13 th Biennial International Chest Conference 2018 Pakistan

OFFICIAL SPECIAL SUPPLEMENT

Mr. Pervez Khattak

Chief Minister Khyber Pakhtunkhwa I feel honoured in welcoming you on the occasion of 13th Biennial International Conference 22nd to 25th March 2018 on “Lung Health, Tuberculosis Critical Care” with the theme of “Breathe Easy, Life Easy” organized by Pakistan Chest Society Center with the Provincial Chapter KP of PCS. Hopefully this is going to be a grand academic occasion and many eminent Chest Physicians, thoracic Surgeon and Family Physicians from with in the Country and abroad are expecting to participate and share their experiences, ideas and research work with one another. The menace of Tuberculosis, Drug Resistant Tuberculosis, Tobacco epidemics, Tobacco related Clinical and Public Health issues, smoking hazards, COPD, Lung Cancer, Environmental pollution, Asthma, Continued on Page 2, Col-2

MRP Rs.100.00

Professor Arshad Javaid Chairman

Organizing Committee President of Chest Society Pakistan It gives me immense pleasure to welcome you to the Serena Islamabad on the occasion of 13th International Biennial conference form 22nd to 25th March 2018 with the theme of “Breath Easy Life Easy” organized by Pakistan Chest Society Center. This conference, as per tradition of PCS was supposed to be held at the provincial capital Peshawar but due to the less accommodation at the PC Peshawar because a large no of International Delegates are expected to participate, The venue has been shifted to Serena Islamabad.

I feel honored to be the President of Pakistan Chest Society today, because from the Humble start just 24 years ago it has now become a large, sole well organized and the representative body of the chest physicians of Pakistan.

Continued on Page 2, Col-2

Dr. Saadia Ashraf

Organizing Secretary Chestcon 2018 Dear Colleagues, Guest and Friends.

It gives me immense pleasure to invite and welcome you to the Beautiful valley of Islamabad, the Federal Capital of Pakistan, on the occasion of 13th Biennial International Chest Conference from 22nd to 25th March 2018 organized

by Pakistan Chest Society. The Pakistan Chest Society is a prestigious body comprising of highly qualified and dedicated Chest Disease Specialists, both physicians and surgeons from all over Pakistan as well as our colleagues working in renowned institutions abroad. It is an honor for me to be the General Secretary Pakistan Chest Society for the period of 2016 to 2018, with the help of my dedicated team members we were able to launch Chestcon 2018 website and Continued on Page 2, Col-2

02 HEALTH NEWS

Last but not the least I am thankful to the print and electronic media Urdu and English both for their sincere cooperation for commemorating different days and events by the Pakistan Chest Society central and provincial levels.

Dr. Mukhtiar Zaman

Chairman Scientific Committee I am honored to be the Chairman of the Scientific Committee of Pakistan Chest Society 13th Biennial Conference 2225th March 2018. Together with the great efforts from our President Prof Dr Arshad Javiad and the Secretary Organizing Committee Dr. Saadia Ashraf the committee has organized a comprehensive scientific curriculum including a wide variety of Post Graduate courses, hands on sessions, state of the art lectures by the top national and international experts, update presentations, postgraduate courses, workshops, panel discussions, interactive sessions, and research abstract presentations for the greater learning experience of all grades of pulmonary specialists and fellowship trainees. The historic city of Islamabad offers a perfect opportunity to enjoy social and-cultural ambience and some great site seeing of natural beauty. Combined with cutting edge scientific program and wonderful opportunities of meeting experts and friends, exchanging experience and ideas and at the same time enjoying a superbly laid out social events, we expect CHESTCON 2018 Islamabad to be a memorable event. The success of the CHESTCON depends on our dedicated and loyal members, and to those of you who have worked hard with dedication and enthusiasm for their presentations as well as research papers. I would like to extend our gratitude and thanks to all the participants. It’s my pleasure to welcome the new members and request the others to join the membership drive during the conference.

Pakistan Chest Society needs your participation for the joint efforts to improve lung health.

Dr. Taj Muhammad

District TB Control Officer Peshawar Dear colleagues, Guests and Participants, It gives me great pleasure to pen theses few words as the Press Information Secretary of the Pakistan chest society since two decades. Pakistan chest society has emerged as the biggest body of chest Physicians in Pakistan. By the grace of Almighty ALLAH the Chest Society its holding 13th biennial international chest Conference at the beautiful city of Islamabad. It will be a great event of chest Physicians, thoracic surgeons family, physicians, starting from 22nd to 25th March 2018, provides a perfect background for such an August even together with the great efforts of the society President Prof Dr Arshad Javaid ,Secretary Organizing Committee Dr Sadia Ashraf and the working group of conference has arranged a comprehensive providing enjoyable social, culture event and healthy walk seeing the natural beauty of Islamabad in the month of March.

This four days event will be largely attended by Chest Specialist from all over Pakistan and abroad. Many renowned speakers from within the country and abroad are participating in the unprecedented clinical and scientific s session of the conference. It will be a really great event to watch. Waiting for your valuable participation. Pakistan Chest Society also provides healthy atmosphere to the pharmaceutical & non pharmaceutical companies along with the Doctors related to the respiratory field to come together to share ideas and experiences.

Our slogan is “Breath Easy Life Easy” for the people of the country.

CHESTCON season is on. A season of refreshing your academic knowledge, meet and greet your old colleagues, a season of fueling and equipping yourself for rest of the year to upgrade your clinical skills. This year 2018 CHESTCON is a whole package of very important hands on workshops and scientific session and meet the experts programs to upgrade your knowledge and clinical skills followed by traditional grand gala Dinner night, mega entertainment and culture show.

