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All rights reserved. Contents are the property of the authors and/or journals cited. Cover Image from “The New Realization About Cribriform Prostate Cancer�


Kenneth A. Iczkowski, MD

I am a surgical pathologist who specializes in urologic (prostate, bladder, kidney) pathology and who has conducted extramurally funded research. I completed a fellowship at Mayo Clinic Rochester in that discipline, and have been in academic pathology most of my career, joining MCW in 2013. Most of my 170 paper publications—clinical and basic science—are about prostate cancer, which forms irregular, small gland spaces.

Fellow, College of American Pathologists Professor Department of Pathology Medical College of Wisconsin

“The New Realization About Cribriform Prostate Cancer” Iczkowski KA, Paner GP, Van der Kwast T. Advances in Anatomic Pathology. 2018;25(1):31-37. As the cancer becomes more high-grade, it progressively loses the ability to form well-formed gland spaces, resulting in fused, ragged glands or even single cells. Most high-grade cancers form small glands (Fig. 1) but some generate large glands that are called cribriform (Fig. 2), meaning like a sieve, since they contain multiple holes. In 2011, our group published a study of men with cribriform prostate cancer and matched controls that weren't cribriform and discovered that cancers with cribriform glands--in any amount--resulted in increased likelihood of recurrence, as measured by postprostatectomy rise in serum prostate-specific antigen (PSA). Since then, dozens of studies have supported this. We also found that these differences extend to molecular alterations such as PTEN loss. This "New Realization About Cribriform Cancer" has changed the practice of pathologists. Figure 1.

Figure 2.


Lubna N. Chaudhary, MD, MS Assistant Professor of Medicine Associate Program Director, Fellowship Program Division of Hematology & Oncology Medical College of Wisconsin

I joined the Division of Hematology and Oncology in the Department of Medicine at MCW as an Assistant Professor in November 2015 after completing my fellowship in Hem/Onc. I also completed a Master’s Degree in Clinical and Translational Science through CTSI at MCW to further enhance my understanding of research and study designs. My research focus is on breast cancer tumor biology, emergence of tumor therapy resistance and developmental therapeutics. I have authored several peer reviewed publications and have successfully collaborated with senior researchers in my field of work. I recently had my investigator-initiated clinical trial funded by the Rock River Foundation and the MCW Cancer Center. The trial is designed to evaluate tumor responses and biology changes with neoadjuvant endocrine therapy in breast cancer patients.

“Triple-Negative Breast Cancer: Who Should Receive Neoadjuvant Chemotherapy?” Chaudhary LN, Wilkinson KH, Kong A. Surgical Oncology Clinics of North America. 2018;27(1):141-153. This review article highlighted the treatment approaches and recommendations for triple negative breast cancer (TNBC), which is an aggressive type of breast cancer with a high risk of distant recurrence. Adjuvant and neoadjuvant chemotherapy approaches are equivalent in terms of disease free and overall survival benefit. Chemotherapy is used to decrease risk of distant recurrence in TNBC. Benefits of neoadjuvant chemotherapy (chemotherapy before surgery) include downsizing large tumors to increase the probability of breast conservation, assessing clinical and pathological tumor responses, providing an opportunity to change treatment in non-responders, conducting clinical trials where pathological complete response (pCR) is a surrogate for long term outcomes, assessing biomarkers and drug development. All patients with triple negative disease who are candidates for systemic chemotherapy should be considered for treatment in the neoadjuvant setting. Table 1. Selected randomized controlled trials of neoadjuvant chemotherapy in breast cancer Study/year GeparDuo/2005

Tumor size T2-T3

Treatment AC-Doc vs ADoc

No. of pts 913

pCR(%) 14.3% vs 7% (p< 0.001)

PCR in TNBC (%) 22.8% (p=0.0001)

Gepar/Trio/2010 GeparQuattro/2010 PREPARE/2011

T2-T4 T1-T4 T2-T4

TAC EC-T ddE-ddT-CMF vs EC-T

2072 1421 733

20.5% 22.3% 18.7% vs 13.2 (p=0.04)

38.9% (p=0.0015) 17.6% 44.6% vs 30.4% (p=0.12)

1-SPY 1/2012 EORTC 10994/2014 NATT 2016

≥ 3cm T2-T4 T2-T4

AC-T* FEC-T vs Doc-EDoc TAC vs TC

221 1289 96

27% 35% 18% 31% 17.6 vs 6.8%, p=0.11 15.4% vs 4.3% (p=0.35)

AC= Doxorubicin/cyclophosphamide, Doc= Docetaxel, TAC= Docetaxel/doxorubicin/cyclophosphamide, E= epirubicin, dd= dose-dense, CMF= cyclophosphamide/methotrexate/5-flourouracil. *95% patients received a taxane after AC.


I am an Assistant Professor in the Department of Pathology at Medical College of Wisconsin. My clinical responsibilities include Gastrointestinal, Liver and Pancreatic pathology. My research interests includes Autoimmune hepatitis, Appendicular mucinous neoplasms and Colorectal cancer carcinogenesis.

