Brigham and Women's Hospital Department of Surgery Harvard Medical School External Review 2017-2021

Funding source: Icahn School of Medicine at Mount Sinai Funding amount: $154,814 Brief description of the study w/goals and objectives: This is a prospective clinical trial from Mt. Sinai comparing the effectiveness of surgery versus stereotactic body radiation for early-stage lung cancer. Name of study: Military Exposure-Related Pleural Mesothelioma: An Innovative Translational Approach to Inform Novel Molecular-Targeted Treatment Development PI: Raphael Bueno, MD Funding source: U.S. Army Medical Research Acquisition Activity Funding amount: $779, 375 Brief description of the study w/goals and objectives: A grant from DoD to investigate mesothelioma in veterans compared to non-veterans. It is a multisite grant across several academic institutions. Name of study: Active and Reconfigurable Topological Mechanical Metamaterials from the Nanoscale to the Macroscale PI: Zi Chen, PhD Funding source: Regents of the University of Michigan Funding amount: $1,044,212 Brief description of the study w/goals and objectives: 1) Design and develop multistable structural components, use strain-engineering approach, build theoretical and computational models to interpret and predict their mechanical behaviors. 2) Integrate the multistable structural components into topological mechanical metamaterials and examine the physics and mechanical behaviors through experiments and computer simulations. 3) Design, build and test bistable helical ribbons to study the principles behind the self-assembly and fractional excitations. 4) Integrate the method of strain engineering with 3D printing for high-throughput fabrication of these mechanical metamaterials. Name of study: Adult Tissue Morphogenesis: Functional Regulation of Intussusceptive Angiogenesis PI: Steven Mentzer, MD Funding source: NIH-NHLBI National Heart, Lung, and Blood Institute Funding amount: $988,045 Brief description of the study w/goals and objectives: Track endothelial progenitor cells (EPC) from their mobilization in the bone marrow to their migration into the lung during parabiotic post- pneumonectomy intussusceptive angiogenesis. Determine the effect of intussusceptive pillars on EPC localization, vascular integration and total angiogenesis. Model the interaction between blood-borne EPC and intravascular pillars during intussusceptive angiogenesis. Exemplary Publications Couger, M. B., S. W. Roy, N. Anderson, L. Gozashti, S. Pirro, L. S. Millward, M. Kim, D. Kilburn, K. J. Liu and T. M. Wilson (2021). Sex Chromosome Transformation and the Origin of a Male-Specific X Chromosome in the Creeping Vole. Science. 372(6542): 592-600. 97

Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, Gnad F, Nguyen TT, Jaiswal BS, Chirieac LR, Sciaranghella D, Dao N, Gustafson CE, Munir KJ, Hackney JA, Chaudhuri A, Gupta R, Guillory J, Toy K, Ha C, Chen YJ, Stinson J, Chaudhuri S, Zhang N, Wu TD, Sugarbaker DJ, de Sauvage FJ, Richards WG, Seshagiri S. Comprehensive Genomic Analysis of Malignant Pleural Mesothelioma Identifies Recurrent Mutations, Gene Fusion and Splicing Alterations. NatGenet. 2016 Apr;48(4):407-16. PMID: 26928227 Bueno R, Richards WG, Harpole DH, Ballman KV, Tsao MS, Chen Z, Wang X, Chen G, Chirieac LR, Chui MH, Franklin WA, Giordano TJ, Govindan R, Joshi MB, Merrick DT, Rivard CJ, Sporn T, van Bokhoven A, Yu H, Shepherd FA, Watson MA, Beer DG, Hirsch FR. Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early-Stage Squamous Lung Cancer (Alliance). J Thorac Oncol. 2020 Jul 24: S1556-0864(20)30558-X. doi: 10.1016/j.jtho.2020.07.005. Epub ahead of print. PMID: 32717408. Yeap BY, De Rienzo A, Gill RR, Oster ME, Dao MN, Dao NT, Levy RD, Vermilya K, Gustafson CE, Ovsak G, Richards WG, Bueno R. Mesothelioma Risk Score: A New Prognostic Pretreatment, Clinical-Molecular Algorithm for Malignant Pleural Mesothelioma. J Thorac Oncol. 2021 Jul 6: S1556-0864(21)02255-3. doi: 10.1016/j.jtho.2021.06.014. Epub ahead of print. PMID: 34242791. Rogers JG, Pagani FD, Tatooles AJ, Bhat G, Slaughter MS, Birks EJ, Boyce SW, Najjar SS, Jeevanandam V, Anderson AS, Gregoric ID, Mallidi H, Leadley K, Aaronson KD, Frazier OH, Milano CA. Intrapericardial Left Ventricular Assist Device for Advanced Heart Failure. New England Journal of Medicine. 2017 Feb 2;376(5):451-460. doi: 10.1056/NEJMoa1602954. D. EDUCATIONAL ACTIVITIES The Division of Thoracic Surgery offers the following residency and fellowship programs to train the next generation of thoracic surgeons. More information about these programs can be found in Appendix 2 and 3. • 5-2 Thoracic (Cardiothoracic) Residency Program: Develops the knowledge and skills needed to perform as academic thoracic and cardiac surgeons at the highest level through a diverse array of supervised operative and non-operative experiences. Residents gain surgical and clinical skills leading to eligibility for American Board of Thoracic Surgery certification, with emphasis on the diagnoses of cardiothoracic disease, assessment of operative risk and application of new technologies to tailor surgical intervention to individual patients. • Integrated (I-6) Thoracic Residency: Provides an optimum number of diverse adult cardiac, congenital cardiac and general thoracic operative and non-operative experiences under supervision to gain surgical and clinical skills leading to eligibility for American Board of Thoracic Surgery certification. Each of the three principal services in this training program (Cardiac Surgery, Thoracic Surgery and Pediatric Cardiac Surgery) has state-of-the-art dedicated facilities for clinical and laboratory research. 98

• General Thoracic Surgery Fellowship: Covers the full range of outpatient, operative and postoperative management of the entire spectrum of minimally invasive general thoracic surgical cases including endoscopic surgery, laparoscopic surgery, minimally invasive thoracoscopic and robotic surgery. • Minimally Invasive Thoracic Surgery Fellowship: Offers trainees preparation in surgical approaches that apply to both chest and abdominal procedures in thoracic surgery and require specialized training; includes several techniques including open, VATS/laparoscopy, robotic and uniportal surgery. • Cardiothoracic Surgery Transplant Fellowship: Prepares trainees in the highly complex and advanced discipline of end-organ heart and lung disease management with four principal disciplines (Heart Transplant, Lung Transplant, Mechanical Circulatory Support, ECMO). Educational activities also include weekly didactic and morbidity and mortality conferences, guest lectures and grand rounds. E. CURRENT CHALLENGES The division continues to grow, at the Brigham and at our network facilities in Massachusetts and Rhode Island. Challenges to further clinical growth include the need for more inpatient beds, more private beds and more ICU beds. With the complexity and age of our patients continuing to rise and with the clear need patients have for more space when in their hospital environment, the resources needed for care are increasing. At the same time, the technology used to treat thoracic disease continues to evolve. The division has raised philanthropic funds to secure these technologies, and partnered in innovative ways within the industry to obtain state-of-the-art equipment such as the DaVinci robot; but for further growth, the hospital will need to help with these investments. Our faculty has increased by 40% over the past five years, which requires more office space and support personnel. These needs also require co-investment by the hospital to keep up our trajectory. Our outcomes continue to be among the best in the world, and sharing this information with our community and the world at large is critical to our mission. We have invested our philanthropic funds in a marketing effort and will need further support from the hospital to further growth of the division. F. VISION AND FUTURE OPPORTUNITIES The goal for the Division of Thoracic Surgery is to remain the top-ranked regional, national and international program in terms of clinical quality, access and innovation. We aim to achieve this goal by expanding multidisciplinary, specialized diagnosis-based programs for patient care, which are linked to collaborative research efforts leading to innovation. 99

Transplant Surgery A. OVERVIEW The Brigham and Women’s Hospital transplant program is one of the oldest programs in the world and is responsible for many innovations that have greatly improved the lives of transplant patients. Our program began with the world’s first successful human organ transplant (a kidney transplanted from one identical twin to another), performed by Dr. Joseph Murray in 1954. Shortly thereafter, Dr. Murray performed the first successful non-identical twin transplant with a deceased donor. For his pioneering work in this field, Dr. Murray was awarded the 1990 Nobel Prize in physiology or medicine. Since that first successful transplant, our The Transplant Surgery division continues to advance the field of transplantation to help more patients lead healthy and productive lives. Our gifted team of expert transplant surgeons, nephrologists, transplant nurses, social workers, pharmacists and nutritionists deliver highly compassionate, coordinated and patient-centered care, from initial evaluation through post-transplant care. The division currently has expertise in both kidney and pancreas transplantation. Cornerstones of Success • State-of-the-art treatment for complex patients, including those who are sensitized and have difficult-to-treat kidney conditions • Ability to successfully match patients through paired kidney exchange programs • Minimally invasive surgical techniques designed to shorten hospital stays and speed recovery for living kidney donors • Leading-edge research studies, including new ways to individualize immunosuppression for recipients and improve donor organ quality • Simultaneous kidney/pancreas or pancreas after kidney transplants for qualifying patients • Patient-centered approach, including a one-day evaluation clinic for patients and multiple opportunities to engage with the team for education and support Major Changes Over the Last Five Years • Outreach: Brigham physicians and surgeons have engaged intensively in outreach programs, including Kidney Crossroads (a collaboration with the National Kidney Foundation). • Access: The time from patient contact to patients being seen, evaluated and listed has been substantially reduced because we are in constant communication with referring providers. Our physicians have received excellent feedback from patients. 100