Continued From Page 1, Col-1 Critical Care Medicine, occupational Lung Diseases, although some work and progress has been made in all these areas in the last few years, but a lot need to be done by the Government, Health Department and Pakistan Chest Society.

I am sure this galaxy of glorified and learned professional will provide the leadership to understand the need importance and attention towards future improvement in the field of Pulmonology, Lung Health and Thoracic Medicine.

I strongly feel that the knowledge of Chest Medicine sharing from this International Conference will help not only in academic but also in patients care and preventive strategies.

I congratulate and appreciate the efforts of organizing committee and wish the conference a splendid success.

Neuron Monthly March 2018

and interventional respiratory health care delivery system.

The Pakistan Chest Society is going to play a very pivotal role in this regard and this conference can set milestones for the stake holders to attain it.

Scientific Committee (has worked very hard to develop a comprehensive programmed with some innovations. A code of conduct for pharma has also been devised in order to ensure that the delegates attend the scientific sessions & benefit from the conference as much as possible with minimum possible distraction.

This conference will go a long way in increasing the awareness and point out the problems and look for their remedies. I hope that a select gathering of experts and managers from all over the country and abroad will critically review the various dimensions of the principal topics of deliberations and formulate practicable recommendations to the government for controlling the spread of various respiratory diseases.

I am extremely grateful and welcome you all participating Honorable, guest Doctors and the members of the organizing committee, Mr. Pervez Khattak sponsors for their efforts and support. I wish you a happy, Chief Minister Khyber Pakhtunkhwa comfortable and pleasant stay in the beautiful City of Continued From Page 1, Col-3 update the website of Pakistan Chest Society to share ideas, disseminate knowledge and to stay in touch with each other.

We proudly announce that we are able to have online elections. Our team will be available to update information on the website during CHESTCON 2018, which has been the primary focus and we have tried our best to ensure that it remains under the spotlight, both nationally and internationally, with the objective of promulgating the views of learned speakers regarding lung health. We have launched chestcon 2018 Mobile App (both for ios & android) to keep you all updated about the updated events of the conference.

We have on board a highly skilled group of speakers (international as well as National) who with their valuable experience will inform the health professionals about the advancements in respiratory diseases.

In the end I would acknowledge the efforts and hard work of the Chairman scientific committee and other members of the organizing committee for their untiring endeavors to put together superb scientific program for the participants of the Conference. We look forward to welcoming you at Islamabad in CHESTCON 2018. I am extremely grateful to the participants and pharma colleagues for their support, cooperation and sincere efforts. I wish the conference a great success and hopeful that it would be a memorable learning experience for all of us to ultimately improve the respiratory health for our patients.

Islamabad.

Professor Arshad Javaid Chairman Organizing Committee President Pakistan Chest Society Pakistan

13th PCS BIENNIAL INTERNATIONAL LUNG CONFERENCE Pakistan Chest society is holding its 13th Biennial International Conference from 22nd to 25th March 2018 at Serena Hotel, Islamabad Pakistan. This Conference is arranged by the Pakistan Chest Society Central with the cooperation of provincial Chapter KPK, and it is a great honor for the Society to have Fourth round of the Biennial Conference at this Province by the pioneers of the Society.

The First Biennial Conference was held in KPK in 1994 with its leadership that Society gets new impetus, Di-reaction and dimension, with the passage of time holding its conference at Lahore, Karachi and Quetta after every Two years. A large number of Chest Physicians, Pulmonologist, thoracic Surgeons, Tuberculosis Control Program Experts, from the country and abroad are participating at the event and will present their research scientific papers with the following topics.

Dr Saadia Ashraf Organizing Secretary Chestcon 2018 General Secretary Pakistan Chest Society Center.

Continued From Page 1, Col-2 It has achieved many of its objectives which a society needs in beginning of its establishment and consolidation. We have a constitution, regularly published journal, a website, strong linkages with national and international bodies like NTR, IUATLD, Global Fund, GTZ,WHO and BTS. Successful Biennial conferences and regular elections have taken place in all the provincial capitals by the Provincial Chapters. Pakistan Chest Society in the last 24 years has embarked on academic, research and public awareness activities like development of guidelines for common chest diseases; issues like Tobacco cessation & ethical protocols; conducting nationwide studies like “Prevalence of Primary drug resistance in Pakistan”; and observance of No Tobacco Day, World TB Day, World Asthma Day, World COPD Day, Quite Smoking Day & Environmental Pollution Day, including Seminars, Walk, Radio/ TV Talks and other Public awareness activities.

These were few examples of our progress but we will need a lot more effort to expand our activities further in order to make this society not only the voice of all the chest doctors of this country but also of our patients and all Health Professionals. We need to expand and collaborate our research activities which are the need of time.

The major issues that we face are still the menace of TB, MDRTB, Tobacco epidemic, COPD, Lung Cancer, Environmental pollution and Asthma. Although some progress has been made in all these areas in the last (few years, a lot need to be done both by the government and the profession. We all know that both the will of the government and commitment of the profession are essential for the success. I wonder time has come to move ahead from conventional respiratory care medicine to more advanced, ‘ innovative, evidence based

TOPICS OF THE CONFERENCE:• Obstructive airways diseases.

• Tuberculosis Management, Control, MDR, XDR/HIV • Respiratory Infections.

• Pleural Diseases.

• Diffuse Parenchymal Lung Diseases.

• Interventional Pulmonology.

• Pulmonary Malignancies.

• Paediatric Pulonology.

• Occuptional Lung Diseases • Sleep Related Disorders • Critical Care Medicine.

• Public Health Issues, including enviremental prolusion • Tobacco related Clinical and Public health issues.

• Chest Radiological Pathological-Clinical correlation.