Mamta Pant, MD Assistant Professor Department of Pathology Medical College of Wisconsin

â&#x20AC;&#x153;Cholesteryl Ester Storage Disease: An Underdiagnosed Cause of Cirrhosis in Adultsâ&#x20AC;? Pant M, Oshima K. Annals of Diagnostic Pathology. 2017;31:66-70. Cholesteryl Ester Storage Disease (CESD) is a rare multisystem autosomal recessive lysosomal storage disorder that can manifest anytime from infancy to adulthood. One of the prominent presentations is unexplained hepatomegaly with elevated transaminases, microvesicular steatosis, liver fibrosis and or cirrhosis. Low awareness of this condition among physicians often results in misdiagnosis as non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis or cryptogenic cirrhosis. Now a recombinant enzyme replacement therapy for CESD is available that has shown promising results of altering the natural course of the disease and limit disease related morbidity and mortality. This makes it even more important that clinicians be familiar with this entity, especially in cases with differential diagnosis of NAFLD or cryptogenic cirrhosis. Images of Cholesteryl Ester Storage Disease


David A. Nelson, PhD, MS Associate Professor Department of Family & Community Medicine Medical College of Wisconsin

I am an Associate Professor of Family & Community Medicine at MCW and the Center for Healthy Communities. I earned my bachelor’s degree in Teaching and Exercise Science at the University of Illinois, Champaign Urbana. I have master’s degrees from the University of Northern Colorado and MCW in Counseling and Epidemiology, respectively. My doctorate in Adult Education is from the University of Tennessee, Knoxville. I completed my post doctorate at MCW in the area of Community-Based Participatory Research. My research interests are varied but focus on either individual or community factors that influence wellness, physical activity and obesity. I’m especially interested in working with populations that live on the margins of society.

“Grant Writing: Moving from Generating Ideas to Applying to Grants that Matter” Nelson D, Ruffalo L. International Journal of Psychiatry in Medicine. 2017;52(3):236-244. Grant writing provides one vehicle to express the narrative and provide a means to fund research and programs within clinic-based and community settings. This paper describes a four- step inquiry process to guide healthcare professionals with varying degrees of clinical and scholarship interests through the grant writing process. They include: 1) Why write grants (Motivations) 2) What is the area of focus? (Interests), 3) Whom should be on the project? (Partnerships), 4) What needs to happen next to move the idea forward? (Actions) The complexity of psychosocial issues means that behavioral science is well suited to develop both hypotheses driven and phenomenological research to understand bio-psycho-social health issues. Figure 1. Steps to identify interests and motivations to write grants among stakeholders Grant Ideas 1. 2. 3. 4.

Personal Interests and Motivations

Clinic Interests and Motivations

Community Interests and Motivations


Rana M. Higgins, MD

I am an Assistant Professor of Surgery in the Division of Minimally Invasive General and Bariatric Surgery. Within this, I specialize in foregut, hernia, bariatric and robotic surgery. My research specialty focuses on clinical quality outcomes and surgical education within the field of minimally invasive general surgery.

Assistant Professor Minimally Invasive and Bariatric Surgery Department of Surgery Medical College of Wisconsin

â&#x20AC;&#x153;Pre-Existing Mesh at the Hiatus in Revisional Surgery Does Not Result in Increased Morbidity: A Case-Control Evaluationâ&#x20AC;? Higgins RM, Schumm M, Bosler ME, Gould JC. Journal of Laparoendoscopic and Advanced Surgical Techniques Part A. 2017;27(10):997-1001. This study sought to determine the impact of pre-existing hiatal mesh on the morbidity of revisional surgery for failed fundoplication. We performed a retrospective chart review of a prospectively collected database of patients who underwent prior revisional antireflux surgery at our institution. These patients were matched to randomly selected control patients who underwent revisional surgery without hiatal mesh. From our results, we found no statistically significant difference in 30-day morbidity, readmission, operative time, and length of hospital stay between patients with or without previous hiatal mesh. There was also no difference in 30-day morbidity in patients who had biologic or synthetic hiatal mesh. This study highlights that in the hands of experienced surgeons, mesh at the hiatus does not seem to have an impact on morbidity or operative time. Table 2. Perioperative outcomes in patients with and without prior mesh at the hiatus. Prior Mesh (n=14)

Without mesh (n=27)

p-value

30-day readmission

4 (28.6%)

7 (25.9%)

1.00

30-day morbidity

4 (28.6%)

10 (37%)

0.73

Intraoperative perforation

1 (7.1%)

0

0.34

Mesh placed at revisional operation

9 (64.3%)

7 (25.9%)

0.02

Operative time

227.5 minutes

247.7 minutes

0.59

Length of stay

2.92 days

4.96 days

0.23


“Modulators of Enterococcus faecalis Cell Envelope Integrity and Antimicrobial Resistance Influence Stable Colonization of the Mammalian Gastrointestinal Tract” Banla IL, Kommineni S, Hayward M, et al. Infection and Immunity. 2017;86(1):e00381-17. Enterococci are major causes of hospital acquired infections. Intestinal colonization is key to the pathogenesis of enterococci and therefore represents a potential therapeutic target. The present work found IreK, a conserved enterococcal protein and determinant of antimicrobial resistance, to be required for intestinal colonization by E. faecalis. In addition, we identified two conserved and previously uncharacterized enterococcal proteins that function antagonistically to IreK and interfere with GIT colonization. As components of the core enterococcal genome, these three proteins could therefore be exploited in the design of novel therapies aimed at disrupting enterococcal colonization of the GIT.

