Medical College of Wisconsin Research Publication Series: December 2017 by Medical College of Wisconsin

Medical College of Wisconsin

Research Publication Series December 2017

Medical College of Wisconsin Research Publication Series:

December 2017 4

Mary Eapen, MBBS, MS “Allele-level HLA Matching for Umbilical Cord Blood Transplantation for Non-malignant Diseases in Children: A Retrospective Analysis”

Melinda Stolley, PhD

Dave R. Lal, MD, MPH

“Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivors”

“Perioperative Management and Outcomes of Esophageal Atresia and Tracheoesophageal Fistula”

Max Wohlauer, MD “Preoperative Hypoalbuminemia is a Risk Factor for Early and Late Mortality in Patients Undergoing Endovascular Juxtarenal and Thoracoabdominal Aortic Aneurysm Repair”

Alexander Helfand, MS

Shira Ronen, MD

“Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase Contribute to Operant Sensation Seeking in Mice”

“PTEN loss and p27 loss differ among morphologic patterns of prostate cancer, including cribriform”

Tina L. Samuels, MS “Association of Gel-Forming Mucins and Aquaporin Gene Expression With Hearing Loss, Effusion Viscosity, and Inflammation in Otitis Media With Effusion”

Chen Chen, MD, PhD

Samantha Sison, BS

10 11 11

“When Escherichia Coli Doesn’t Fit the Mold: A Pertussis-like Toxin with Altered Specificity”

“Astrocyte-produced miR-146a as a Mediator of Motor Neuron Loss in Spinal Muscular Atrophy”

Eric Segal, MD “Comparing Outcomes of Matched Related Donor and Matched Unrelated Donor Hematopoietic Cell Transplants in Adults With B-Cell Acute Lymphoblastic Leukemia”

Phillip Prior, PhD “Technical Note: Is Bulk Electron Density Assignment Appropriate for MRI-only Based Treatment Planning for Lung Cancer?”

Pan Pan, PhD “Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer”

Alvin Chan & Sean M. Lew, MD

William S. Ragalie, MD & Michael E. Mitchell, MD

“False Localization With Subdural Electroencephalography due to Gyrus Overlap”

I am a Professor in the Division of Hematology-Oncology, Department of Medicine. My research focuses on extending access to hematopoietic cell transplantation, a life-saving treatment for those with malignant and non-malignant hematologic diseases. Through the Center for International Blood and Marrow Transplant Research, I study the effectiveness of utilizing donors other than HLA-matched siblings for hematopoietic cell transplantation. As HLAmatched siblings are available for less than a third of patients who may benefit from transplantation, most transplants utilize alternative donors. My work has identified strategies to improve outcomes after hematopoietic cell transplantation in regards to HLA-mismatched related and HLA-matched or mismatched unrelated donor transplantation including umbilical cord blood.

Mary Eapen, MBBS, MS Professor of Medicine Division of Hematology & Oncology Senior Scientific Director – Research Center for International Blood and Marrow Transplant Research Medical College of Wisconsin

“Allele-level HLA Matching for Umbilical Cord Blood Transplantation for Non-malignant Diseases in Children: A Retrospective Analysis” Eapen M, Wang T, Veys PA, et al. The Lancet. Haematology. 2017;4(7):e325-e333. Present standards for selecting unrelated adult donors for non-malignant diseases transplantations support matching donors and recipients at the allele-level at HLA-A, HLA-B, HLA-C and HLA-DRB1 and for cord blood, less stringent standards with priority for the unit with the highest total nucleated cell dose. Therefore, the importance of allele-level HLA matching at HLA-A, HLA-B, HLA-C and HLA-DRB1 for cord blood transplantation for non-malignant disease was studied (Lancet Haematol 2017; 4:e325-33). Compared to HLA-matched transplantations, survival was lower (Figure 1) and graft failure was higher (Figure 2) for transplantations mismatched at two or more alleles. The median cell dose of cord blood units was 10 x 107/kilogram recipient weight, substantially higher than the generally accepted 4-5 x 107/kilogram for nonmalignant diseases. The data support a change from current practice. As most transplants for non-malignant disease are in children, cell dose is not a barrier and selection should prioritize the best allele-level HLAmatched unit.