• Waitlist: We have worked to expand the waitlist for patients awaiting kidney and pancreas transplants. Kidney waitlist volumes have increased by 62%, from 274 in 2016 to 446 in 2021. Our kidney/pancreas waitlist volume has also increased from two in 2016 to 10 in 2021. • Organ Optimization: Our program is proud to be utilizing available organs in an optimized way. All offers are discussed by surgeons and nephrologists; we have increased and promoted the utilization of Hepatis C positive donor organs and have performed two- for-one transplants. • Innovation: Our research (funded through several NIH RO-1/UO-1 grants) has focused on a bedside-to-bench-to-bedside approach. We have published the largest series of hand-assisted retroperitoneal donor nephrectomies. We have also assembled a multidisciplinary uterus transplant team supported by active IRBs that planned to launch a clinical program prior to the COVID-19 pandemic. • Transplant Service Line: Transplantation across organs has been streamlined as a transplant service line. This initiative works on expanding volume and outreach, while optimizing quality and outcomes. • Community: Brigham Transplant surgeons have supported local transplant programs at both Boston Medical Center (BMC) and Tufts Medical Center by covering clinical services and on-call demands. This support continues currently with BMC. Faculty/Leadership Stefan G. Tullius, MD, PhD, a world-renowned clinician/scientist, is the chief of the division. He holds the first Joseph E. Murray Distinguished Chair in Transplant Surgery and is a professor of surgery, co-director of the Schuster Transplant Center and director of the Transplant Surgery Research Laboratory. He has published more than 300 peer-reviewed articles and leads a productive NIH-funded research laboratory focusing on the effects of organ quality, transplant outcome, organ preservation, immunosenescence, metabolism and more recently, novel approaches to rejuvenate organs. Sayeed K. Malek, MD, is the clinical director of the division, an assistant professor of surgery and serves as Quality Assurance and Performance Improvement (QAPI) lead physician and the clinical director of the newly created Brigham transplant service line. In addition, he is the program director for two HMS post-graduate medical education programs: The Global Leadership in Management Program and the Southeast Asia Leadership Program. His research interests have included the study of racial and ethnic disparities in transplantation and delivering a strategy for stem cell transplant for Type 2 diabetes. B. CLINICAL SERVICES • One-day Evaluation Clinic: The evaluation clinic in the Schuster Transplant Center allows many patients (donors and recipients) to complete nearly all their on-site testing and medical evaluations for kidney and pancreas transplants in a single visit. They meet with a multidisciplinary team that includes surgeons, nephrologists, social workers, financial coordinators, nutritionists and pharmacists. This approach has resulted in significantly shorter 101

wait times for patients to complete their evaluation and decreased the number of visits to the hospital. • Medical and Surgical Expertise: In addition to providing comprehensive clinical expertise in treating issues related to transplantation, our program also provides access to experts in urological care, evaluation and placement of dialysis access and other procedures. • Renal Transplant Volume: Over the last five years, renal transplant volumes increased by 20%, with an average of 66 per year. This increase has been the consequence of an expansion in both deceased and living donor transplants. Notably, the kidney waitlist has grown by 62% in the past five years. • Pancreas Transplant Program: To improve the care of kidney patients with diabetes, a pancreas transplant program was established at the Brigham in 2006. Our waitlist has increased substantially, and outcomes have been excellent. • Live Donor Nephrectomies: We are a leader in performing minimally invasive retroperitoneal donor nephrectomies, a safe and reliable technique designed to shorten hospital stays and speed recovery, for living kidney donors. An ERAS program has been implemented that has shortened the hospital stay. • Living Donor Center: The Living Donor Center has been honored as a Center of Excellence by the National Kidney Registry for its outstanding paired kidney exchange program; 56 paired kidney exchanges have been performed during the last five years (compared to 17 in the prior five years). Our Living Donor team also performs all donor nephrectomies for Boston Children’s Hospital, with an average of 12 per year. • Patient Education and Community Outreach: In the past five years, the transplant team has increased community outreach by providing regular educational programs on various aspects of transplantation. We are constantly in touch with nephrologists to keep them updated on the status of their patients. C. RESEARCH ACTIVITIES The division’s research continues to study pioneering methods for protecting the integrity of transplanted kidneys and improving outcomes for kidney transplant recipients. Our research is focused on the following objectives: • Individualize immunosuppression for recipients and improve donor organ quality. • Improve the utilization of available deceased donor kidneys. • Explore the potential in modifying alloimmune responses and weight loss in patients who are obese. • Study the link between innate and adaptive immunity during aging. • Study the link between sex hormones and the alloimmune response. • Study specific aspects of rejection subsequent to composite tissue transplantation. 102

Key Grants Name of study: Consequences of Aging on Immune Response and Transplant Outcome PI: Stefan Tullius, MD, PhD Funding source: NIH Funding amount: $1,539,960 Brief description of the study w/goals and objectives: This grant explores mechanisms of donor and recipient age-dependent modifications of immune responses. Name of study: Microbiota and Allograft Rejection: Novel Investigations into the Consequences of Obesity PI: Stefan Tullius, MD, PhD Funding source: NIH Funding amount: $2,296,559 Brief description of the study w/goals and objectives: The major goal of this project is to investigate the causal impact of various microbial communities on alloimmunity. Name of study: Senescent Cells Drive Mt-DNA Accumulation and Inflamm-Aging PI: Stefan Tullius, MD, PhD Funding source: NIH Funding amount: $2,671,787 Brief description of the study w/goals and objectives: The long-term goal of this project is to dissect pathways driving augmented immunogenicity and compromised repair in old organs. Name of study: The KAPP-Sen Tissue Mapping Center Collaborative PI(s): Kuchel, Garovic, Musi, Robson; Site PI/Co-investigator: Stefan Tullius, MD, PhD Funding source: NIH/NIA Funding amount: $13,500,000 (all collaboratives) BWH funding amount: $330,873 Brief description of the study w/goals and objectives: This proposal seeks to establish the KAPP-Sen Tissue Mapping Center Collaborative (TMC) as part of the Cellular Senescence Network: Tissue Mapping Centers Effort (RFA-RM-21-008). Exemplary Publications Tullius SG, Rabb H. Improving the Supply and Quality of Deceased Donor Organs for Transplantation. N Engl J Med. 2018 May 17; 378 (20):1920- 1929. Iske J, Seyda M, Heinbokel T, Maenosono R, Minami K, Nian Y, Quante M, Falk CS, Azuma H, Martin F, Passos JF, Niemann CU, Tchkonia T, Kirkland JL, Elkhal A, Tullius SG. Senolytics Prevent Mt-DNA-Induced Inflammation and Promote the Survival of Aged Organs Following Transplantation. Nat Commun. 2020 Aug 27;11(1):4289. 103

Maenosono R, Nian Y, Iske J, Liu Y, Minami K, Rommel T, Martin F, Abdi R, Azuma H, Rosner BA, Zhou H, Milford E, Elkhal A, Tullius SG. Recipient Sex and Estradiol Levels Affect Transplant Outcomes in an Age- Specific Fashion. Am J Transplant. 2021 Oct;21(10):3239-3255. Quante M, Iske J, Heinbokel T, Desai BN, Cetina Biefer HR, Nian Y, Krenzien F, Matsunaga T, Uehara H, Maenosono R, Azuma H, Pratschke J, Falk CS, Lo T, Sheu E, Tavakkoli A, Abdi R, Perkins D, Alegre ML, Banks AS, Zhou H, Elkhal A, Tullius SG. Restored TDCA And Valine Levels Imitate the Effects of Bariatric Surgery. Elife. 2021 Jun 22;10: e62928. Kumar S, Witt RG, Tullius SG, Malek SK. Hand-Assisted Laparoscopic Retroperitoneal Donor Nephrectomy: A Single-Institution Experience of Over 500 Cases — Operative Technique and Clinical Outcomes. Clin Transplant. 2018 Jun. D. EDUCATIONAL ACTIVITIES The Division of Transplant Surgery is enriched by HMS students’ enthusiastic participation and response to our various programs. One of the highlights of our educational program is the HMS Student Surgery Clerkship program for second-year students. This program includes a two-week rotation and combines clinical and didactic learning opportunities on topics such as kidney and pancreas transplantation, vascular access, organ allocation, research and pharmacology. Other educational initiatives for students include the Surgical Preceptor program for the Introduction to Clinical Medicine course and the HMS mentorship program, both for first-year students; the ongoing mentorship of our research postdocs; and the ongoing lectures on transplantation to HMS students and transplant immunology to surgery residents. E. CURRENT CHALLENGES Organ transplantation is challenged in many ways, some of which can be (and have been) addressed programmatically. Others are related to nationwide programmatic changes and to an overall scarcity of organs. External Factors Organ Allocation: The organ allocation system has recently changed; now organs must be procured from an area that is 250 nautical miles around the donor hospital. Programs in New England must share with programs in other metropolitan areas, including New York City, which have traditionally had longer wait times. With organ allocation driven by waitlist composition, the new organ allocation system has therefore “moved” organs away from New England toward New York City. 104

Discrepancy Between Supply and Demand: The scarcity of organs has been linked to high rates of morbidity and mortality on the waiting list. We have addressed this issue with an optimized utilization of available organs for transplants. Internal Factors Staffing: Current and subsequent to the COVID-19 pandemic, it has been difficult to fill administrative and nursing positions. We are currently understaffed for existing and developing programs, including the uterus transplantation program. Faculty: The division currently has two transplant surgeons who share the call burden. Each surgeon is therefore on call one out of two days/nights. We are actively recruiting for a third faculty member. Competition: Currently, Boston has six adult kidney transplant and three pancreas transplant programs. The competition is strong, and we have responded with improved service, outreach and excellent care. Education: Insulin-replacement therapy has become complex and sophisticated. As a consequence, pancreas transplantation needs to be repositioned in the available armamentarium of available treatments. We are in constant contact with providers to provide this education. F. VISION AND FUTURE OPPORTUNITIES The Division of Transplant Surgery continuously strives for clinical expansion, improved service and the application of innovation. • Expanding Living Donor Transplants: We have established a Living Donor Center and have expanded our outreach and education for live donor transplants. Moreover, our current business plan is focusing on expanding live donor transplants and aims to increase volume by 50% over the next three years. • Innovation: We continue to work on translating our most productive research into clinical applications. Basic research efforts in improving organ quality are now also tested in human organs ex-vivo with a goal of clinical implementation. • Uterus Transplant Program: We have active IRBs for live and deceased donor uterus transplants and are currently working on a clinical implementation. • Transplant Service Line: Recognition as a service line is expected to streamline outreach and to increase transplant volume. 105