Ismael Banla Graduate Student, 6th Year MSTP Nita Salzman Lab Department of Microbiology & Immunology

Salvatore Molino, PhD Postdoctoral Fellow for Jeffrey A. Medin, PhD Department of Pediatrics Postdoctoral Industry Consultants

“Sphingolipid Pathway Enzymes Modulate Cell Fate and Immune Responses” Molino S, Tate E, McKillop WM, Medin JA. Immunotherapy. 2017;9(14):1185-1198. We reviewed the role of sphingolipid pathway enzymes in cancer, and in acquired resistance to therapy. The use of inhibitors and gene silencing approaches targeting these pathways was also explored. Finally, we elaborated on the role of the sphingolipid pathway enzymes in the tumor microenvironment and their effect on immune cell function. As enzymes involved in sphingolipid synthesis or catabolism are altered in cancer cells, we may be able to target these enzymes to improve therapeutic treatment strategies.


“Recent Developments in the Probes and Assays for Measurement of the Activity of NADPH Oxidases” Zielonka J, Hardy M, Michalski R, et al. Cell Biochemistry and Biophysics. 2017;75(3-4):335349. NADPH oxidases are a family of enzymes capable of transferring electrons from NADPH to molecular oxygen to produce reactive oxygen species. Increased activity of NADPH oxidases has been implicated in various pathologies, including cardiovascular disease, neurological dysfunction, and cancer. In this review paper, we describe the development of new, stateof-the-art assays for measuring the activity of NADPH oxidases enabling the highthroughput screening for NADPH oxidase inhibitors. This work is a result of more than 10 years of research on the rigorous methods to assay superoxide radical anion and hydrogen peroxide, using fluorescence, EPR and HPLC techniques.

Jacek Zielonka, PhD, DSc Research Director Free Radical Research Center

Nikolai Mickevicius, PhD Research Scientist I Department of Radiation Oncology

“Simultaneous Orthogonal Plane Imaging” Mickevicius NJ, Paulson ES. Magnetic Resonance in Medicine. 2017;78(5):1700-1710. For abdominal and thoracic tumors, precisely delivering radiation in the presence of respiratory motion can be quite difficult. During MRI-guided radiation therapy, images of “slices” of anatomy can be rapidly acquired to make a “movie” of the motion of the tumor. This work aimed to develop and validate a novel MRI method to obtaining movies of orthogonal slices at the same time to improve tumor localization. The resulting technique is faster and more accurate than conventional imaging methods used to acquire the orthogonal slices separately.


“Increasing Convex Order on Generalized Aggregations of Stochastically Arrangement Increasing (SAI) Random Variables with Applications” Pan X, Li X. Journal of Applied Probability. 2017;54(3):685-700.

This paper investigated general aggregation of stochastically arrangement increasing random variables, including both the generalized linear combination and the standard aggregation as special cases. In terms of monotonicity, supermodularity and convexity of the kernel function, we developed several sufficient conditions for the increasing convex order of the new results on the generalized aggregations. We presented some applications in reliability and risk management as well.

Xiaoqing Pan, PhD AHA SFRN Postdoctoral Fellow Department of Physiology

Katie Schultz, PhD Research Scientist I Department of Biophysics

“High-Pressure EPR Spectroscopy Studies of the E. coli Lipopolysaccharide Transport Proteins LptA and LptC” Schultz KM, Klug CS. Applied Magnetic Resonance. 2017;48(11-12): 1341-1353. We determined the effect of pressure on the essential periplasmic lipopolysaccharide (LPS) transport protein from Escherichia coli, LptA, and one of its binding partners, LptC. LptA unfolds under pressure and is not appreciably stabilized upon LPS binding. LptC adopts an altered, likely monomeric, folded conformation under pressure with only its C-terminus unraveling. The pressure-induced changes likely correlate with functional changes associated with binding and transport of LPS.


Medical College of Wisconsin Office of Research 8701 W Watertown Plank Road Milwaukee, WI 53226-0509 mcw.edu/office-of-research.htm

Medical College of Wisconsin Research Publication Series: April 2018  

Medical College of Wisconsin Research Publication Series: April 2018

Medical College of Wisconsin Research Publication Series: April 2018  

Medical College of Wisconsin Research Publication Series: April 2018

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