04 HEALTH NEWS

Neuron Monthly March 2018

Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey

Abstract

The diagnosis of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILD) presents significant clinical challenges. To gain insights regarding the diagnostic experience of patients with ILD and to identify potential barriers to a timely and accurate diagnosis, we developed an online questionnaire and conducted a national survey of adults with a self-reported diagnosis of ILD.

Methods

A pre-specified total of 600 subjects were recruited to participate in a 40-question online survey. E-mail invitations containing a link to the survey were sent to 16 427 registered members of the Pulmonary Fibrosis Foundation.

Additionally, an open invitation was posted on an online forum for patients and caregivers (www.inspire.com). The recruitment and screening period was closed once the predefined target number of respondents was reached. Eligible participants were adult U.S. residents with a diagnosis of IPF or a non-IPF ILD.

Results

A total of 600 eligible respondents met the eligibility criteria and completed the survey. Of these, 55% reported ≥ 1 misdiagnosis and 38% reported ≥ 2 misdiagnoses prior to the current diagnosis. The most common misdiagnoses were asthma (13.5%), pneumonia (13.0%), and bronchitis (12.3%). The median time from symptom onset to current diagnosis was 7 months (range, 0–252 months), with 43% of respondents reporting a delay of ≥ 1 year and 19% reporting a delay of ≥ 3 years. Sixty-one percent of respondents underwent at least one invasive diagnostic procedure.

Conclusions

While a minority of patients with ILD will experience an appropriate and expedient diagnosis, the more typical diagnostic experience for individuals with ILD is characterized by considerable delays, frequent misdiagnosis, exposure to costly and invasive diagnostic procedures, and substantial use of healthcare resources. These findings suggest a need for physician education, development of clinical practice recommendations, and improved diagnostic tools aimed at improving diagnostic accuracy in patients with ILD.

Background

Interstitial lung disease (ILD) encompasses a broad and diverse group of diffuse parenchymal lung disorders that are characterized by alveolar inflammation, fibrosis, and other cellular changes. Of the more than 150 recognized ILDs, idiopathic pulmonary fibrosis (IPF) is among the most common and the most lethal . The clinical course is characterized by progressive exertional dyspnea and a decline in pulmonary function that severely limits routine physical activity . Two recently approved therapies have been shown to attenuate the decline in pulmonary function [4, 5]; however, neither agent is a cure and neither agent improves lung function, symptoms, or quality of life. Timely and accurate diagnosis could potentially improve outcomes by permitting earlier initiation of antifibrotic therapy, avoiding

exposure to harmful or ineffective treatments, and improving access to important treatments that improve quality of life, such as supplemental oxygen and pulmonary rehabilitation .

The diagnosis of IPF is challenging for even the most experienced clinicians. Accurate diagnosis requires careful exclusion of alternative etiologies and skillful integration of findings from clinical, radiologic, and pathologic exams .

Current diagnostic guidelines define characteristic radiologic and histopathologic features that suggest a diagnosis of IPF,

however, high resolution computed tomography (HRCT) considerable progress in the understanding of IPF and other scans and lung biopsies frequently exhibit mixed or discordant ILDs, these findings suggest a dichotomy in the diagnostic experience, with some patients receiving timely and accurate diagnoses, but a much larger proportion of patients experiencing significant challenges. This latter group the focus of the remaining discussion.

We identified several potential obstacles to a timely and accurate diagnosis. First, the common and non-specific nature of the symptoms often leads patients to dismiss initial symptoms and forego seeking medical attention. From the physician’s perspective, the typical presenting symptoms are more likely to be an indication of a common respiratory or cardiovascular condition, thus potentially leading to delays while such diagnoses are ruled out. Second, due to the diagnostic complexity of IPF and other ILDs, patients often undergo multiple diagnostic tests and procedures, including spirometry, serology, chest x-ray, HRCT, bronchoscopy, exercise tests, and surgical lung biopsy. Delays related to patterns, and findings in patients with IPF and other ILDs scheduling and availability, interpretation of test results, and are often marked by subtle differences . Studies evaluating the need to repeat certain tests and procedures contribute to diagnostic agreement among pulmonologists, radiologists, the lengthy diagnostic process which, in turn, is reported to and pathologists have reported only modest inter-observer impose a considerable burden on patients and their caregivers. agreement, even among expert observers . Additionally, early Indeed, a novel finding of the survey was the observation diagnosis is further complicated by the insidious onset and that 28% of respondents reported that the burden imposed nonspecific nature of the initial symptoms, which patients by the diagnostic process was a factor in their decision to often initially attribute to age or deconditioning, leading to a apply for disability benefits or retire. While further research is necessary to quantify the economic impact in terms of lost delay in seeking medical attention.

To gain insights regarding the diagnostic experience of wages and reduced retirement benefits for both the patient patients with ILD and identify potential barriers to a timely and the primary caregiver, the observation that more than and accurate diagnosis, we developed a structured online one-quarter of respondents reported that the diagnostic questionnaire and conducted a national survey of adults with process was a contributing factor in the decision to retire or file for disability benefits suggests a need for meaningful a self-reported diagnosis of ILD. improvements in diagnostic methods, timeliness, and Methods accuracy. Finally, limited access or proximity to tertiary A structured online survey (The INTENSITY Survey) was care-level expertise was commonly identified as an obstacle developed to collect data on the diagnostic experiences of to obtaining a timely and accurate diagnosis. Notably, 68% of adults with ILD. The quantitative survey comprised 40 For patients with IPF who experience continued progression defined-choice and open-ended questions related to the of disease during the diagnostic process, the consequences following topics: demographics, current and prior diagnoses, of a delay or misdiagnosis are particularly grave. studies initial onset and duration of symptoms, the number and type of physicians consulted, diagnostic tests and procedures, medication history, comorbidities, and quality of life. For the latter, respondents were asked to indicate the degree to which they agreed or disagreed with a series of statements designed to elicit information on the following domains: emotional, physical, financial, personal, and professional.