Trauma, Burn, and Surgical Critical Care A. OVERVIEW The Division of Trauma, Burn and Surgical Critical Care (TBSCC) at Brigham and Women’s Hospital provides services that span the full spectrum of general surgery, including trauma, burn, emergency general surgery, surgical critical care, and metabolic and nutritional support. The division was formally established in 2005 under the direction of Selwyn Rogers, MD, and is currently led by Ali Salim, MD. The division is an integral part of the Brigham’s accredited Level I Trauma Center and verified Burn Center. Our physicians and surgeons provide 24-hour, state-of-the-art emergency medical and surgical care for the most critically ill and injured patients. The division provides coverage for the entire emergency general surgery service as part of the acute care surgery model. With this model, we are able to address the care of the surgical patient who needs urgent and emergent surgical interventions, including emergency general surgery, resuscitation, critical care and trauma. Our faculty members account for more than 40% of the attending coverage in the multidisciplinary surgical intensive care units, including the general SICU and cardiac SICU. In 2015, the division was tasked with recruiting and forming a trauma/emergency general surgery team at South Shore Hospital (SSH) to staff their (now) Level II Trauma Center. We currently have five board- certified trauma surgeons who staff the trauma service at SSH, with plans of adding an additional two faculty members, who will provide 24/7 trauma, emergency general surgery and SICU coverage. The Gillian Reny Stepping Strong Center for Trauma Innovation, created in 2017, is now led by Dr. Salim and falls within the TBSCC division. The mission of the center is to catalyze multidisciplinary collaborations that inspire innovation, effective prevention and compassionate intervention to transform care for civilians and military heroes who endure traumatic injuries and events. The division continues to grow in many ways: • Recruiting high-quality faculty to join our team • Actively developing new clinical pathways 106

• Working within our communities to collaborate on trauma, burn and emergency general surgery transfers • Broadening community impact through violence intervention and prevention programs Members of the division aim to be thought leaders in our specialty, which has been demonstrated through our published research, national leadership and teaching. Leadership Team • Ali Salim, MD, FACS BWH Distinguished Chair in Surgery, Brigham and Women’s Hospital Chief, Division of Trauma, Burn, Surgical Critical Care and Emergency General Surgery Vice Chair for Surgical Critical Care, Department of Surgery Co-Medical Director, The Gillian Reny Stepping Strong Center for Trauma Innovation Medical Director, Trauma Program • Anupama Mehta, MD, Medical Director, Burn Program • Reza Askari, MD, Medical Director, Surgical ICU • Joaquim Havens, MD, Medical Director, Emergency General Surgery • Robert Riviello, MD, Kletjian Distinguished Chair in Global Surgery, Brigham and Women’s Hospital Medical Director, Metabolic Support Service Major Changes Over the Past Five Years Over the past five years, we have implemented a number of initiatives that have significantly improved both patient care and patient experience across all programs within the division. These include: • Established a patient service navigator role to bridge the gap between inpatient/discharge/post- op care for injured patients. • Established the Stepping Strong Injury Prevention Program and hired the program’s first injury prevention postdoctoral research fellow. The mission of the program is to reduce the burden of injury by advancing evidence-based prevention activities through community outreach, research of best practices, and training of health care professionals at the Brigham and beyond. • Hired our first full-time burn surgeon, Dr. Mehta, in 2020 to support the growing Burn Program. B. CLINICAL SERVICES Trauma Center The Brigham and Women’s Hospital is an ACS-verified Level I Trauma Center that provides emergency resuscitation and care for any injured patient. The Trauma Center is directed by Dr. Salim. Multidisciplinary surgical and medical treatment is managed by the on-call trauma attendings who work 107

together with trauma specialists in the areas of plastic and reconstructive surgery, neurosurgery, orthopedics, cardiothoracic surgery, vascular surgery and radiology. The Brigham Emergency Department sees more than 8,000 trauma-related visits annually, and more than 2,000 of these patients are admitted for further trauma care. We were re-verified as a Level I Trauma Center in May 2019. The Brigham was commended for its “demonstrated commitment to provide superior trauma care.” We offer a “just say yes” approach to every trauma-related patient transfer. Burn Center The Brigham and Women’s Hospital is a Level I Burn Center verified by the American Burn Association and American College of Surgeons. The Burn Program is led by Dr. Mehta, who is a full-time, dedicated burn surgeon. The Burn Center provides treatment and follow-up for patients with minor to severe burns, as well as those who have suffered from burn injury and seek a better functional and aesthetic outcome. Burn and plastic surgeons work closely with a strong, multidisciplinary team, including occupational therapists, physical therapists, dietitians, social workers and skilled wound care staff. Under Dr. Mehta’s leadership, the Burn Center was re-verified in September 2021. The Burn Center continues to see growth in surgical and outpatient volume, currently admitting more than 150 burn and complex wound patients per year. Emergency General Surgery Service Our faculty members provide 24 hours a day, 7 days a week in-hospital consultation and surgery for emergency surgery patients admitted through the Emergency Department, transfers from outside hospitals, as well as those admitted to other services. The service sees the complete spectrum of emergency general surgery diagnoses. In addition, we collaborate with teams across the hospital to address specialized and complex problems in oncology and ICU patients, including surgical palliative care and geriatric surgery. While most surgical services experienced a significant reduction in volume during the COVID-19 pandemic, the emergency general surgery service had a 30% increase in volume. This was in part due to changes in transfer patterns during the pandemic and an increase in overall case complexity, which were caused by later presentations and delays in seeking preventive care. Surgical Critical Care Service This multidisciplinary service is led by Dr. Salim, vice chair for Surgical Critical Care. The surgical critical care service consists of the general SICU, the thoracic SICU and the cardiac SICU. All units are staffed by surgeons, anesthesiologists, pulmonologists and emergency physicians. The services provide 24/7 coverage for high-acuity patients and offer training for critical care fellows and residents in general surgery, anesthesia, pulmonary medicine and emergency medicine who rotate through the service. Over 108

the past five years, Dr. Salim has created and implemented ICU overflow guidelines and standardized admission/discharge criteria, which has improved the quality of patient care and length of stay. Metabolic Support Service The metabolic support service (MSS), a subdivision of the Department of Surgery, is a dedicated team of surgeons and physician assistants that provides surgical evaluation and placement of airway, enteral and intravenous access for patients in the hospital, and patients in the ambulatory setting. Robert Riviello, MD, manages the MSS team, which consists of four faculty members, a surgical nutrition fellow, an outpatient dietitian, four full-time physician assistants and medical assistants. Medical direction for the PICC service, which is also partly staffed by IV Therapy nurses, is provided by Naomi Shimizu, MD. Trauma/Acute Care Surgery at South Shore Hospital South Shore Hospital is the first and only verified Level II Trauma Center south of Boston, including Cape Cod and the Islands. They are equipped to handle all critical injuries, 24 hours a day, 7 days a week. The Trauma Program is staffed primarily with faculty from the Division of Trauma, Burn and Surgical Critical Care. Christopher Burns, MD, serves as the Trauma medical director and works closely with both Brigham and SSH leadership. He successfully led the center through their most recent re-verification visit in June 2021 with the American College of Surgeons. The division has five full-time faculty and are currently recruiting for two additional providers to provide trauma, emergency general surgery and surgical ICU care for patients at South Shore Hospital. C. RESEARCH ACTIVITIES In addition to superior patient care provided by the Level I Trauma Center and Burn Center, faculty actively participate in research. Members of the research program bring together expertise in clinical, basic science and translational research. Using a patient-first approach, the goal is to define the best evidence to improve short- and long-term outcomes of trauma and emergency general surgery patients. Under the direction of Dr. Salim, our research program is focused on surgical effectiveness, wound repair and healing, patient outcomes, organ donation, trauma immunology, injury prevention, as well as many other areas of interest. Currently, we are learning how to improve long-term outcomes of trauma patients, decrease the incidence of surgical infection sites, and provide better care for older and frail patients. Dr. Salim also oversees research projects for the Stepping Strong Injury Prevention Program. In addition, our faculty collaborates with the department’s Center for Surgery and Public Health (CSPH) on various database studies. Multiple trauma physicians lead research cores at the CSPH. 109

Key Accomplishments Over the last five years the division has: • We published over 300 manuscripts and presented work at more than 15 regional and national conferences. • Submitted applications for new grants (R01, R03, K, PCORI, R21) and various foundation grants, of which 24 were awarded. • Led a total of three industry-sponsored clinical trials:  Phase III clinical trial of a new immunomodulating drug to promote improved outcomes in patients with necrotizing soft tissue infections  Phase III clinical trial evaluating the safety and efficacy of a drug for patients with sepsis-associated acute kidney injury  Post-market, prospective, multicenter, single-arm trial of XenMatrix AB surgical graft in all CDC wound class ventral or incisional midline hernias • Recruited around 4,000 patients into Functional Outcomes and Recovery after Trauma Program. • Developed one of the only trauma and acute care surgery, academic global surgery programs. Current Research Activities Functional Outcomes and Recovery after Trauma Emergencies (FORTE) Since 2016, the FORTE project has produced and disseminated several important findings, as well as demonstrated that routine collection of long-term trauma outcomes is feasible. Among these findings, it was discovered that patient factors (age, gender, race, education) are more important than injury- related factors (injury severity or location) in predicting long-term outcomes, and that poor long-term outcomes after injury tend to be associated with each other, within, and across health domains (mental, physical, social). We also collected data related to COVID-19, to measure the pandemic’s effect on the recovery of trauma survivors. Recently, the FORTE study was awarded $28,000 to determine the feasibility and acceptability of using smartphone technology to collect data among trauma survivors post-discharge. Reza Askari, MD His research focuses on the areas of critical care, trauma, and acute care surgery with a focus on surgical infections. Dr. Askari is the PI for several ongoing research studies, including acting as a site PI for an NIH-funded multi-center study. His other research includes understanding factors contributing to bone marrow transplant infections and investigating the relationship among obesity, nutritional status and necrotizing soft tissue infections. Additionally, he is collaborating with our basic scientist in looking at immunologic phenotyping of severe trauma patients. Joaquim Havens, MD His research focuses on the factors affecting outcomes for patients in trauma and emergency general surgery. His work is dedicated to the development of quality and safety measures that improve patient 110

outcomes. Dr. Havens successfully implemented several clinical interventions, operative communication techniques and surgical safety tools through this work. He developed the first application of an evidence-based communication checklist and intraoperative huddle for emergency general surgery, which led to greater shared awareness of intraoperative events. His research was instrumental in defining the core diagnoses that define emergency general surgery. In addition, he received funding to develop a Surgical Device Briefing Tool used to promote safety and introduce a new surgical device in the OR. Zara Cooper, MD Her research aims to improve palliative care and geriatric care for older, seriously ill surgical patients. Her goal is to integrate palliative care and geriatrics into routine surgical care for seriously ill and older surgical patients. Her work has largely focused in three areas: 1) studying long-term outcomes in seriously ill and older surgical patients, 2) measuring palliative care delivery in older trauma and surgical patients and 3) developing structures and processes to spur integration of palliative care and geriatrics into routine surgical care for seriously ill patients. She is recognized in the surgical, palliative care and aging research communities as the primary thought leader in this space. She was recently awarded an NIH RO1 grant for her project, “A Layered Examination of the Patient Experience to Elucidate the Role of Palliative Care in Surgical Care for Seriously Ill Adults.” In addition to identifying the role of palliative care in surgery to inform bedside clinical decisions, this project also aims to implement targeted palliative care interventions to improve care of older, seriously ill surgical patients. Robert Riviello, MD | Geoffrey Anderson, MD | Nakul Raykar, MD |Kristin Sonderman, MD Their primary goal is to improve equity in surgical care for destitute sick and injured people by developing the capacity of clinicians, scholars and leaders in the burgeoning field of global surgery. Their research aims to understand the need for human capacity in surgery in low- and middle-income countries; develop innovative platforms for surgical care delivery to address gaps in these settings; and implement programs to strengthen a country’s human capacity to deliver equitable health care to its population. Stephanie Nitzschke, MD | Naomi Shimizu, MD | Anupama Mehta, MD Their research is focused on surgical and clinical outcomes for burn and trauma patients, the diagnosis and care of patients with necrotizing soft-tissue infections, as well as faculty development and resident wellness. James Lederer, PhD, MPH Dr. Lederer is the division’s basic scientist. His research interests and goals are aimed at contributing a better understanding of how traumatic injuries influence the immune system. His work has focused on gaining an understanding of how injuries disrupt immune system homeostasis. His research also includes radiation injury, autoimmune diseases and tumor/cancer immunology. His research works toward translating trauma and infection immunology for clinical use to improve patient care outcomes following severe injuries. He is also working with Dr. Askari in studying immunologic phenotyping of severe trauma patients. 111

