody to bevacizumab. In patients with a contraindication to bevacizumab, the addition of antiEGFR antibody to chemotherapy improves PFS and ORR compared with chemotherapy alone.

The consistent effects on response and survival from RAS mutations outside of KRAS exon 2 clearly suggests that mutation testing for ant-EGFR prediction should move from selective KRAS testing to broader RAS testing.

Recently, data from the FIRE-3 study [45-46], which is the first head-to-head comparison between two biological agents for the treatment of mCRC, have been designed to compare FOLFIRI + cetuximab with FOLFIRI + bevacizumab in the first-line setting for patients with KRAS exon 2 WT mCRC. The primary endpoint of this study, the ORR, was not met (62% for FOLFIRI-cetuximab vs 58% for FOLFIRI-bevacizumab). No difference in PFS was observed (10.0 months vs 10.3 respectively), however, a significant difference in OS was observed in favor of FOLFIRI-cetuximab (28.7 months vs 25.0 respectively).

In a preliminary analysis, the effects of mutations in KRAS and BRAF on ORR, PFS, and OS were evaluated. Patients with WT RAS had a median OS of 33.1 months in the FOLFIRI-cetuximab group vs 25.6 months with FOLFIRIbevacizumab. However, in patients with mutant RAS, there was no difference between the two regimens. Therefore, a complete determination of RAS status may be necessary

A.-M. HENAINE et al. – Metastatic colorectal cancer: new therapies

before prescribing EGFR inhibitors in first-line treatment of mCRC, and the prescription of cetuximab should be restricted to patients with WT RAS (and WT KRAS). Thus far, the factors that contribute to the difference in OS are unclear.

Figure 2 summarizes the therapeutic strategies in the treatment of metastatic colorectal cancer.

CONCLUSION and PERSPECTIVES

The outlook for the adjuvant treatment of CRC results out of the progress in the treatment of mCRC for the last five years. Such progress has been marked by the advent of combination therapies and the very recent emergence of biotherapy improving the effectiveness of chemotherapy. With the discovery of selective targeted drugs, a new era for the treatment of mCRC has been opened. Adding these drugs, such as bevacizumab and/or cetuximab, to standard chemotherapy resulted in improved PFS and OS in patients with mCRC, either as first or second-line of therapy.

Considering the substantial cost of targeted therapies for mCRC, their cost-effectiveness has also to be measured within the Lebanese society’s perspective. This type of evaluation is currently ongoing based on data from two Lebanese university hospitals [8].

Lebanese Medical Journal 2015 • Volume 63 (4) 225

Chemotherapy for metastatic colorectal cancer in a patient appropriate for intensive therapy

Initial therapy

Therapy after 1st progression

Therapy after 2nd progression

Therapy after 3rd progression

FOLFOX or XELOX or FOLFOX + Bevacizumab or XELOX + Bevacizumab

OR

FOLFOX + Cetuximab or Panitumumab (KRAS/NRAS WT gene only)

FOLFIRI or FOLFIRI + Bevacizumab or FOLFIRI + ziv-Aflibercept or Irinotecan or Irinotecan + Bevacizumab or FOLFIRI + Cetuximab or Panitumumab (KRAS/NRAS WT gene only) or Irinotecan + ziv-Aflibercept or Irinotecan + Cetuximab or Panitumumab (KRAS/NRAS WT gene only)

FOLFIRI or FOLFIRI + Bevacizumab or FOLFIRI + ziv-Aflibercept or Irinotecan or Irinotecan + Bevacizumab or Irinotecan + ziv-Aflibercept

Cetuximab or Panitumumab (KRAS/NRAS WT gene only) + Irinotecan or Regorafenib

Regorafenib or clinical trial or best supportive care

Regorafenib (if not given previously) or clinical trial or best supportive care

FIGURE 2 Chemotherapy for advanced or metastatic disease applied in the Lebanese hospitals [8].

FOLFIRI: infusional 5-Fluorouracil/folinic acid/irinotecan FOLFOX: infusional 5-Fluorouracil/folinic acid/oxaliplatin NRAS: RAS oncogene WT: wild type or non-mutated

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CAS CLINIQUE / CASE REPORT CEREBRAL ANEURISMAL RUPTURE WITH SUBARACHNOID HEMORRHAGE DURING PREGNANCY: A CASE REPORT http://www.lebanesemedicaljournal.org/articles/63-4/case1.pdf 1

1

2

1

David ATALLAH , Fersan MANSOUR , Elie SAMAHA , Nadine EL KASSIS , Joseph NASSIF

3

Atallah D, Mansour F, Samaha E, El Kassis N, Nassif J. Cerebral aneurismal rupture with subarachnoid hemorrhage during pregnancy : a case report. J Med Liban 2015 ; 63 (4) : 228-231.