E-mail invitations containing a link to the online survey were sent to 16 427 registered members of the Pulmonary Fibrosis Foundation, a nonprofit advocacy, education, and research organization dedicated to serving people living with pulmonary fibrosis, their caregivers, and healthcare professionals. Additionally, an open invitation was posted on the website of Inspire™ (www.inspire.com), an online health community and support network designed to connect patients have shown that reductions in forced vital capacity as small and caregivers with common interests. Survey participants as 5–10% over 6 months are associated with a significant were offered the choice of a nominal honorarium in the form increase in the risk of death, and delayed referral to of a $20 gift card or a donation in the equivalent amount to subspecialty care has been shown to confer an increased the Pulmonary Fibrosis Foundation. The recruitment and risk of death in patients with IPF . Additionally, a delay in screening period closed once the pre-defined target of 600 obtaining an accurate diagnosis can delay evaluation for lung eligible respondents completed the survey. transplantation, potentially resulting in the loss of eligibility Eligible participants were U.S. residents with a diagnosis due to advanced age or frailty. Lastly, while the typical of IPF or a non-IPF ILD. At the start of their online presenting symptoms of IPF mimic those of many other participation, prospective participants were informed about common pulmonary and cardiovascular disorders, they the content and purpose of the survey and advised that their are uniquely unresponsive to agents frequently used in the responses would be anonymous. Screening for eligibility was treatment of other ILDs. Misdiagnosis therefore carries the accomplished by means of three online screening questions added risk of exposure to ineffective or harmful therapies. which prospective participants were required to complete In the present survey, one in five respondents with a current prior to gaining access to the research questions. diagnosis of IPF reported prior treatment with a systemic The survey was conducted in full compliance with the corticosteroid a potentially harmful therapy that carries a American Association for Public Opinion Research best strong negative recommendation in the current international practices for research, including the reporting of outcome treatment guidelines. measures . Completed survey results were tabulated by an independent research organization (Outcomes Insights Inc., Conclusions Thousand Oaks, CA). Data are summarized descriptively A nationwide survey of adults with ILD found that the and presented as the median (range) for continuous variables diagnostic process is characterized by considerable delays, and number and percentage of respondents for categorical frequent misdiagnosis, exposure to costly and invasive diagnostic procedures, and substantial use of healthcare variables. resources. Moreover, the experience is associated with Discussion meaningful adverse emotional, physical, social, and We have shown that the diagnostic experience for a professional consequences for patients and their caregivers. substantial percentage of U.S. adults with ILD is characterized These findings underscore the need for physician education, by repeated physician visits, multiple and often repeated practical clinical guidelines, and improved diagnostic tools diagnostic tests, frequent misdiagnosis, exposure to invasive that increase the speed and accuracy of diagnosis and procedures, and treatment with multiple therapies. Despite facilitate early therapeutic intervention.

Neuron Monthly March 2018

06 HEALTH NEWS

Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab

Abstract Objectives

Between December 2015 and February 2017, 38 advanced NSCLC patients were treated in our institution. All the patients were enrolled in our single-institutional, prospective, observational cohort study (UMIN000024414).

IrAEs were defined as having a potential immunological basis that required more frequent monitoring and potential intervention. We divided the patients into two groups (irAEs group or no-irAEs group) and evaluated the objective response rate (ORR) and progression-free survival (PFS).

for both progression-free survival (PFS) and OS compared with platinum-doublet chemotherapy in chemo-naïve NSCLC patients with strongly positive expression of tumor program-death ligand. On the other hand, patients treated with ICIs sometimes experience their unique adverse events, called immune-related adverse events (irAEs). Thyroid dysfunction and gastrointestinal toxicity are common types of irAEs, and they are rarely, but critically manifested in interstitial lung disease, type I diabetes, or hypophysitis.

Recently, its patterns and prevalence have been reported, but several clinical questions about irAEs remain. Regarding the mechanisms of ICIs, the occurrence of irAEs may also reflect antitumor responses. Among melanoma patients treated with ICIs, one report suggested that patients who exhibited irAEs demonstrated higher antitumor responses, but in another report, there was no correlation. Recently, nivolumab and pembrolizumab have been approved for NSCLC in Japan; this correlation has not been fully investigated. Here, we conducted a preliminary analysis to elucidate the correlation between irAEs and efficacy in NSCLC patients treated with nivolumab.

Results

2. Materials and methods

Patients treated with nivolumab often experience its unique adverse events, called immune-related adverse events (irAEs). Regarding the mechanisms of immune-checkpoint inhibitors (ICIs), the occurrence of irAEs may also reflect antitumor responses. Here, we report the clinical correlation between irAEs and efficacy in NSCLC patients treated with nivolumab.

Materials and methods

The median age of the patients was 68.5 years (range 49– 86 years); male/female ratio was 28/10; squamous/nonsquamous cell carcinoma cases were 10/28; performance status was 0–1/2/3, 7/26/5. Among the overall population, ORR was 23.7% and median PFS was 91 days. At the data cutoff, 14 irAEs were observed. The most common irAE was interstitial pneumonia (n = 5). Other irAEs were hypothyroidism (n = 4), hyperthyroidism, hypopituitarism, liver dysfunction, rash, and elevated thyroid stimulating hormone levels (n = 1, each). Patients with irAEs had significantly higher ORRs compared with no-irAE patients (63.6% versus 7.4%, p < 0.01). Similarly, the PFS among irAE patients was longer (median: not reached [95% confidence interval {CI}: 91 days to not applicable]) than no-irAE patients (median 49 days [95% CI: 36–127 days], hazard ratio [HR] 0.10 [95% CI: 0.02–0.37, p < 0.001]). Landmark analysis of patients who achieved PFS ≥60 days demonstrated similar tendencies, but this was not significant (HR 0.28 [95% CI: 0.04–1.46], p = 0.13).