Ali Salim, MD For the past decade, Dr. Salim’s research has focused on the care and outcomes of trauma patients and on improving the physiology of organ donors and the rate of donation. Most recently, his research has focused on racial disparities in organ donation, specifically among Hispanic Americans in Southern California, and on identifying and quantifying long-term physical, emotional and psychosocial effects following moderate to severe traumatic injury. Key Grants Name of study: U.S. Academic Consortium for the Rwanda Human Resource for Health (HRH) Program PI: Robert Riviello, MD (Co-PI) Funding source: USAID/Global Fund/CDC Funding amount: $1,175,790 Brief description of the study w/goals and objectives: This is a training and capacitation grant from the U.S. government to the Rwandan Ministry of Health. By supporting the recruitment of U.S. faculty across the health care spectrum via a consortium of 13 U.S. universities, the major goal of the grant is to mentor Rwanda health care trainees and faculty, develop and strengthen Rwanda’s academic health care departments, and thus at the end of the 8-year program, help Rwanda be free of dependence on foreign aid to sustain its HRH development goals. This program is renewed for year 5 ($1,175,790), year 6 ($616,460) and year 7 ($1,972,225). Name of study: Beyond 30 Days: Patient-Oriented Outcomes Among Older Adults After Emergency General Surgery PI: Zara Cooper, MD, MSc Funding source: NIH/National Institute on Aging Funding amount: $800,000 Brief description of the study w/goals and objectives: The purpose of this research was to describe one-year mortality, health utilization, palliative care needs and end-of-life outcomes among older adults who experience emergency abdominal surgery. Name of study: Large Scale Implementation of a Device Briefing Tool and Surgical Safety Checklist PI: Joaquim Havens, MD Funding source: Medical Devices and Diagnostic Global Services, LLC Funding amount: $1,972,225 Brief description of the study w/goals and objectives: The purpose of this project was to implement and measure the effect of a device briefing tool and surgical safety checklist in a large-scale health system in Singapore. 112

Name of study: Developing a National Trauma Research Action Plan for the United States (NTRAP) PI: Zara Cooper, MD, MSc (PI: Bulger) Funding source: Department of Defense/National Trauma Institute Funding amount: $486,723 Brief description of the study w/goals and objectives: The purpose of this research was to define the research agenda and inform federal funding priorities for injury prevention. Name of study: A Layered Examination of the Patient Experience to Elucidate the Role of Palliative Care in Surgical Care of Seriously Ill Adults PI: Zara Cooper, MD, MSc Funding source: NIH Funding amount: $3,966,414 Brief description of the study w/goals and objectives: This study will provide an innovative and layered examination of the role of palliative care in surgery in order to directly inform bedside clinical decisions and the implementation of targeted palliative care interventions to improve care for older seriously ill surgical patients. Exemplary Publications 1. Scott JW, Olufajo OA, Brat GA, Rose JA, Zogg CK, Haider AH, Salim A, Havens JM. Use of National Burden to Define Operative Emergency General Surgery. JAMA Surg. 2016 Jun 15;151(6):e160480. PMID: 27120712. 2. Seshadri A, Brat GA, Yorkgitis BK, Keegan J, Dolan J, Salim A, Askari R, Lederer JA. Phenotyping the Immune Response to Trauma: A Multiparametric Systems Immunology Approach. Crit Care Med. 2017 Sep;45(9):1523-1530. PMID: 28671900. 3. Lee KC, Senglaub SS, Walling AM, Mosenthal AC, Cooper Z. Quality Measures in Surgical Palliative Care: Adapting Existing Palliative Care Measures to Improve Care for Seriously Ill Surgical Patients. Ann Surg. 2019 Apr;269(4):607-609. PMID: 30480563 4. Havens JM, Castillo-Angeles M, Jarman MP, Sturgeon D, Salim A, Cooper Z. Care Discontinuity in Emergency General Surgery: Does Hospital Quality Matter? J Am Coll Surg. 2020 Jun; 230(6):863- 871. PMID: 32113028. 5. Haider AH, Herrera-Escobar JP, Al Rafai SS, Harlow AF, Apoj M, Nehra D, Kasotakis G, Brasel K, Kaafarani HMA, Velmahos G, Salim A. Factors Associated with Long-Term Outcomes After Injury: Results of the Functional Outcomes and Recovery After Trauma Emergencies (FORTE) Multicenter Cohort Study. Ann Surg. 2020 06; 271(6):1165-1173. PMID: 30550382. D. EDUCATIONAL ACTIVITIES Under Dr. Askari’s direction, TBSCC offers a two-year acute care surgery and surgical critical care fellowship track (each component is also available as a one-year fellowship). The first year is the ACGME-accredited surgical critical care fellowship, leading to eligibility for the ABS Certificate in Surgical Critical Care. The second year is a non-ACGME fellowship based on the American Association for the 113

Surgery of Trauma (AAST) Acute Care Surgery Curriculum and focused on trauma and non-trauma emergency surgery. The division also developed a clinical nutritional support fellowship, under the leadership of Malcolm Robinson, MD. This fellowship offers a curriculum in nutrition, metabolism, translational research and related surgical procedures, excluding bariatric surgery. For more information about the fellowships, refer to Appendix 3. The division provides a key teaching and education rotation for the residents and medical students. This core learning experience has enabled multiple members of the division to be appointed to important leadership positions for the Department of Surgery and the Medical School. Dr. Nitzschke was appointed the general surgery residency director. Dr. Shimizu was appointed as the residency’s associate program director. Dr. Askari was appointed the surgery clerkship director for the Medical School. Educational activities include the weekly didactic and morbidity and mortality conference and SICU daily didactics. E. CURRENT CHALLENGES Due to the continued high hospital occupancy, accepting outside hospital trauma, burn and emergency general surgery transfers has been challenging. The result has been a decrease in hospital admissions to our service. In addition, the COVID-19 pandemic has shifted the admission and transfer patterns within the institutions, which has also impacted our clinical growth. These continued challenges may affect the Trauma and Burn centers’ verification, as well as resident and fellowship education training. There have been a number of initiatives that should address these capacity and throughput challenges. F. VISION AND FUTURE OPPORTUNITIES In the coming years, we aim to expand our clinical footprint, both at the main campus and at South Shore Hospital. As previously noted, the goal is to increase our trauma team at SSH from five to seven FTEs, which would allow us to operate as an independent trauma center. We are partnering with the other acute care hospitals within the Mass General Brigham system to establish a trauma system that would optimally serve our community. This collaboration will also enhance the educational opportunities for our fellowships. We are also working toward expanding the research portfolio; for example, we hope to expand the FORTE project to establish a national, multi-institutional study. We will continue to develop our Injury Prevention Program, with the ultimate goal of achieving Center for Disease and Control (CDC) funding. Lastly, we are working to establish a civilian and military partnership for trauma care, working closely with partners in the Stepping Strong Center for Trauma Innovation. 114

Urology A. OVERVIEW The Division of Urology at Brigham and Women’s Hospital (BWH) has helped set the standard for international excellence in urologic care, providing advanced care and performing thousands of life- changing procedures and surgeries each year, while conducting groundbreaking scientific research. Under the direction of Adam S. Kibel, MD, our board-certified urologists deliver comprehensive and personalized attention to men and women with a range of genitourinary problems — from prostate and bladder disorders to male sexual health concerns, urinary infections, incontinence, stone disease and anatomic abnormalities. The division provides expert, individualized care for a range of urologic conditions, from the common to complex, including the best in cancer care through our role as surgical oncologists for Dana- Farber/Brigham Cancer Center. Our urologic surgeons collaborate among the world's best cancer experts in a multidisciplinary environment to give patients a united force in the fight against urologic cancer. And as leaders in genitourinary medicine, we train the next generation of surgeons through the Harvard Urology Residency Program and are engaged in ongoing scientific research — pioneering breakthroughs in the prevention, diagnosis and treatment of urinary diseases and conditions. The division currently has 18 faculty members, including eight new providers who joined the practices over the past five years. With this growth, Urology is now structured into sections of general, benign and oncology. The following shows the leadership of two of these sections, with an ongoing search for a section chief of Benign Urology. • Steven Lee Chang, MD, MS - Section Chief of Urologic Oncology • Michael J. Malone, MD - Section Chief of Urology at Brigham and Women’s Faulkner Hospital • George Haleblian, MD – Director of the Residency Program • Michael P. O’Leary, MD, MPH – Director of the Men’s Health Center • Mark A. Preston, MD, MPH – Director of Urological Research • Quoc-Dien Trinh, MD, FRCSC – Director of Clinical Operations Major Changes Over the Past Five Years • Community Urology Initiative: The division has provided an additional clinic at BWH and Brigham and Women’s Faulkner Hospital, along with staffing multidisciplinary clinics at the BWH ambulatory sites to better meet the needs of the primary care community. In addition, we have begun to provide services at non-BWH sites such as Milford Regional Medical Center and South Shore Hospital, with the prospect of more opportunities on the horizon. This expansion is a 115

direct result of the increased demands and evolution of community urology over the past five years. • Men’s Health Clinic: Expanded to a new suite at the Brigham and Women’s Faulkner Hospital site, which provides opportunities for many new prostate cancer treatments and multidisciplinary visits. • Clinic Services: Transitioned some services out of the OR and into the clinic, which generally provides for a better patient experience and creates capacity for higher revenue cases in the OR. Marketing has also been an important focus. We have seen a significant improvement in visibility as measured by U.S. News & World Report. Following three years of improvement, we were ranked 19th this year, which is the highest-ranking in New England. This was achieved through measures such as: • Sharing our research accomplishments with present and past urologists from BWH • Increasing social media presence • Creating more patient brochures for treatments and procedures, and also developing MD profile cards and physician directories • Increasing physician visibility on a national and international level through expanded speaking engagements In addition to these changes, the division continues to experience considerable growth, with visit volume increasing steadily at 8-9% per year and case volume increasing at 12% per year. 116