Atallah D, Mansour F, Samaha E, El Kassis N, Nassif J. Rupture d’anévrisme cérébral avec hémorragie méningée pendant la grossesse : étude d’un cas. J Med Liban 2015 ; 63 (4) : 228-231.

ABSTRACT • Background : Intracranial hemorrhage due to arteriovenous malformation or intracranial aneurysm is a rare but severe complication of pregnancy with maternal and fetal mortality of 20% and 33% respectively. Whether to deliver the patient first, or to treat the aneurysm first is still controversial, but an emergency cesarean section followed by aneurismal treatment appears to be a widely accepted strategy in pregnant women with cerebral aneurysmal complications. Case : A 38-year-old patient, G3P2A0, presented at 36 gestational weeks with a diffuse bilateral subarachnoid hemorrhage with fourth ventricle bleeding and hydrocephalus. She had a cerebral aneurysm of the left posterior communicating artery on arteriography. A cesarean section was performed on the first day of admission, and an external ventricular derivation with clipping of the aneurysm on the left posterior communicating artery were done immediately after the cesarean section. Mother and newborn were discharged from hospital in a good health status except Broca’s aphasia in the mother. Conclusion : In the absence of categorical recommendations, we stress the role of combined care by both neurosurgeons and obstetricians, on a case to case basis according to gestational age, mother neurological status and experience of caregivers.

Keywords : cerebral aneurysm, pregnancy, subarachnoid hemorrhage

RÉSUMÉ • Mise au point : L’hémorragie intracrânienne due à une malformation artério-veineuse ou à un anévrisme intracrânien est une complication rare et grave de la grossesse. Les mortalités maternelle et fœtale sont de l’ordre de 20% et 33% respectivement. Accoucher la patiente en premier lieu ou bien traiter l’anévrisme est un sujet de débat.

Pourtant, une césarienne d'urgence suivie d'un traitement d'anévrisme semble être une stratégie conventionnelle pour les femmes enceintes présentant des complications d’anévrisme cérébral. Étude de cas : Une femme, G3P2A0, âgée de 38 ans, se présente à 36 semaines d’aménorrhée à notre service avec une hémorragie sous-arachnoïdienne bilatérale accompagnée de saignement au niveau du quatrième ventricule et d’hydrocéphalie. Elle avait un anévrisme cérébral de l’artère communicante postérieure gauche sur l’artériographie. Une césarienne a été réalisée le premier jour de son admission. Ceci a été immédiatement suivi par une dérivation ventriculaire externe avec clippage de l’anévrisme au niveau de l’artère communicante postérieure gauche. La mère et son nouveau-né sont sortis de l’hôpital en bon état de santé, sauf pour l’aphasie de Broca chez la mère. Conclusion : En l’absence de recommandations, nous insistons sur le rôle des soins combinés des neurochirurgiens et obstétriciens, au cas par cas, en fonction de l’âge gestationnel, l’état neurologique de la mère et de l’expérience des professionnels de santé.

INTRODUCTION

orrhage due to aneurismal rupture can prove to be difficult [5-7]. Aneurismal subarachnoid hemorrhage (SAH) during pregnancy occurs more often in primiparae and in the third trimester of pregnancy [6,8-10]. The confirmation of the diagnosis is made by computed tomography (CT) or lumbar puncture and cerebral angiography.

Aneurismal management should be performed in an emergency but fetal prognosis should be considered. A review of the literature yielded on Pubmed displayed three case reports [11-13] or series of fifteen cases or less [1,5,8,14-16]. Whether to deliver the patient first, or treat the aneurysm first, is still controversial, but an emergency cesarean section followed by aneurismal treatment appears to be a widely accepted strategy in pregnant women with cerebral aneurysmal complications [5,8,16].

We report here the case of a female patient with ruptured cerebral aneurysm at 36 weeks of gestation which presented to our department.

Intracranial hemorrhage due to arteriovenous malformation or intracranial aneurysms is a rare but severe complication of pregnancy with maternal and fetal mortality of 20% and 33% respectively [1]. Cerebral aneurysms have a variable clinical presentation during pregnancy [2]. Unruptured ones can be asymptomatic or present as hyperemesis gravidarium [3-4]. Whereas rupture can cause headaches, consciousness alterations and sometimes the difference between eclampsia and cerebral hem1

Department of Obstetrics and Gynecology, Hôtel-Dieu de France University Hospital, St Joseph University (HDF-USJ), Beirut, Lebanon.

2 Department of Neurosurgery, HDF-USJ. 3 Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon.

Correspondence : David Atallah, MD. e-mail: david.atallah@gmail.com

228 Lebanese Medical Journal 2015 • Volume 63 (4)

CASE PRESENTATION

We report a case of a patient, 38 years old, G3P2A0 (two normal deliveries), pregnant at 36 gestational weeks without any pregnancy complication. She has no significant medical or surgical histories.