Figure 1.

Figure 2.

100

Probability, %

80 60 Matched: 79% 1 allele mismatch: 74%, p=0.40 2 allele mismatch: 71%, p=0.02 3 allele mismatch : 60%, p= 0.001 ≥4 allele mismatch: 50%, p<0.0001

40 20 0 0

3 Years

Melinda Stolley, PhD Professor Department of Medicine Associate Director for Cancer Prevention & Control Medical College of Wisconsin

I am a health psychologist with expertise in developing, implementing and examining the effects of behavioral interventions on patient reported and cancer outcomes. My studies also examine how changes in lifestyle behaviors impact biomarkers that link adipose tissue to cancer. An important aspect of this work is my focus on minority and underserved populations. I have extensive experience adapting traditional cognitive-behavioral interventions to meet the needs of high risk or underserved populations. My intervention efforts span the cancer care continuum from prevention to control, and the developmental continuum from childhood to adulthood.

â&#x20AC;&#x153;Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivorsâ&#x20AC;? Stolley ML, Sheean P, Gerber B, et al. Journal of Clinical Oncology. 2017;35(24):2820-2828. African-American women with breast cancer have higher cancer specific and overall mortality rates. Obesity, which contributes to breast cancer progression and many chronic conditions, is common among AfricanAmerican women. Weight loss interventions among breast cancer survivors positively impact multiple outcomes, yet few target African-Americans. In this community-based study, early stage (I-III) African American breast cancer survivors (AABCS) were randomized to a 6-month interventionist guided (n-125) or self-guided (n=121) weight loss program. Anthropometric, body composition, and behavioral data were collected at baseline, 6 months and 12-months. Mean + SD age and BMI were 57.5 + 10.1 years and 36.1 + 6.2 kg/m2 respectively. Both groups lost weight. However, mean and % weight loss, as well as body composition and behavioral changes were greater in the guided versus self-guided group.

Body Weight 214

Guided

212

Self-Guided

210

Self-Guided:

208

-2.9 lbs (SD= -10.1); -1.3% (SD=3.7)

206 204 202

Guided:

200

-8.0 lbs (SD=-1.3); -3.7% (4.9)

198 Pre-Program

Post-Program

Retention at 6 months: 86%; Retention at 12 months: 84%

Dave R. Lal, MD, MPH Associate Professor of Surgery Children’s Hospital of Wisconsin Medical College of Wisconsin

I attended medical school at Creighton University, followed by my general surgery residency at UW-Madison. I completed a pediatric surgery oncology fellowship at Memorial SloanKettering Cancer Center in New York, followed by an advanced minimally invasive gastrointestinal surgery fellowship at the University of Washington, Seattle and a pediatric surgery fellowship at MCW. I joined the faculty in the Department of Surgery, Division of Pediatric Surgery in 2007. I am currently an Associate Professor of Surgery, an Associate Program Director for the General Surgery Residency Training Program at MCW, and the President-Elect of the Medical Staff at Children’s Hospital of Wisconsin. My clinical and research interests include resident education, pediatric foregut disorders (including achalasia and esophageal atresia) and pediatric oncology.

“Perioperative Management and Outcomes of Esophageal Atresia and Tracheoesophageal Fistula” Lal DR, Gadepalli SK, Downard CD, et al. Journal of Pediatric Surgery. 2017;52(8):1245-1251. Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare congenital anomaly lacking contemporary data detailing patient demographics, medical/surgical management and outcomes. Substantial variation in the care of infants with EA/TEF may affect both short- and long-term outcomes. The purpose of this study was to characterize the demographics, management strategies and outcomes in a contemporary multi-institutional cohort of infants diagnosed with EA/TEF to identify potential areas for standardization of care. A multi-institutional retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals between 2009 and 2014 was performed. Over the 5 year period, 396 cases were identified in the 11 centers (7 ± 5 per center per year). All infants with a diagnosis of EA/TEF made within 30 days of life who had surgical repair of their defect defined as esophageal reconstruction with or without ligation of TEF within the first six months of life were included. Demographic, operative, and outcome data were collected and analyzed to detect associations between variables. Results are shown in Table 5. Contemporary treatment of EA/TEF is characterized by substantial variation in perioperative management and considerable postoperative morbidity and mortality. Future studies are planned to establish best practices and clinical care guidelines for infants with EA/TEF. Table 5. Postoperative Complications and Outcomes