Conclusion

Between December 2015 and February 2017, 38 advanced NSCLC patients were treated with nivolumab (3 mg/kg, every 2 weeks), and were enrolled in our single-institutional, prospective, observational cohort study (UMIN000024414).

Informed consent was obtained from all the patients. In this study, responses were evaluated using the Response Evaluation Criteria for Solid Tumors (RECIST) ver. 1.1. by chest computed tomography and/or brain magnetic resonance imaging (MRI) every 6–8 weeks. PFS was assessed from the first day of treatment with nivolumab to the earliest signs of disease progression or death from any cause. Toxicity was followed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. IrAEs were defined as having a potential immunological basis that required more frequent monitoring and potential intervention with immune suppression and/or endocrine replacement therapy, which was previously mentioned by Weber et al. Based on this, we divided patients into two groups (irAE group and no-irAE group), and subsequently evaluated the overall response rate (ORR) and PFS in each group.

We used the Kaplan–Meier method and log-rank test There was a correlation between irAE and efficacy in NSCLC to evaluate PFS. Landmark analysis ≥60 days was also patients treated with nivolumab. performed to explore the correlation between irAE and PFS in patients other than those who experienced rapid 1. Introduction progression. This time point was determined from PFS data Immune-checkpoint inhibitors (ICIs) have been of no irAE patients. A p-value of <0.05 indicated statistical established as novel standard treatment for various types of significance. All the analyses were performed using JMP malignancies including non-small cell lung cancer (NSCLC). ver.13.0 (SAS Institute Inc, USA).

In pivotal phase III trials, nivolumab, the first-in-class PD-L1 immunohistochemistry was performed at the ICI, demonstrated prolongation of overall survival (OS) Pathology Institute (Toyama, Japan) using formalin-fixed compared with docetaxel in patients with previously treated paraffin-embedded tissue of 4-μm thickness with antiNSCLC . Pembrolizumab, another anti-programmed death-1 human PD-L1 rabbit monoclonal IgG antibody (ab205921, (PD-1) inhibitor, demonstrated outstanding efficacy results clone 28-8 from Abcam, Cambridge, MA). Two independent

lung pathologists evaluated the expression of PD-L1 in tumor cells in accordance with pivotal phase 3 trials. Briefly, tissues including 100 or more tumor cells were regarded as evaluable and cells with any staining intensity on the membrane at expression levels of 0%, 1–49%, and 50% or higher in a section were recorded.

3. Results

At the time of analysis, the median follow-up time was 157.5 days (range 13–437 days), and 62.5% of the patients discontinued nivolumab treatment. The most common reason of discontinuation was disease progression. The median duration of nivolumab administration was 102 days (range 6–287 days). Baseline patient characteristics are listed. The median age was 68.5 years (range 49–86 years); male/female, 28/10; squamous/non-squamous cell carcinoma, 10/28; and Eastern Cooperative Oncology Group performance status of 0–1/2/3, 7/26/5. One-third of the patients were strongly positive for PD-L1 (≥50%). Among overall population, ORR was 23.7% (95% confidence interval (CI): 11.4–40.3%) and median PFS was 91 days (95% CI: 48 days to not reached).

4. Discussion

Although mechanism of irAE was not fully understood, its clinical significance has been noticed. Previously, retrospective reports in melanoma patients treated with PD-1 inhibitors suggested significant correlation between skin AE and efficacy. In patients with NSCLC, recent retrospective study showed that irAE patients had favorable efficacy compared with those without (ORR: 52% versus 28% and landmark analysis of PFS: 9.2 months versus 4.8 months) . Although they include relatively large number of patients (n = 134), they did not mention how to evaluate efficacy and irAE in their multi-institutional retrospective study.

Teraoka et al., conducted a prospective study and they also demonstrated that irAE patients had higher ORR and longer PFS than no-irAE patients (ORR: 37% versus 17% and PFS: 6.4 months versus 1.5 months) [8]. However, characteristics of irAE was slightly different from pivotal trials [1–3]. In their analysis, about 40% of irAE was consisted of pyrexia or rash, and any endocrine AEs was not reported. Because they observed all the participant under administration, pyrexia and rash could be overestimated. In our study, all patients were assessed with pre-defined time schedule and methods described above. As a result, almost irAE was diagnosed from objective data (chest CT or serological tests). Efficacy and irAE profiles in our study were almost consistent with previous report. Furthermore, our data revealed the detailed information about medication and durable response after discontinuation among irAE patientsv Small sample size is the most critical limitation in our analysis. This might affect the result of landmark analysis which failed to demonstrate statistically significant difference. It also hampered to explore the impact of the accumulated number of irAEs or their timing (early versus late) on efficacy. To investigate further, larger cohorts and longer follow-up period are required. In addition, other potential biomarkers to prevent irAE like serum cytokines should be investigated. This may be helpful to consider the optimal treatment duration with ICIs. In conclusion, a correlation between irAEs and efficacy in NSCLC treated with nivolumab monotherapy is suggested.

08 HEALTH NEWS

Neuron Monthly March 2018

Restoring lipid synthesis could reduce lung fibrosis

Pulmonary fibrosis, an ongoing process of scarring that leaves patients chronically short of breath, can progress in severity until the only course of treatment is lung transplant. A new study shows that restoring the lipids that help keep lung tissue flexible and inflated can help slow disease progression in laboratory models of pulmonary fibrosis.

“This is the first paper to show that rather than being a ‘second hit’ to help initiate the disease, blocking lipid synthesis alone with no other insult to the lungs can instigate fibrotic scaring,” said Ross Summer Professor of Medicine at Thomas Jefferson University and physician-researcher in the Jane and Leonard Korman Respiratory Institute.