She presented with acute onset headache and vomiting.

An alteration of her consciousness developed few hours later (Glascow score = 8). She was intubated and sedated.

Her laboratory tests showed hematocrit of 34.0%, hemoglobin 11.2 g/dL, serum sodium level of 141.0 mmol/L, potassium 3.5 mmol/L and a blood type of A+. A cerebral CT-scan showed a diffuse bilateral SAH with fourth ventricle bleeding and hydrocephalus. An arteriography, with protection of the abdomen, showed a cerebral aneurysm of the left posterior communicating artery with arteriographic signs of hydrocephalus (Figure 1).

A cesarean section was performed on the first day of admission (clear amniotic fluid), and an external ventricular derivation with clipping of the aneurysm on the left posterior communicating artery were done immediately after the cesarean section.

The male newborn had an Apgar score of 2 over 10 at one minute of life. He was intubated and transferred to the neonatalogy department for neonatal respiratory distress.

He weighed 2475 g, had a cranial perimeter of 34 cm and 48 cm of length. He was treated with antibiotics (cefotaxime and ampicilline) for ten days. A chest X-ray showed a bilateral bronchogram. He was extubated on the third day of life. Thereafter, a chest X-ray was done on the ninth day of life showing a superior left lobe atelectasia.

As a result, the neonate left the department on the twelfth day of life in very good health status.

When it comes to the mother, she was extubated the next day of the interventions with normal neurologic status except for a Broca’s aphasia which ameliorated during her hospital stay. On the fourth postoperative day, a cerebral CT-scan showed a shrinking of 30% of the ven-

FIGURE 1. Arteriography showing cerebral aneurysm of the left posterior communicating artery.

D. ATALLAH et al. – Cerebral aneurysm rupture in pregnancy

tricles’ size with regression of the SAH. Also was noted a left fronto-parietal hygroma measuring 5 mm. The external ventricular derivation was ablated. This CTscanning was repeated on the fourteenth postoperative day with a complete regression of the SAH. A majoration of 50% of the hygroma’s size was noted without mass effect on the median line. A hypodense left frontoparietal lesion with disappearing of the interface between the white and gray matter was also noted, suggesting ischemia. Normal ventricular size was found. Then a transcranial Doppler was done showing a severe vasospasm. Prior to her discharge, the patient had a cerebral magnetic resonance imaging (MRI) showing a recent left superficial sylvian ischemia with a little chronic subdural hematoma in the left fronto-temporo-parietal region. The ventricles were slightly enlarged.

DISCUSSION

Since the first case published by Feldman et al. in 1955 [17], the treatment of cerebral aneurysms in pregnancy is still debated. This problem is critical because over 50% of ruptured arterial aneurysms in women under the age of 40 are pregnancy-related [18].

While the obstetrical management of women known to have a cerebral vascular malformation is controversial [14], cerebral aneurysms are treated whether they rupture or not. The risk of bleeding from cerebral arteriovenous malformations is not significantly increased during pregnancy. However, the risk of hemorrhage is slightly increased at the end of pregnancy, but unchanged during labor and delivery, in women with arterial aneurysms [14]. This difference can be due to the hemodynamic and endocrine changes in the growth and rupture of aneurysms [6,19]. In fact, on one hand, cardiac output increases by 60% at the end of the second trimester as blood volume and blood pressure reached their maximum values at term [20]. On the other hand, pregnancy hormones (estrogen, progesterone and human chorionic gonadotropin) predispose to intracranial aneurysms formation, enlargement and rupture [21].

Lynch JC et al. report that surgical management of the aneurysms is associated with lower maternal and fetal mortality than the conservative endovascular treatment; they treated some aneurysms before delivery [1].

According to Mosiewicz et al., ruptured intracranial aneurysms should be treated similarly in pregnant and non-pregnant patients [6-7,19]. When the aneurysm is successfully clipped, the pregnancy can be allowed to progress to term. In these cases, vaginal delivery is preferred by most clinicians. Moreover, unruptured aneurysms should be treated if they are symptomatic or enlarging. Other aneurysms should be treated on an individual basis [19]. Cesarean section would be indicated in several circumstances: 1) when the clinical state of the mother is severe (coma, brain stem damage); 2) if the aneurysm is diagnosed during labor, or 3) if the period between the neurosurgical treatment of aneurysm and

Lebanese Medical Journal 2015 • Volume 63 (4) 229

labor is less than eight days [6]. In all other cases, a vaginal delivery is preferable under epidural anesthetic which should be given if medical induction is carried out, and where instrumental delivery is being carried out systematically, unless radical treatment is being performed. Our patient was admitted unconscious in our department, which justifies the C-section followed by the clipping of the aneurysm.