Max Wohlauer, MD Assistant Professor Department of Surgery, Division of Vascular Surgery Cardiovascular Center Medical College of Wisconsin

I am an Assistant Professor of Surgery, Division of Vascular Surgery, at MCW. I received my MD from Albany Medical College, Albany, New York, in 2007. I completed General Surgery residency at University of Colorado in Denver in 2014, including a 2-year NIH Trauma Research Fellowship from 2009-2010. I completed my fellowship in Vascular Surgery at Cleveland Clinic in Cleveland, OH, in 2016. My research focus is exploring the role of platelets in symptomatic peripheral vascular disease and in preoperative frailty screening. My clinical interests include abdominal aortic aneurysm, carotid artery disease, peripheral vascular disease, venous disorders including May-Thurner Syndrome, among others.

“Preoperative Hypoalbuminemia is a Risk Factor for Early and Late Mortality in Patients Undergoing Endovascular Juxtarenal and Thoracoabdominal Aortic Aneurysm Repair” Wohlauer M, Brier C, Kuramochi Y, Eagleton M. Annals of Vascular Surgery. 2017;42:198-204. Nearly half of all operations in the US are currently performed on elderly patients. Frailty is an emerging clinical syndrome in elderly patients which confers high risk for disability and mortality. This is particularly relevant to vascular surgery, where advances in endovascular aneurysm repair allow high-risk patients with complex aortic aneurysms to be treated with a minimally invasive approach. In 1089 consecutive patients, we found that age was only mildly associated with increased mortality (OR 0.08). Severe hypoalbuminemia was associated with significantly increased mortality (OR 2.4) and increased complication rates. In conclusion, patients with hypoalbuminemia have significantly increased mortality risk. Age alone is an unreliable predictor of outcomes. Albumin level is influenced by 2 components of frailty: nutritional intake and inflammation due to chronic disease, which make it a useful part of pre-operative frailty assessment.

Severe hypoalbuminemia (albumin <2.4 g/dL) is associated with increased 30-day mortality. The 30-day mortality rate was more than 3 times higher than the group with normal albumin levels (*P = 0.025, OR: 4.967, 95% CI: 1.385–17.814, normal versus severe). CI, confidence interval; OR, odds ratio.

“Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase Contribute to Operant Sensation Seeking in Mice” Helfand AI, Olsen CM, Hillard CJ. International Journal of Molecular Sciences. 2017;18(8):E1635.

Human evidence and preclinical models support a role for the endocannabinoid system in the execution of motivated or goal-directed behaviors. Operant sensation seeking (OSS) is a task using sensory stimuli to reinforce and maintain operant responding. This study explored the role of endocannabinoid signaling in OSS utilizing cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) knock out(KO) mice. CB1R KO mice exhibited significantly fewer active responses and earned significantly fewer reinforcers than controls. FAAH KO mice exhibited increased active responses and earned more reinforcers than controls in fixed but not progressive ratio schedules. These findings support the role of endocannabinoid signaling in motivated behaviors.

Alexander Helfand, MS MSTP Student Binder Lab Department of Biophysics

Shira Ronen, MD Anatomic and Clinical Pathology Resident PGY-III Department of Pathology