“This suggests that failure to produce lipids, perhaps because of injury or age-related metabolic changes in lung cells, may be an underappreciated process in development of lung fibrosis, one that may also offer a new and potentially easier path to new treatment of this disease,” said Dr. Romero lead author and NIH-funded investigator on the study published Feb 21st in the American Journal of Respiratory Cell and Molecular Biology. Surfactants, or lipids produced inside the lung tissue, allow airways to inflate and deflate with ease. In

fact, surfactants are often one of the first treatments given to premature infant to help ensure the lungs inflate and develop properly. In addition, all cells within the lung need lipids as signaling molecules and to build their internal and external membranes. But in earlier work Drs. Summer and Romero have shown that when lung tissue is injured by things like viral infection, particulate inhalation, or other insults lung

that this drug alone was capable of instigating lung fibrosis.

In the converse experiment, the group showed that when increasing lipid production in lungs of animals already injured and developing pulmonary fibrosis, lung scarring could be reduced by 70-80 percent.

Lung fibrosis is thought to also come about when the endoplasmic reticulum (ER) in the cells of the lung becomes stressed and can no longer properly fold and unfold proteins.

“We think that the chronic ER stress might ensue because of the inability of cells to produce sufficient lipids to supply their vast amount of ER membranes. Without appropriate lipid stores, the ER cannot properly manufacture or remove damaged proteins out of the cell into lysosomes, as a result, damage accumulates in these lung cells leading to irreversible fibrosis.

Dr. Summer and colleagues are currently working to develop a therapy that could restore lipid production in the lungs of pulmonary fibrosis patients and slow the fibrotic process. As cells eventually stop producing lipids in order to conserve a physician who treats patients with pulmonary fibrosis in a multidisciplinary clinic at Jefferson, the research has a sense energy for other cellular repairs.

In this study, the teams of Drs. Summer and Romero used a of urgency. “I’d like to be able to offer my patients better drug that inhibited lipid production in the lung and showed options for this disease,” he said.

Making milestones against non-small cell lung cancer

Hard to detect in its early stages and hard to treat as it advances, lung cancer is the leading cause of cancer mortality around the world, with an estimated 1.6 million deaths each year. New treatments, however, are bettering the odds for people with non-small cell lung cancer (NSCLC), which makes up about 85 percent of lung cancer cases.

“Progress has been enormous in the past 20 years,” said Roy Herbst, M.D., Ph.D., chief of Medical Oncology at Yale Cancer Center and professor of Medicine and Pharmacology at Yale School of Medicine.

Traditionally, NSCLC has been treated by surgery followed by chemotherapy or radiation or both. “Options for treatments have improved in recent years with the advent of two classes of drugs, molecularly targeted therapies and more recently immunotherapies,” said Herbst, co-lead author on a paper reviewing advances in NSCLC treatment published in the journal Nature. (Co-lead authors include: Daniel Morgensztern, M.D., associate professor of Medical Oncology at Washington University, and Chris Boshoff, senior vice president for Global Product Development for Oncology, Pfizer Inc., and adjunct professor, Yale School of Medicine.)

body’s immune T cells from attacking tumors, by inhibiting a protein called PD-1 on the surface of T cells or its partner protein PD-L1 on tumor cells. Patients whose tumors show high levels of PD-L1 are generally the best candidates to benefit from such immunotherapies.

To date, immune checkpoint blockers work well for about one-fifth of NSCLC patients. “However, we’ve seen that although many tumors express PD-L1, many don’t, and PD-L1 inhibition won’t work for those,” said Herbst. “Even among tumors that have high PD-L1 expression, many don’t have any T cells in the tumor microenvironment, so that doesn’t work either. We need to figure out how we’re going to ‘warm up’ tumors and make them more sensitive to these different therapies.” Additionally, as with targeted therapies, most tumors become resistant to immunotherapies over time.

Novel immunotherapies addressing other components of the immune system will be critical to overcome these challenges, Herbst suggested. Another key will be to combine immunotherapies, or to pair them up with chemotherapy, targeted therapy, medicines that suppress the growth of blood vessels, or other forms of cancer treatments.

Molecularly targeted drugs aim to attack tumor cells that have mutated genes such as EGFR that can drive cancer. The Food & Drug Administration (FDA) gave its first approval for an EGFR inhibitor for NSCLC in 2004, and about a quarter of NSCLC patients now can be treated with various targeted drugs. Research is underway at Yale and many other Institutions to discover additional molecular targets.

However, patients eventually develop resistance to these medicines, Herbst said.

“We need to move the personalized approach that we’ve used for targeted therapy to immunotherapy, matching the right patient to the right medicine at the right time,” Herbst emphasized.

Other research efforts are creating new approaches to detect lung cancer and track it as it evolves in each patient. Last year, the FDA approved a “liquid biopsy” test for NSCLC that can find certain types of EGFR mutations by sequencing fragments of tumor DNA that circulate in the blood. More advanced tests of this “circulating free tumor DNA” are being developed to support individualized lung cancer treatment.

“A liquid biopsy lets you see things in real time, and you can do multiple biopsies because they are less invasive for the patient,” Herbst said. “Liquid biopsies are not quite as sensitive as a tumor biopsy, but some evidence suggests that they might actually give a more realistic view of the disease throughout the entire body.”

Clinical research in NSCLC is being accelerated by innovative large clinical studies, such as the Lung Master Protocol (Lung-MAP) trial, which has enrolled more than 1400 patients to test a host of targeted drug candidates among previously treated patients with squamous cell lung cancer.

Lung-MAP is now extending its scope to test combinations of targeted medicines and immunotherapies.