Recent trends are the endovascular treatment with successful maternal and fetal outcome [11-12,14]. Shahabi et al. performed this treatment after emergency cesarean delivery in a patient at 38 weeks of pregnancy [12]. It should also be noted that recurrence of an aneurysm following coiling can occur in 25% to 30% of cases with an average time of 12 months [22]. Moreover, surgical clipping was shown to be superior to endovascular coiling in terms of total occlusion rate, in an international subarachnoid aneurysm trial [23-24].

Neurosurgical considerations generally take precedence over obstetric ones to avoid the two great risks that follow, namely recurrence of hemorrhage and ischemia.

Van Buul BJ et al. reported the effect of general anesthesia in surgical repair for intracranial aneurysm in pregnancy on fetal heart rate (FHR). There was a complete disappearance of FHR variability without decelerations or bradycardia. At 41-gestational week, a healthy girl of 4015 g was born [13].

Subarachnoid hemorrhage in pregnancy can be easily missed due to the rarity of the condition and similarity of symptoms with eclampsia. In fact, the most common differential diagnoses of intracranial hemorrhage during pregnancy include aneurysm, arteriovenous malformation and preeclampsia [25].

First, patients with aneurysmal subarachnoid hemorrhage present with a sudden onset of severe headache, with or without alteration of consciousness, and meningeal irritation. Nausea and vomiting are more frequent after the rupture. Hematoma or vasospasm are also responsible for focal neurologic deficits [25]. As for preeclamptic patients, they present with diastolic hypertension, proteinuria, pathological edema and accelerated weight gain [25]. Preeclampsia becomes eclampsia when a grand mal seizure occurs with or without thrombocytopenia, signs of hemolysis or disseminated intravascular coagulation. Seizure may be followed by a temporary coma. The latter can be prolonged in presence of important cerebral edema or intracranial hemorrhage [25]. As such, a high index of suspicion of subarachnoid hemorrhage is important for early diagnosis and prevention of morbidity and mortality.

Lastly, in the absence of categorical recommendations, we stress the role of combined care by neurosurgeons, obstetricians, anesthesiologists and interventional radiologists, on a case to case basis according to the gestational age, the mother’s neurological status and the experience of caregivers.

The authors indicate that written informed consent was

230 Lebanese Medical Journal 2015 • Volume 63 (4)

obtained from the patient for publication of her case report and the accompanying figure. This paper has not been presented in a national medical society and no financial support was attributed to its writing.

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Lebanese Medical Journal 2015 • Volume 63 (4) 231

IN MEMORIAM http://www.lebanesemedicaljournal.org/articles/63-4/inmemoriam1.pdf

Joseph Chucri Moubarak 1931 - 2015 Nous ne trouvons pas les mots pour décrire notre douleur quand nous avons appris le décès de Joseph Moubarak le 20 septembre 2015 à l’âge de 84 ans après une cruelle lutte contre plusieurs tares métaboliques, à laquelle il a fait face avec courage et sérénité.

Avec lui, c’est un des grands noms de la médecine générale libanaise qui disparaît couronnant une carrière médicale tout à fait exceptionnelle.

Né à Rechmaya le 28 mai 1931, Libanais de pure souche, Joseph franchit brillamment toutes les étapes de la carrière médicale universitaire à la faculté de médecine de l’Université SaintJoseph où il acquit son titre de docteur en médecine en 1957. II approfondit ses connaissances entre Bordeaux et Paris pour s’installer à Beyrouth en 1960, entre son cabinet privé à Achafrieh et l’Hôpital Libanais, centre hospitalier universitaire à Geitaoui. Il s’est marié en 1972.

II exerçait sa profession en pleine conscience, spécialement dans sa région, Aley. Il y excellait par ses qualités remarquables de clinicien et d’homme de science. II est resté tout au long de sa carrière attaché à une certaine conception de la médecine, tout en étant très largement ouvert aux progrès auxquels il a contribué.

II a toujours fait l’unanimité autour de lui. Nous pleurons tous cet homme merveilleux auquel j’étais lié par une amitié profonde depuis 1980 (étant interne à Geitaoui), forgée par de nombreuses rencontres régulières, entourés d’amis communs.

La disparition de Joseph Moubarak est une grande perte. Que son épouse Jeanine et ses enfants, Jocelyne et Jean-Paul, ainsi que toute sa famille, reçoivent nos sentiments de sympathie attristée.

Dr Georges SALIBA Président du Comité de formation médicale continue de l’OML

LMJ LEBANESE MEDICAL JOURNAL October-December 2015 Octobre-Décembre Vol. 63 (4) - pp 171-232 JOURNAL MEDICAL LIBANAIS JML

ISSN 0023-9852 Indexed by • Index Medicus • Embase (Excerpta Medica) • Cab Abstracts and Global Health - CABI Publishing

VOLUME 63 No 4

Octobre-Décembre October-December

2015