B. CLINICAL SERVICES The division provides a comprehensive clinic at the BWH main campus and two clinics at Brigham and Women’s Faulkner Hospital (BWFH). Our ambulatory clinic services include new patient visits, post- operative and return visits, and urological treatments. We have moved many of the procedures that were historically performed in the OR into the ambulatory clinic to better serve our patients. We have standardized and centralized certain procedures and treatments for better patient care and access. Our expanded operations include a urology clinic at BWFH, as well as a Men’s Health Clinic. We have expanded to see patients 5 days each week in Foxborough and have obtained dedicated space for growth in a new building. Faculty members also see patients in the community in Pembroke, Milford and Westwood. The goal is to bring the urologist to the primary care physician and the community satellites. Lastly, we see patients at Dana-Farber Cancer Institute (DFCI) and have expanded to the new DFCI clinic in Chestnut Hill. At all of these community sites, our clinic nurses rotate back and forth to provide continuity and seamless transitions for the faculty and patients. Within the clinics, we not only see patients but also perform procedures such as prostate biopsies, cystoscopies, video urodynamic and SpaceOARs. In the future, we have plans to move more clinical procedures up from the OR and into the clinic setting; however, space and compliance may be a barrier. Many urology procedures across the country are performed in the clinic setting, and that is becoming the standard of care. Procedures include Cysto/Botox, Cysto/biopsy, Cysto/stent changes, Rezum Therapy, etc. We are hopeful to start the process soon of increasing clinical procedures. As a result of these changes, there has been tremendous growth in Urology. OR cases have also increased. The increase is not as steep as clinic volume in part due to moving standard cystoscopic cases out of the main OR and into the clinic. OR time and surgeon availability have also been issues, therefore recruitment of additional surgeons with OR time is a critical need of the division. Current booking of routine cases is three months out. Other changes that have been instituted and contributed to the growth of the division include: • Standardized treatment clinics for efficiency o Includes BCG clinics, Chemo clinic, Cysto and UDS clinics o Increased dedicated focused clinics for patient satisfaction • Created a complex and comprehensive APP team o Revenue-generating independent providers o Independent clinics in all locations for continuity of care o Focus on team-based care to improve patient access and patient satisfaction o Patient access has been dramatically improved as a result of this team 117

• Restructured New Patient Coordinators Office into a comprehensive Access Team o With new patient scheduling averaging 250 per week and e-referrals from PCPs averaging 75 per week, there was an urgent need to standardize new patient access and onboarding. This resulted in the development of a multifaceted supportive access center. o The new center also incorporates new technology and communication resources Urologists at the Brigham collaborate with medical oncologists, radiation oncologists, radiologists, pathologists, nurse specialists and other relevant health care professionals to provide multidisciplinary care between Brigham and Women’s Hospital and the Genitourinary Cancer Treatment Center at Dana- Farber Cancer Institute. All specialists are involved in the evaluation and management of genitourinary cancer to determine the best course of action and treatment for each patient. C. RESEARCH ACTIVITIES With about $3 million in peer-reviewed funding, clinical research and trial development is a broad initiative and a strength of the division. In the urology clinic, surgeons divide their time between patient care, medical education and research. Our division is currently engaged in a variety of studies that further our research endeavors, provide solid academic traction, address previously unmet research niches and, most importantly, provide alternative therapies for current patients. As a nationally known leader in investigating and treating various urological diseases, the Division of Urology is committed to investigating the underlying causes of diseases, as well as developing preventative treatment measures. While there are a variety of traditional treatment options, our surgeons also explore alternative, investigational treatments through the wide range of clinical trial options. These investigations include: • Laboratory studies using genomic and biochemical approaches to investigate molecular mechanisms of prostate cancer development and progression • Patient-reported outcomes studies evaluating short-term surgical results and their ability to translate into long-term care; utilizing questionnaires and surveys administered in clinic allow surgeons a better understanding of long-term results of different treatment options • Clinical trials assessing existing, alternative and investigational therapies 118

Key Grants Name of study: Androgen Receptor Pathway Inhibition Through Targeting PARP2 in Castration-Resistant Prostate Cancer PI(s): Li Jia, PhD Funding source: National Cancer Institute Funding amount: $2,047,315 Brief description of the study w/goals and objectives: PARP2 is a critical component in androgen receptor signaling through the interaction with FOXA1. Selective targeting of PARP2 blocks the PARP2/FOXA1 interaction, which in turn inhibits androgen receptor-mediated gene expression and prostate cancer growth. In this project, we will define PARP2 as a therapeutic target in castration- resistant prostate cancer. Name of study: PSA Level During Midlife and Undiagnosed Prostate Cancer at Autopsy: Understanding Tumor Biology and Racial Disparities PI(s): Mark A. Preston, MD, MPH Funding source: U.S. Army Medical Research Acquisition Activity Funding amount: $774,000 Brief description of the study w/goals and objectives: This study aims to further develop the evidence basis for a risk-stratified baseline PSA screening strategy by conducting an autopsy study among Black and white men to assess how PSA in midlife relates to the pre-diagnosis natural history of prostate cancer and how this varies by race. Name of study: Pilot Study of an Implantable Microdevice to Test Multiple Drug Responses in Prostate Cancer Patients PI(s): Adam S. Kibel, MD; Oliver Jonas, PhD; and Nobuhiko Hata, PhD Funding source: National Cancer Institute Funding amount: $3,457,508 Brief description of the study w/goals and objectives: To evaluate the feasibility and safety of MR- guided microdevice placement in prostate tumors. Name of study: Consolidating Care of Complex Patients in the Capitol Region PI(s): Quoc-Dien Trinh, MD, FRCSC Funding source: Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Funding amount: $591,329 Brief description of the study w/goals and objectives: The goal is to study and model the potential impact of centralization of complex surgical care on costs and outcomes for the U.S. military health system. 119

Name of study: The Role of PARP2 in Prostate Cancer PI(s): Li Jia, PhD Funding source: U.S. Army Medical Research Acquisition Activity Funding amount: $1,007,624 Brief description of the study w/goals and objectives: The goal of this project is to study the oncogenic role of PARP2 in androgen-dependent prostate cancer beyond its DNA repair function. Name of study: Risk Prediction of Aggressive Prostate Cancer Using Baseline PSA During Midlife and Inherited Genetic Variants in African American and Caucasian Men PI(s): Mark A. Preston, MD, MPH Funding source: Prostate Cancer Foundation Funding amount: $225,000 Brief description of the study w/goals and objectives: This study leverages two unique, ethnically diverse study populations, with a focus on African Americans, to devise smarter PSA screening strategies by comprehensively investigating the ability of baseline PSA at midlife along with inherited genetic variants to predict future risk of aggressive prostate cancer. Exemplary Publications Mossanen M, Carvalho FLF, Muralidhar V, Preston MA, Reardon B, Conway JR, Curran C, Freeman D, Sha S, Sonpavde G, Hirsch M, Kibel AS, Van Allen EM, Mouw KW. Genomic Features of Muscle-Invasive Bladder Cancer Arising after Prostate Radiotherapy. Eur Urol. 2021 Dec 22: S0302-2838(21)02212-0. doi: 10.1016/j.eururo.2021.12.004. Epub ahead of print. PMID: 34953602. Haeuser L, Marchese M, Schrag D, Trinh QD, Chang SL, Kibel AS, Gore JL, Noldus J, Mossanen M. The Impact of Smoking on Radical Cystectomy Complications Increases in Elderly Patients. Cancer. 2021 May 1;127(9):1387-1394. doi: 10.1002/cncr.33308. Epub 2020 Dec 22. PMID: 33351967. Cole AP, Fletcher SA, Berg S, Nabi J, Mahal BA, Sonpavde GP, Nguyen PL, Lipsitz SR, Sun M, Choueiri TK, Preston MA, Kibel AS, Trinh QD. Impact of Tumor, Treatment, and Access on Outcomes in Bladder Cancer: Can Equal Access Overcome Race-Based Differences in Survival? Cancer. 125(8):1319-29, 2019. PMID: 30633323. Gui B, Gui F, Takai T, Feng C, Bai X, Fazli L, Dong X, Liu S, Zhang X, Zhang W, Kibel AS, Jia L. Selective Targeting of PARP-2 Inhibits Androgen Receptor Signaling and Prostate Cancer Growth through Disruption of FOXA1 Function. Proc Natl Acad Sci U S A. 2019; 116(29):14573-14582. Preston MA, Gerke T, Carlsson SV, Signorello L, Sjoberg D, Markt SC, Kibel AS, Trinh QD, Steinwandel M, Blot W, Vickers AJ, Lilja H, Mucci LA, Wilson KM. Baseline Prostate-Specific Antigen Level in Midlife and Aggressive Prostate Cancer in Black Men. Eur Urol. 2019 Mar;75(3):399-407. doi: 10.1016/j.eururo.2018.08.032. Epub 2018 Sep 17. 120

D. EDUCATIONAL ACTIVITIES The Division of Urology has a strong and historical commitment to the education and professional development of medical students, residents and faculty. The division currently has three educational programs that are integrated into our clinical and research missions. Medical Student Program We have rotations for Harvard Medical School students. Residency Program We currently have 15 residents over a five-year period. The residency training program in urology is a distinct program accredited by the ACGME and is not considered a subspecialty of surgery. The program has a specific curriculum with core competencies that must be achieved under the mandate of ACGME and the American Board of Urology (ABU). At the completion of training, residents must pass a two-part qualifying examination to become board-certified. Our residents rotate through four institutions during their training: BWH, BWFH, Boston Children’s Hospital and the Boston VA Medical Center. For more information about the residency, please refer to Appendix 2. • In addition to excellent clinical training, the residents also receive outstanding research training and collaborate with investigators from within the Brigham, the Harvard T.H. Chan School of Public Health and other institutions including Harvard Business School. • As a testament to the strength of our program, the AUA in 2018 approved the Brigham program in urology as a site for the Physician Research Scientist Training Program, one of five programs selected in the country to participate. This unique program is an eight-year training tract designed to foster basic science research among practicing urologists. Fellowship Program Fellowships are becoming increasingly important given the shorter residency and work hours regulations. We currently have a joint urologic oncology fellowship program with Mass General Hospital (MGH). This is approved by the Society of Urologic Oncology. It is a two-year program, one research and one clinical, and is split equally between the two institutions. This has been a very successful partnership with MGH and serves as a model for future partnerships. We have a high number of applicants and have matched two of our top five candidates every year. For more information about the fellowship, see Appendix 3. 121