Herbst directs Yale’s Specialized Program of Research Excellence (SPORE) for lung cancer, one of three lung cancer SPOREs funded by the National Cancer Institute. The program brings together experts in oncology, immunobiology, pharmacology, molecular biology, pathology, epidemiology and addiction science to attack the disease. “We aim to bring results from the lab to the clinic and back again,” he said.

“Overall, we’re seeing unprecedented benefits for people with NSCLC, but it’s a very tough disease,” Herbst summed up.

“We’re still only helping 30 or 35 percent of patients. Our research has to remain novel and innovative. We still have a lot of work to do.”

Another wave of treatment options began to arrive in 2015 when the FDA approved the first “immune checkpoint blocker” for patients with advanced NSCLC. These immunotherapies clog up mechanisms that prevent the

New study offers insights on genetic indicators of COPD risk Cigarette smoking has long been the most common cause of COPD, but not all smokers develop the condition, and many non-smokers do. Why that is so has never been fully understood, but a team of researchers now have a clue after discovering that genetically programmed airway tree variation is linked to a higher prevalence of COPD among older adults. “This work raises many interesting questions for researchers. Understanding precisely why these genes influence the development of COPD may lead to entirely new and more effective ways of preventing or treating this disease,” said James Kiley, M.D., director of the NHLBI Division of Lung Diseases. “This novel study suggests that a CT scan, which is widely available, can be used to measure airway structure and predict who is at higher risk for smoke-induced lung injury.” COPD, a progressive disease that makes it hard to breathe, is the fourth leading cause of death in the United States. An estimated 16 million people are currently diagnosed with COPD, and millions more are

believed to have the condition.Until recently, researchers believed that COPD developed later in life as a result of prolonged exposure to cigarette smoke or air pollution, which accelerated the decline in lung function. However, recent studies have shown that many older adults with COPD had low lung function early in life and experienced the normal lung function decline associated with aging, not an accelerated decline. “In the current study, we found that central airway branches of the lungs, which are believed to form early in life, do not follow the textbook pattern in one quarter of the adult population and these non-textbook variations in airway branches are associated with higher COPD prevalence among older adults,” said the study’s first author Benjamin M. Smith, M.D. M.S., assistant professor at Columbia University Medical Center. “Interestingly, one of the airway branch variants was associated with COPD among smokers and non-smokers. The other was associated with COPD, but only among smokers.”

These airway tree variations are identifiable on low-dose screening lung CT scans, which are currently indicated clinically for lung cancer screening in older patients with a history of heavy smoking in the prior 15 years. Before CT scans are used outside of this group for the identification of airway variants in clinical practice, the study authors say more research will be needed to confirm that preventive or therapeutic interventions based on the presence of airway tree variations can improve patients’ outcomes.In the meantime, the researchers say they will be investigating another important finding -- this one around family history.

Their study identified a common airway branch variation that occurs within families and is associated with COPD among non-smokers. Smith said while other developmental events that occur within families may be involved, his research team is looking into whether there is a genetic basis for this variant. “If proven,” he said, “this would represent a novel mechanism of COPD among non-smokers.”

10 HEALTH NEWS

Pulmonary Sarcoidosis

Author: Dr. Taj Muhammad

(District TB Control Office, Peshawar, Pakistan) Definition:Sarcoidosis is an inflammatory disease that affects multiple organs in the body, but mostly the lungs and lymph glands.

In people with sarcoidosis, abnormal masses or nodules (called granulomas) consisting of inflamed tissues form in certain organs of the body. These granulomas may alter the normal structure and possibly the function of the affected organ(s). Sarcoidosis most often occurs between 20 and 40 years of age, with women being diagnosed more frequently than men. The exact cause of sarcoidosis is not known. It may be a type of autoimmune disease associated with an abnormal immune response, but what triggers this response is uncertain.

The cause of sarcoidosis is unknown , but it is considered to be an autoimmune disease that affects 2 in every 10,000 people in the UK. It is thought that the immune system goes into overdrive ; white blood cells that would normally be released to isolate and destroy foreign bodies clumps together in various organs for no apparent reason leading to inflamation affecting each person differently. The most common organ affected is the lungs, occurring in around 90% of patients.

It has an active and a nonactive phase, in active phase the granulomas firm and grow. In the Non-active phase the inflammation goes down and the granulomas stay the same size or shrink but the scar may remain and cause symptoms.

Treatment usually does not affect scar tissue. There is no known way to prevent sarcoidosis. Sarcoidosis was identified in the late 1860s.

Signs and Symptoms of Sarcoidosis:The symptoms of sarcoidosis can vary greatly, depending on which organs are involved. Most patients initially complaining of a persistent dry cough, wheezing, pain in the middle of the chest when you breath deeply or cough (rare), fatigue, and shortness of breath. It can involve skin causing erythema Nodosum, lupuspernio, eyes, heart, joints, liver, parotid, salivary gland, nervous system and pituitary gland. Other symptoms may include: • Enlarged and tender lymph glands in the neck, inguinal and axillary .

• Enlarged lymph glands in the chest and around the lungs.

• Tender reddish bumps or patches on the skin.

• Red and teary eyes or blurred vision.

• Swollen and painful joints.

• Hoarseness of voice.

• Pain in the hands, feet, or other bony areas due to the formation of cysts (an abnormal sac-like growth) in bones.

• Kidney stone formation.

• Enlarged liver.

• Development of arrhythmias, pericarditis or heart failure.

• Nervous system effects, including hearing loss, meningitis, seizures, or psychiatric disorders (for example, dementia, depression, psychosis).

In some people, symptoms may begin suddenly and/or severely and subside in a short period of time.

Diagnoses:• Clinical/Medical History.

• Medical Examination.

• Chest X-ray for pulmonary infiltrates or Hilar lymphadenopathy.

• Negative Response to the Tuberculin test.

• The kveim Test positive in most cases but takes upto 6 weeks to become positive.