“PTEN loss and p27 loss differ among morphologic patterns of prostate cancer, including cribriform” Ronen S, Abbott DW, Kravtsov O, Abdelkader A, Xu Y, Banerjee A, Iczkowski KA. Human Pathology. 2017;65:85-91. The presence and extent of cribriform pattern of prostate cancer portend recurrence and cancer death. The relative expressions within this morphology of the prognostically adverse loss of PTEN, and the downstream inactivation of cell cycle inhibitor p27/Kip1 had been uncertain. In this study, we examined 52 cases of cribriform cancer by immunohistochemistry for PTEN, p27, and CD44 variant(v)7/8, and a sub-set of 17 cases by chromogenic in situ hybridization using probes for PTEN or CDKN1B(gene for p27). Immunostaining results demonstrated that PTEN loss was significant for fused small acini, cribriformcentral cells, small cribriform acini, and Gleason grade 5 cells in comparison with other acini; p27 loss was significant only for cribriform-peripheral cells and borderline significant for fused small acini in comparison with benign acini; and CD44v7/8 showed expression loss in cribriform-peripheral cells. In conclusion, molecular disparitiese merged between the fused small acini and cribriform patterns of Gleason 4 cancer. PTEN or p27 loss as prognostic factors demands distinct assessment in the varieties of Gleason 4 cancer, and in the biphenotypic peripheral versus central populations in cribriform structure.

“Association of Gel-Forming Mucins and Aquaporin Gene Expression With Hearing Loss, Effusion Viscosity, and Inflammation in Otitis Media With Effusion” Samuels TL, Yan JC, Khampang P, et al. JAMA Otolaryngology – Head & Neck Surgery. 2017;143(8):810-817. Viscous middle ear effusion produced during pediatric otitis media (OM) increases likelihood of surgery, hearing loss and associated developmental delays. This represents the first investigation of molecular correlates of effusion viscosity and hearing loss in an OM population toward the end goal of personalized, targeted therapies to reduce effusion viscosity, facilitate clearance, and prevent disease chronicity and hearing loss in OM patients. Expression of an aquaporin water channel (AQP5) correlated with effusion viscosity, and expression of a specific gel-forming mucin (MUC5B) correlated with effusion viscosity and hearing loss, providing the first evidence of a molecular basis for OM-attributed hearing loss.

Tina L. Samuels, MS Research Associate II Departments of Microbiology & Molecular Genetics and Otolaryngology

Chen Chen, MD, PhD Postdoctoral Fellow Department of Microbiology & Molecular Genetics

“When Escherichia Coli Doesn’t Fit the Mold: A Pertussis-like Toxin with Altered Specificity” Chen C, Barbieri JT. Journal of Biological Chemistry. 2017;292(36): 15159-15160. Bacterial toxins introduce protein modifications such as ADP-ribosylation to manipulate host cell signaling and physiology. Several general mechanisms for toxin function have been established, but the extent to which previously uncharacterized toxins utilize these mechanisms is unknown. A study of an Escherichia coli pertussis-like toxin demonstrates that this protein acts on a known toxin substrate but displays distinct and dual chemoselectivity, suggesting this E. coli pertussis-like toxin may serve as a unique tool to study G-protein signaling in eukaryotic cells.

“Astrocyte-produced miR-146a as a Mediator of Motor Neuron Loss in Spinal Muscular Atrophy” Sison SL, Patitucci TN, Seminary ER, Villalon E, Lorson CL, Ebert AD. Human Molecular Genetics. 2017;26(17):3409-3420. Spinal Muscular Atrophy (SMA) is the leading genetic cause of infant mortality and is caused by the loss of the survival motor neuron-1 (SMN1) gene which leads to motor neuron degeneration. Motor neurons exhibit the most profound loss, however the extrinsic factors that contribute to this loss, such as those arising from astrocytes, are not well understood. Here we identified microRNA-146a (miR-146a) to be significantly upregulated in iPSC-derived astrocytes. Further, we showed that increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas inhibition of miR-146a prevented SMA astrocyte-induced motor neuron loss.