F. CURRENT CHALLENGES Urology has faced many challenges over the past few years. The demand in patient care is constant and difficult to meet despite hiring more providers. Many new urology treatments and procedures are evolving and developing quickly, and it takes time and energy to have them adopted within our systems. • Aging Facility: Brigham facilities are quite dated, and the lack of available space is stunting our ability to grow within the main campus, as well as at the off-site locations. • Off-Site Facilities: Urology’s patient population is very much in the community. We need to take our providers to the patients; however, this is very challenging. Working with off-site practices involves space, staffing, management of overall operations, procedures and obtaining equipment. Off-site facilities cannot be a “one size fits all” since each practice runs very differently. Many off-site practices do not understand complex clinic operations, and working with floating staff and limited space becomes difficult for the providers and the patients. • Staffing: As with many areas within health care, the division is struggling with the current staffing environment. Difficulty recruiting and retaining staff has put a strain on the division’s ability to provide timely access to the growing number of patients seeking our care. • Equipment: Urology procedures and treatments are evolving quickly, and many of them require new drugs and equipment. It is a lengthy process to work with vendors and Mass General Brigham to obtain approval for funds, contract negotiations, drugs, etc. Our competition seems to be able to navigate this more quickly, which allows them to increase market share. E. VISION AND FUTURE OPPORTUNITIES We plan to continue to grow our clinical, educational and research portfolio. At the current time, the Division of Urology is a national leader in all three domains, but has identified the following opportunities for improvement. • Clinical: Provide expanded care in the community by placing urologists in the community who can provide high value care onsite and refer tertiary care to the AMC. We have hired three new faculty members this year who will provide care in community locations. We also have opportunities to develop new services within specialty care. For example, in collaboration with Plastic and Reconstructive Surgery, we are starting a gender affirmation program. We have also begun a collaboration with the MGH Department of Urology to develop a MGB Urology Service Line, which will leverage the strengths of both groups in efforts to increase capacity to care for patients, improve the patient experience, reduce total medical expense (TME), and enhance quality of care. • Research: Our focus has been primarily in health services research, but we are increasing work in clinical trial design and translational research. • Educational: The oncology fellowship has become one of the best in the country. We will leverage this success to explore additional fellowships in men’s health, stones, and 122

reconstructive urology. These new programs will, in large measure, be developed in partnership with MGH. 123

Vascular and Endovascular Surgery A. OVERVIEW The Division of Vascular and Endovascular Surgery manages patients with peripheral arterial occlusions, abdominal and thoraco-abdominal aortic aneurysms, peripheral aneurysms, carotid artery disease, dialysis access needs and venous insufficiency. The division has implemented a disease-focused team approach that transcends the boundaries of conventional disciplines to ensure optimal cost-efficient patient care, and to address the following dynamics in treating patients with systemic vascular disease: • The aging patient population, with complex comorbidities • The rapidly changing field of cardiovascular care, with its increasingly complex pharmacology • The proven efficacy of percutaneous transluminal angioplasty and stents The division’s multidisciplinary approach also benefits its research and education programs, allowing faculty and residents to participate in a wide range of clinical, basic and translational research projects. Heritage The division was established in 1990, with continued leadership provided by Michael Belkin, MD, who was appointed chief of the division in 2001. Marcus Semel, MD, joined the division in 2014 upon completion of his two-year fellowship at Brigham and Women’s Hospital. Garima Dosi, MD, joined the division in 2015 upon completion of her two-year fellowship at the University of Maryland Medical Center. Edward Marcaccio, MD, joined the division in 2016, bringing a vast amount of knowledge in limb salvage and minimally invasive endovascular surgery. Mohamad Hussain, MD, PhD, who is highly respected for his many research endeavors, joined the division in 2019 after a two-year fellowship at the University of Toronto. Current Leadership • Michael Belkin, MD – Chief, Division of Vascular and Endovascular Surgery; Director, Noninvasive Vascular Laboratory, Brigham and Women’s Faulkner Hospital • Edwin C. Gravereaux, MD – Director, Endovascular Surgery and Interventional Therapy • Edward J. Marcaccio, MD – Chief, Division of Vascular Surgery, South Shore Hospital; Director, Noninvasive Vascular Lab, South Shore Hospital; Interim Director, Center for Wound Healing, South Shore Hospital • Matthew T. Menard, MD – Co-Director, Endovascular Surgery; Program Director, ACGME • Louis L. Nguyen, MD, MBA, MPH – Vice Chair, Digital Health Systems, Department of Surgery; Director, Clinical and Outcomes Research, Division of Vascular Surgery; Director, Quality, Safety and Value, Division of Vascular Surgery 124

• C. Keith Ozaki, MD – Executive Vice Chair, Department of Surgery • Marcus Semel, MD, MPH – Assistant Program Director, ACGME B. CLINICAL SERVICES State-of-the-art operative techniques in complex open surgery, endovascular techniques, standard and in situ vein grafting, and intraoperative ultrasonography and other imaging are available for patient care, as well as standard treatments for peripheral arterial disease. The division is part of the Carl J. and Ruth Shapiro Cardiovascular Center, which includes the team’s outpatient management program. This center provides patients with the most optimum care in a multidisciplinary environment. New Clinical Programs Outpatient Vein Treatment Program: New sites have been established that provide outpatient vein care, including endovenous treatments and sclerotherapy. Full accreditation is secured. Expanded Hemodialysis Access Care: In partnership with Interventional Nephrology, joint Saturday clinics have been established, and services have been extended to Brigham and Women’s Faulkner Hospital (BWFH) for improved patient access. Additionally, operative cases are now offered monthly at BWFH. Quality Assurance Beginning in 1978, the Division of Vascular and Endovascular Surgery has retrospectively collected selected preoperative, perioperative, postoperative, and follow-up data on major surgical and endovascular procedures performed by the attending surgeons of the division for the treatment of cerebrovascular disease, arterial aneurysms and peripheral arterial disease. Historically, this data was entered into a computerized registry, beginning with shared mainframe space at the Harvard T.H. Chan School of Public Health. The database is now part of the Vascular Quality Initiative international data collection system, which is maintained by a dedicated division staff member. The collected data has been used to document quality of care and the long-term efficacy of standard treatment modalities. Subsets of the data have been analyzed for presentation and publication at internal, regional and national meetings. The data has also been used to compare Brigham results and outcomes with nationally published data. 125

C. RESEARCH ACTIVITIES Our division aims to improve vascular surgery patient care by leveraging not only our basic research initiatives but also the active participation in investigator-initiated, industry-sponsored projects and health services research. Dr. Khalil, senior investigator, and Dr. Ozaki lead basic vascular surgery research. Dr. Hussain and Dr. Nguyen lead health services initiatives. The clinical research program includes clinical trials that span the vascular disease areas of carotid stenosis, thoracic and abdominal aortic aneurysms, peripheral arterial disease and hemodialysis access surgeries. Some of the clinical trials in which the division has participated in recent years include: • A fenestrated stent graft trial for juxtarenal and pararenal aneurysms • An expanded multicellular therapy trial to promote angiogenesis in critical limb ischemia patients with no revascularization options • A stent graft trial for aortic aneurysms with highly angulated necks • Three trials of an investigational drug and an external stent designed to help achieve and maintain patency of AV fistulas; and • A bioengineered conduit for arterial bypasses and dialysis access. Below is a summary of our most significant research over the past five years. Mohamad Hussain, MD, PhD Dr. Hussain’s research interests include the study of vascular diseases, using observational epidemiology, health services research, prospective clinical trials and knowledge translation. Dr. Hussain has more than 50 manuscript publications in journals such as Circulation, the Journal of the American College of Cardiology, and JAMA Surgery, and over 70 research presentations/published abstracts. He has received several research grants/awards from institutions such as the Canadian Institutes of Health Research (CIHR) and the European Society of Cardiology (ESC). Matthew Menard, MD The focus of Dr. Menard’s research is in open versus endovascular approaches to lower extremity arterial occlusive disease. He is co-PI of the international NIH-funded Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) Trial, which was designed to compare treatment efficacy, functional outcomes, quality of life and cost in patients undergoing best endovascular or best open surgical revascularization. Louis Nguyen, MD, MBA, MPH The focus of Dr. Nguyen’s research is outcomes translational research, in which he combines clinical outcomes with economic analysis, and quantitative modeling of complex socioeconomic factors and interactions in patient care. His unique education and experiences allow him to bring medical expertise to health economics research and to bring econometric analytical techniques to medical research. 126