• The Serum Calcium/Urine Calcium.

• The sputum Examination direct microscopy and culture for AFB and FUNGI. • Serum Globulins.

• Peripheral Blood examination.

• X-Ray of the Hands and Feets.

• HRCT scan (high resolution CT) to provide an even more detailed look at the lungs and lymph nodes than provided by a chest X-ray.

• Pulmonary function tests.

• Bronchoscopy to inspect the bronchial tree and biopsy to look for granulomas and to obtain material to rule out other infections.

• Biopsy of the lymph node and tissue for the description of sarcoid tissue.

Differential Diagnosis of Pulmonary Sarcodosis:• Tuberculosis • Lymphoma • Leukaemia • Metastatic Malignancy • Leprosy • Beryllium Disease • Cat Scratch Disease (Cat Scratch Fever) • Enlarged Pulmonary Arteries • Extrinsic Allergic Alveolitis • Fibrosing Alveolitis • Lymphatic Carcinomatosis • Miliary Tuberculosis • Pneumoconiosis • Alveolar Cell Carcinoma • Eosinophilic Granuloma • Honeycum Lung Treatment:There is no known curative treatment for the sarcoidosis, but the disease may get better on its own over time. Many people with sarcoidosis have mild symptoms and do not require any treatment. The purpose of the Treatment is to reduce symptoms and to maintain function of the affected organs.

Treatments generally fall into two categories : 1. Maintenance of good health practices.

• Regular medical check-ups by the Doctors.

• Well-balanced diet with fresh fruits and vegetables.

• Taking of enough fluids every day.

• Regular exercise and managing body weight.

• Quitting smoking

2. Drug treatment.

Drug treatments are used to relieve symptoms and reduce the inflammation of the affected tissues. The oral corticosteroid prednisone is the most commonly used treatment. Fatigue and persistent cough are usually improved with steroid therapy . Corticosteroids are indicated when vital organs are involved or if there is systemic upset and to prevent severe disability, irreversible fibroses.

In Pulmonary sarcoidosis treatment is indicated when there is progressive involment of the lung parenchyma as shown by the progression of the radiographic changes. Treatment with Corticosteroid is also indicated for the Eye involment , persistent hyper Calciuria, CNS, Myocardial, Symptomatic muscles sarcoidosis, persistent or recurreng Erythema, Nodosoum with important systemic upset, parotid and lachrymal gland enlargement. Minimum duration of treatment is 3-6months. Other medicines used as suppressive effect on sarcoidosis are oxyphenbutazone, chloroqine, chlorambucil, methotrexate And azathioprine.

Neuron Monthly March 2018

Private organisations engaged to improve TB detection

4Opc cases of this lung disease in KP are undetected

By Ashfaq Yusufzai

P

ESHAWAR: The health department has enlisted the support of private organisations to improve the TB detection rate in the province. The move is part of the department’s strategy to take the TB detection rate to 80 per cent by 2020 and 90 per cent by 2025 in the province, where 40 per cent of the cases of the contagious lung disease remain undetected every year.

“At present, we diagnose and treat 45,000 patients in the province every year, which make 60 per cent of the actual total cases, as the World Health Organization insists there are 270 TB patients in every 100,00() people,” project director of the TB Control Programme Dr Maqcood All Khan told Dawn.

According to him, TB 1a1 lent s in the province actually total 70,000 suggesting that the health department has to do a lot to reach the undetected patients. With the TB cure rate being almost 100 per cent, 97 per cent of patients get free treatment for six months and the rest for eight months. Dr. Maqsood said the undetected cases had turned out to be a daunting challenge for the department, which was banking on the private sector to find all patients and give them treatment in line with the WHO’s guidelines.

The Global fund has been supporting the anti-TB programme by providing technical support as well as medicines to patients. Of late, the government involved private clinics and declared TB as notifiable disease but the detection rate has yet to show signs of improvement. Thereafter, the department made an agreement with the Indus Health Network (IHN), which began mobile service in five districts, including Nowshera, Karak, Swabi, Lakki Marwat and Dera Ismail Khari, to ensure that all infected population is tested and treated.

Cricketer Younas Khan is the brand ambassador of the IHF under which the ‘Aao TB Metao’initiative has been launched in the designated districts. Four trucks equipped with digital X-ray machines and equipment for sputum tests carry out investigation of the suspected population in remote areas.

The IHN, which is one of the three recipients of the GF aid, was invited by the KP TB Control Programme to cope with the missed patients. It plans to extend services to other districts in future. It organized camps for TB screening.

The Mercy Corps, another recipient of the CF funds, is supporting the health departments through a local NCO, Association for Cornmunity development (ACD), in 13 districts, where ii will work with private practitioners to register the maximum number of TB patients. Dr Maqsood said the establishment of a reference laboratory in Peshawar had played a significant part in the training of the relevant staff members of 230 laboratories functioning in government hospitals across the province.

He said every district had a focal person for TB, who maintained liaison with the provincial office. The project director said the lab having the services of the people with MPhil and PhD degrees generated electronic reports as part of external quality assurance of services. “The enhanced monitoring, training and surveillance are the core strategies of the programme. Also, we have engaged three leprosy centres in Nowshera, Swabi and Kohistan to improve TB detection,” he said. Dr Maqsood said the programme had put in a place a mechanism to ensure the uninterrupted drug Supply to patients. “We also give financial assistance to a patient along with a relative as transport cost,” he said adding that special committees were formed to monitor and evaluate drugs and do research to run the programme along scientific lines and ensure the detection of more patients.

Dr Maqsood said the Khyber Medical University’s students doing MPhil and PhD were working in the reference lab, which had records of 500,000 patients.

“We want to improve the TB detection rate as one patient can infect 10 to 15 persons a year,” he said.

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