Samantha Sison, BS Laboratory Technologist I, Ebert Lab Department of Cell Biology, Neurobiology & Anatomy

Eric Segal, MD Resident, PGY-2 Diagnostic Radiology Medical College of Wisconsin Affiliated Hospitals

“Comparing Outcomes of Matched Related Donor and Matched Unrelated Donor Hematopoietic Cell Transplants in Adults With B-Cell Acute Lymphoblastic Leukemia” Segal E, Martens M, Wang HL, et al. Cancer. 2017;123(17):3346-3355. This study investigated outcomes of allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia (ALL), comparing transplants from human leukocyte antigen (HLA)-matched related donors with 8/8 and 7/8 HLA-matched unrelated donors. Post-transplant outcomes for 1458 ALL patients from 2000-2011 were analyzed. Recipients of related donor and 8/8 HLA-matched unrelated donor transplants had similar transplantrelated and all-cause mortality. 7/8 HLA-matched unrelated donor transplant was associated with greater risk of transplant-related and all-cause mortality. Unrelated donor transplants had lower relapse risk. We concluded that 8/8 unrelated-donor transplant is a viable alternative to related-donor with similar survival outcomes in adults with ALL.

“Technical Note: Is Bulk Electron Density Assignment Appropriate for MRIonly Based Treatment Planning for Lung Cancer?” Prior P, Chen X, Gore E, Johnstone C, Li XA. Medical Physics. 2017;44(7):3437-3443. MRI-based treatment planning in radiation therapy (RT) is prohibitive, in part, due to the lack of electron density (ED) information within the image. The dosimetric differences between MRI- and CT-based IMRT lung planning were investigated to assess the appropriateness of bulk ED assignment using six representative lung cases patients. “Simulated MRI-based plans” were generated by assigning bulk ED value to all contoured structured. Dosimetric differences with the CT-based plan were made. Variations as large as 10% or more were observed in dose-volume parameters. The commonly-used ED assignment in MRI-only based planning may not be appropriate for lung cancer.

Phillip Prior, PhD Medical Physicist Department of Radiation Oncology

Pan Pan, PhD Postdoctoral Fellow Department of Medicine Division of Hematology & Oncology

“Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer” Pan P, Kang S, Wang Y, et al. Frontiers in Immunology. 2017;16:997. The current study investigated the potential effects of black raspberries (BRBs) on modulating natural killer (NK) cells during the progression of colorectal cancer (CRC). We used two mouse models to mimic human familial adenomatous polyposis and sporadic CRC. Tissue-infiltrating NK cells decreased along the CRC progression, and depletion of NK cells significantly promoted the CRC development. BRBs significantly suppressed the CRC progression and increased the tissue-infiltrating NK cells in both mouse models. Moreover, we observed an increased number and an enhanced cytotoxicity of NK cells by BRB consumption in the human biopsy specimens collected from our previous BRB intervention trial.

“False Localization With Subdural Electroencephalography due to Gyrus Overlap” Chan AY, Youssef PE, Lew SM. Pediatric Neurology. 2017;73:106-107. Localization of seizure producing brain tissue with invasive subdural grids is typically accurate and reliable. This case involved subdural grids that led to false localization. The subdural grids implicated two cortical gyri but the electro-encephalography (EEG) data suggested a singular gyrus. In reality, the seizure producing gyrus undercut an adjacent one. The seizure activity recorded from the adjacent gyrus was derived from below (i.e., the seizure producing undercutting gyrus). The study shows that although subdural grids are reliable, clinical judgment must be used to properly localize seizure producing brain tissue. Alvin Y. Chan Senior Medical Student Department of Neurosurgery

William S. Ragalie, MD Research Resident Department of Surgery

Sean M. Lew, MD Michael E. Mitchell, MD Director of Regional Surgical Services Section Chief, Cardiothoracic Surgery, CHW Professor, Division of Congenital Heart Surgery Department of Surgery

Program Director, Neurosurgery Epilepsy, CHW Director, Residency Program Professor & Chief Pediatric Neurosurgery Department of Neurosurgery

“Side-to-Side Tracheobronchoplasty to Reconstruct Complex Congenital Tracheobronchial Stenosis” Ragalie WS, Chun RH, Martin T, Ghanayem NS, Berens RJ, Beste DJ, Mitchell ME. Annals of Thoracic Surgery. 2017;104(2):666-673. This work describes a novel treatment for complex tracheobronchial stenosis which involves an abnormal branching pattern of the mainstem bronchi. This case series describes four critically ill children with tracheal stenosis and a bridging bronchus who underwent tracheal reconstruction, all with excellent results.

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