Recent areas of investigation include behavioral economic methods in cost reduction and improving environmental sustainability in procedural areas. C. Keith Ozaki, MD The Ozaki Basic Vascular Biology Laboratory broadly aims to delineate the mechanisms by which physical forces alter the morphology of the blood vessel wall. The lab team holds expertise specifically in the adaptations of the vein bypass graft, an extreme example of acute perturbation of the hemodynamic environment combined with vascular trauma. Recent investigative efforts have focused on inflammatory-driven mechanisms of these adaptations. Future research directions expand this foundation of knowledge via exploration of short-term dietary interventions to impact the vascular response to trauma, investigations into links between adipose biology and vascular adaptations, and robust analyses of the longitudinal interplay between local hemodynamic factors and biochemical mediators. Raouf Khalil, MD, PhD The focus of the Vascular Surgery Research Laboratory, or Khalil Lab, is to study the cellular mechanisms of vascular tone under physiological conditions and the changes in these mechanisms in pathological conditions, such as coronary artery disease, salt-sensitive hypertension, abdominal aortic aneurysm and other chronic vascular diseases. State-of-the-art equipment is available to study various aspects of the vascular system, including the whole animal, tissue, cellular and molecular level. Powerful techniques such as physiological bioassays, radioimmunoassays, mRNA and protein analysis, cell and organ culture, immunofluorescence, digital imaging and confocal microscopy are also available. Key Grants Name of study: Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) Trial PI: Matthew Menard, MD (Co-PI) Funding source: NIH Funding amount: $27,300,000 Brief description of study w/goals and objectives: The BEST-CLI trial is a prospective, open-label, multicenter, multispecialty, randomized, controlled trial designed to compare treatment efficacy, functional outcomes, quality of life and cost in patients with Rutherford 4-6 CLI undergoing best open surgical or endovascular revascularization. Name of study: Adipose-Dependent Mechanisms of Dietary Protein Restriction Protective Effects on Vein Graft Adaptations PI: C. Keith Ozaki, MD Funding source: NIH Funding amount: $1,024,600 Brief description of study w/goals and objectives: The project aims to enhance the durability of vein bypass grafts by way of understanding how the local and systemic milieu (perturbed by dietary 127

interventions) impacts biology. Specifically, the work explores the ties between short-term protein restriction, adipose biology and vein graft adaptations. Name of study: Dialysis Access Dysfunction Treatment Device PI: C. Keith Ozaki, MD Funding source: NIH Funding amount: $224,928 Brief description of study w/goals and objectives: Joint effort with small engineering firm to develop a novel clot removal catheter designed for hemodialysis access conduits. This work is performed jointly with Interventional Nephrology. Name of study: Proteon PRT-201-310; Proteon PRT-201-320 PI: C. Keith Ozaki, MD Funding source: Proteon Therapeutics, Inc. Funding amount: $400,000 Brief description of study w/goals and objectives: Multicenter, double-blind, placebo-controlled clinical trials of recombinant human elastase administration immediately after radiocephalic arteriovenous fistula creation in patients with chronic kidney disease to enhance maturation. Dr. Ozaki was involved not only in several phase III trials related to this compound, but he also spearheaded data reporting. Name of study: Watching Our Waste: A Systematic Behavioral and Educational Program to Reduce the Environmental Impact in Procedural Areas PI: Louis L. Nguyen, MD, MBA, MPH Funding source: Brigham and Women’s Hospital, Brigham Care Redesign Incubator and Startup Program (BCRISP) Funding amount: $50,000 Brief description of study w/goals and objectives: The project aims to reduce waste, increase recycling, and increase instrument reprocessing in the operating room and other procedural areas. Education, choice architecture, and tracking/reporting will serve as the foundation to implement new programs to minimize the environmental impact, while providing safe and effective patient care. Exemplary Publications Madenci AL, Ozaki CK, Gupta N, Raffetto JD, Belkin M, McPhee JT. Perioperative Outcomes of Elective Inflow Revascularization for Lower Extremity Claudication in the American College of Surgeons National Surgical Quality Improvement Program Database. Am J Surg. 2016;212(3):461-467. Arnaoutakis D, Deroo EP, McGlynn P, Coll MD, Belkin MB, Ozaki CK. Improved Outcomes with Proximal Radial-Cephalic Arteriovenous Fistulas Compared to Brachial-Cephalic Arteriovenous Fistulas. J Vasc Surg. 2017; 66(5):1497-1503. 128

Scully RE, Schoenfeld AJ, Jiang W, Litpsitz SR, Chaudhary MA, Learn PA, Koehlmoos T, Haider AH, Nguyen LL. Defining Optimal Opiate Pain Medication Prescription Following Common Surgical Procedures. JAMA Surg. 2017 Sept PMID 28973092. Longchamp A, Mirabella T, Adruini A, MacArthur M, Das Abhirup, Treviño-Villarreal JH, Hine C, Ben- Sahra I, Knudsen N, Brace LE, Reynolds J, Mejia P, Tao M, Sharma G, Wang R, Corpataux JM, Haefliger JA, Ahn KH, Lee CH, Manning BD, Sinclair DA, Chen C, Ozaki CK, Mitchell JR. Amino Acid Restriction Triggers Angiogenesis Via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell. 2018;173(1):117-129. McGlynn P, Arnaoutakis D, Deroo EP, Ozaki CK, Hentschel DM. Post-Anesthetic Ultrasound Facilitates More Preferential Hemodialysis Access Creation without Impacting Access Patency. J Vasc Surg. 2019; 69(3):898-905. Bertges DJ, Smith L, Scully RE, Wyers M, Eldrup-Jorgensen J, Suckow B, Ozaki CK, Nguyen LL. A Multicenter Prospective Randomized Trial of Negative Pressure Wound Therapy for Infrainguinal Revascularization with a Groin Incision. J Vasc Surg. 2021 Feb 4 PMID 33548422. D. EDUCATIONAL ACTIVITIES The vascular training program, directed by Matthew Menard, MD, remains nationally preeminent. It is a fully ACGME-accredited two-year program, providing increased opportunities for residents to perform clinical research, participate in minimally invasive procedures and certify in noninvasive laboratory evaluation. Since the last reporting cycle, an additional fellowship slot was approved. The fellowship includes unique opportunities for elective rotations, travel, clinical research and postgraduate courses, as well as a full array of curricular activities. The division has established a research and education fund for the purposes of supporting special educational opportunities and selecting seed money for research. For more information about the fellowship, see Appendix 3. Mentoring The mentorship of general surgery residents in the field of vascular surgery is a key focus and responsibility of the division. This mentorship takes many forms. At the most basic level, are the daily teaching interactions, which include teaching in the operating rooms, clinics, on rounds and the vascular laboratory. Over the last decade, the division has instituted a daily teaching conference where x-rays and cases are reviewed at the beginning of the workday. The residents (particularly junior residents) have found this useful in understanding the complex nature of vascular surgical care. Attendings also have formal walk rounds and a comprehensive interdisciplinary teaching conference once a week. Those residents expressing interest in vascular surgery are invited to the regional and national meetings. Members of the division are actively involved in the HMS student education in surgery, giving didactic lectures and working as preceptors. 129

To stimulate general surgery residents toward a career in academic vascular surgery, general surgery residents are invited to participate in clinical research projects on the vascular surgery service. This has resulted in presentations at regional and national societies and publications in major surgical journals. E. CURRENT CHALLENGES As a division, it is a challenge to continue to maintain high-quality, multidisciplinary care in an ever- changing environment, with multiple clinic practice sites and increasing patient and operating room volumes, while maintaining fiscal solvency and competitiveness, as well as our research and education missions. F. VISION AND FUTURE OPPORTUNITIES In the coming years, we aim to grow our venous care and hemodialysis access programs clinically. We must strategically transition to new faculty for key positions such as division chief and research leaders, while consciously enhancing our team’s diversity at all levels. Additionally, in the medium term, we are exploring opportunities for joint initiatives with Massachusetts General Hospital for enhanced clinical care and education. 130

Research A. OVERVIEW The Department of Surgery (DOS) has a proud history of academic achievement dating back to 1923, when Dr. Eliot Cutler performed the world’s first successful heart valve surgery. In 1953, Dr. Joseph Murray performed the first successful human organ transplant – a kidney transplanted from one identical twin to another. In 1990, Dr. Murray was honored with the Nobel Prize for this achievement. Investigators in the department continue to do pioneering work. • In 2008, Brigham and Women’s Hospital surgeons were the first in the nation to perform transoral obesity surgery. • In 2011, a plastic surgery team was the first in the country to perform a full-face transplant. • In 2016, Brigham surgeons performed a first-of-its-kind surgical amputation procedure, in collaboration with investigators from the Massachusetts Institute of Technology, that resulted in the patient’s brain interacting with a specially made robotic prosthesis. Ongoing research efforts span clinical, basic and translational work that is recognized nationally and internationally. Research is a critical element of the department’s mission to advance scientific research leading to critical breakthroughs that positively impact patients today and for generations to come. Research is conducted by members of all 11 clinical divisions, as well within three centers: The Center for Surgery and Public Health (CSPH), The Gillian Reny Stepping Strong Center for Trauma Innovation, and the Patient Reported-Outcomes, Value, and Experience (PROVE) Center. The department also houses three core facilities, which are discussed later in this section. Research is performed and supported by more than 100 faculty members and staff, including MD and PhD investigators, research fellows and laboratory staff, clinical research staff, and research administrative staff who work at the main Brigham campus and at Dana-Farber Cancer Institute (DFCI). The DOS currently has 454 active research funds, including almost 200 active grants and contracts. Among the funding mechanisms are R01, R21, K08, K76 and U01 grants from the National Institutes of Health (NIH), as well as grants from the Department of Defense (DOD), foundations, nonprofit organizations and industry. 131

The department has a well-organized administrative structure led by Gerard Doherty, MD, and Elizabeth Mittendorf, MD, PhD, the vice chair for Research. Dr. Mittendorf oversees a DOS Research Oversight Committee. There is also a central research administration office that provides support for pre- and post-award, as well as clinical research, contracting and all other research-related matters. Report from the Vice Chair – Key Accomplishments • Restructured the central research administration team to include an administrative director who works closely with Dr. Mittendorf to grow and support the research faculty in the DOS. • Strengthened support of clinical research activities by creating a senior clinical research manager position to oversee clinical research efforts. • Enhanced pre- and post-award processes to better support faculty. The pre-award process was streamlined by implementing Elizabeth Mittendorf, MD, PhD a standardized intake form, which has facilitated compliance with recently implemented institutional guidelines; grants must be submitted for review by central research management prior to submission to funding agencies. Post-award has been enhanced by creating standardized financial reports for faculty members. • Increased support for junior faculty by creating the Beal Fellowship (awarded annually) and formalizing a grant writing seminar in collaboration with the departments of surgery at Beth Israel Deaconess Medical Center and Massachusetts General Hospital. • Completed review of assigned laboratory space and reallocated to increase funding density. Central Research Infrastructure The DOS has established central research infrastructure to support investigators from the clinical divisions and centers. Led by an administrative director, the Central Research Team has eight team members and supports all aspects of research: pre- and post-award, laboratory operations, space management, and clinical and human subject research. Services include: • Pre-award support, including identification and dissemination of funding opportunities, proposal preparation and ensuring that all proposals submitted comply with agency guidelines • Post-award support, including award set up, fund monitoring, regular financial reporting, assistance with progress reports and closeouts, and effort management and reporting • Laboratory operations and compliance support, ensuring staff are up to date on all required compliance training, assisting with the management of IACUC protocols, and providing guidance on general laboratory policies, biohazard waste and chemical usage • Clinical and human subjects research support, including the review and negotiation of clinical trial agreements and budgets, assisting with submission of regulatory documents with the Institutional Review Board (IRB), and assisting with monitoring and oversight of studies 132

Research Oversight Committee The Research Oversight Committee has responsibility for the Surgical Research Office and research activities of the DOS, including the review and recommendation of funding support for DOS research activities, specifically including bridge funding and utilization of start-up funding. The Research Oversight Committee also oversees the General Surgery resident research placement and funding process. Exhibit 7: Department of Surgery Research Oversight Committee Membership Division Member Breast Surgery Christina Minami, MD Tsuyoshi Kaneko, MD Cardiac Cardiac - Basic Marie Billaud, PhD General and Gastrointestinal Eric Sheu, MD, PhD Surgery General and Gastrointestinal James Yoo, MD Surgery Herve Sroussi, DMD, PhD Oral Surgery Jennifer Shin, MD Otolaryngology Indranil Sinha, MD Plastic Surgery Surgical Oncology Jiping Wang, MD, PhD Steven Mentzer, MD Thoracic Assunta De Rienzo, PhD Thoracic - Basic Stefan Tullius, MD, PhD Joaquim Havens, MD Transplant Mark Preston, MD, MPH Trauma Urology Keith Ozaki, MD Vascular Quoc-Dien Trinh, MD Joel Weissman, PhD CSPH - Clinical CSPH - Nonclinical Andrea Pusic, MD Mark Fairweather, MD PROVE Center Resident Research The committee meets quarterly and is comprised of 18 members representing each division and center. Both clinical and basic investigators are members of the committee. 133

B. RESEARCH FUNDING Research Expenditures Research expenditures in the Department of Surgery totaled $38.2 million in FY21. The decrease from research expenditures in FY19 and FY20 reflects the impact of the COVID-19 pandemic on research activities. Importantly, direct cost revenue increased during FY21. Below are snapshots of the research expenditures over the last five years for the DOS as a whole, then broken down by sponsor type. Exhibit 8: Five-Year Research Expenditures: All Sponsors (in millions) Total Expenditures ( millions $) 45.00 5.70 8.20 7.70 6.60 40.00 25.00 6.70 32.70 31.60 35.00 FY17 FY20 FY21 30.00 26.40 31.80 25.00 20.00 15.00 10.00 5.00 - FY18 FY19 TDC IC Exhibit 9: Five-Year Research Expenditures: Department of Health & Human Services (DHHS) Total Expenditures ( millions $) 25.00 2.70 3.20 4.60 4.00 3.60 20.00 13.60 14.30 18.00 18.10 18.10 15.00 FY17 FY20 FY21 10.00 5.00 - FY18 FY19 TDC IC 134

Exhibit 10: Five-Year Research Expenditures: Other Federal Funding (i.e., Department of Defense) Total Expenditures ( millions $) 3.50 0.80 0.80 0.47 0.68 2.30 1.90 3.00 FY20 FY21 2.10 2.30 2.50 FY18 FY19 2.00 0.53 TDC IC 1.50 1.00 1.60 0.50 - FY17 Exhibit 11: Five-Year Research Expenditures: Federal Subcontracts Total Expenditures ( millions $) 4.50 1.30 1.40 1.40 0.82 2.30 1.30 4.00 2.60 2.40 FY20 FY21 3.50 FY18 FY19 TDC IC 3.00 1.10 2.50 2.00 1.50 1.00 2.40 0.50 - FY17 135

Exhibit 12: Five-Year Research Revenue: Industry & Corporate Total Expenditures ( millions $) 2.50 0.62 0.35 0.36 0.90 0.89 2.00 0.47 FY20 FY21 1.40 1.50 0.39 0.83 1.00 FY18 FY19 0.50 1.20 TDC IC - FY17 Exhibit 13: Five-Year Research Expenditures: Foundations Total Expenditures ( millions $) 1.80 0.24 0.14 0.10 1.60 0.16 0.77 0.56 1.40 0.14 FY20 FY21 1.20 1.30 1.00 0.80 1.50 0.86 0.60 0.40 FY18 FY19 0.20 TDC IC - FY17 136

Exhibit 14: Five-Year Research Revenue: Non-Profit Organizations Total Expenditures ( millions $) 3.00 0.23 0.27 0.27 1.90 2.00 2.50 2.50 FY20 FY21 0.11 2.00 0.94 0.36 FY18 FY19 1.50 TDC IC 1.00 1.70 0.50 - FY17 Exhibit 15: Five-Year Research Revenue: Internal & All Other Sponsors Total Expenditures ( millions $) 9.00 0.66 0.85 0.96 0.56 6.40 6.80 8.00 FY20 FY21 4.90 7.00 3.80 6.00 FY18 FY19 TDC IC 5.00 4.00 0.46 3.00 2.00 3.30 1.00 - FY17 The chart on the next page shows the sponsor mix for FY21, with the U.S. Department of Health and Human Services representing 57% of research expenditures. 137

Exhibit 16: FY21 Research Sponsors 2% 3% 6% 6% 20% 6% 57% All Other Sponsors (including Internal) DHHS (NIH) Federal - Subcontracts Federal - Other (including DOD) Foundations Industry/Corporate Non-Profit Grant Submissions and Success Rates In FY21, the Department of Surgery submitted 219 proposals and agreements across all sponsors and funding mechanisms, with a 41.1% success rate. Proposal volume and success rate over the past five years is depicted in the chart below. The significant increase in proposal submissions since 2020 reflects restructuring of the DOS central research administrative team with increased pre-award support for DOS investigators. Exhibit 17: Proposal Volumes and Success Rates 250 235 60.0% 223 201 50.0% 42.6% 40.0% 200 176 48.1% 158 150 42.0% 41.8% 37.4% 30.0% 100 84 76 88 95 74 20.0% 50 10.0% 0 0.0% FY17 FY18 FY19 FY20 FY21 Proposals Awards Success Rate 138

C. RESOURCES Research Space The Department of Surgery currently occupies 35,968 square feet of assigned research space. Laboratories are located in the Thorn Building and the Eugene Braunwald Research Center. The department also has “dry lab” space at One Brigham Circle. Exhibit 18: Net Assignable Square Feet (NASF) 37,000 32,347 34,940 34,658 36,387 35,968 36,000 2017 2018 2019 2020 2021 35,000 34,000 33,000 32,000 31,000 30,000 Brigham and Women’s Hospital has an indirect cost (IDC) recovery rate of 79% for onsite projects. In FY21, the Department of Surgery generated $5.48 million in on-site indirect costs, with an indirect cost density of $152 per square foot. Over the past year, the department has undertaken a thorough assessment of space utilization in an effort to align space allocation with funding, thereby maximizing the indirect cost density. Exhibit 19: Funded Research Space ($/square foot) $600 $354 $340 $469 $507 $396 $500 $125 $143 $188 $189 $152 $400 $300 2017 2021 $200 $100 $- 2018 2019 2020 MTDC Density IC Density 139

Research Cores The DOS houses three core facilities that provide scientific investigators across the Brigham with critical tools to support their research efforts. CyTOF Antibody Technical Resource and Core Director: James Lederer, PhD Mass cytometry (CyTOF) is a transformative cell phenotyping technology routinely used in immunophenotype complex cell mixtures from blood or tissues, using specialized metal isotope-labeled antibodies. The data generated by CyTOF provides high dimensional and comprehensive single-cell phenotyping data to provide unprecedented views of the immune cell landscape in the blood or tissues of patients, or in mouse models for human diseases. The Harvard Medical Area (HMA) CyTOF Antibody Technical Resource and Core was established in 2016 with initial funding support from the Brigham Biomedical Research Institute and the Infectious and Immunological Research Center. This research core was founded as a technical resource for CyTOF with specific aims to develop a collection of human and mouse CyTOF-ready antibody reagents at a no-profit cost structure, and to provide a resource for implementing CyTOF technology workflows for the research community. The HMA CyTOF core currently has a collection of more than 600 validated CyTOF-ready labeled human and mouse antibodies to support clinical and pre-clinical research programs. Core technicians label, validate and distribute CyTOF antibodies to many research groups in Boston, nationally and overseas. Last year, the core had $165,000 in net sales of CyTOF-ready antibodies; 650 orders have been fulfilled over the past five years. More importantly, the CyTOF core has benefited the immunology research community by providing letters of support for approximately 30 different NIH-supported research programs, including technical support for six junior investigators who secured their first NIH research awards. The laboratory is well-known for using CyTOF technology and has been awarded six different NIH research awards on topics ranging from autoimmune diseases, traumatic injury, skin diseases and cancer, totaling $3.5 million over the past five years. The CyTOF core research group has authored 16 CyTOF-centric papers over the last five years in high impact journals. Future plans for the HMA CyTOF Antibody Technical Resource and Core include continuing to support the immunology research community by providing access to an expanding collection of human and mouse CyTOF-ready antibodies, and by sharing novel technical advances in using CyTOF as a valuable research tool. 140

Tissue and Blood Repository Director: William Richards, PhD The Brigham Tissue and Blood Repository was established as a fee-for-service research core resource in 2000 with the involvement of Brigham departments of Surgery, Pathology and Medicine. The core’s mission is to provide a centralized mechanism to acquire, process, store and distribute fresh and frozen human biospecimens for the purpose of supporting clinical trials and correlative translational research. Complementing the activities of the Histopathology and Crimson cores – which provide research access to archived clinical tissue blocks and leftover portions of clinical laboratory specimens, respectively – the Tissue and Blood Repository provides high quality biorepository services primarily for portions of surgically resected tissue specimens not retained for diagnostic pathology purposes, as well as biopsy and phlebotomy specimens obtained explicitly for research purposes under IRB-approved protocols. Services include the timely acquisition, processing, cataloguing, linked de-identification, protected storage and distribution of biospecimens. The core also has an “honest broker” role, ensuring compliance with regulatory controls relevant to biospecimens as specified by the Common Rule, HIPAA and the provisions of individual IRB-approved protocols governing the supported research. Such activities include: • permanent, protected information storage • status confirmation of IRB protocol approval • patient informed consent to biospecimen collection/use, and • required designation and certification of study staff receiving protected information. Core operations adhere to evolving best practices and standards issued by biobanking associations, state and federal agencies, as well as Good Laboratory Practice and appropriate regulatory policies required by the hospital. The Tissue and Blood Repository annually processes specimens from approximately 1,200 surgical cases, representing primarily resections of solid tumor but also a variety of benign disease and uninvolved normal tissues. Clients of the core range from individual investigators to disease programs and multidisciplinary teams, which are mostly located at the Brigham and DFCI. Some core services are also available to academic researchers at other centers. The operations director and manager have overseen core activity since its inception. Daily operations performed by core staff adhere to SOPs agreed upon by each client account among core management, client investigators and disease site-specific section chiefs in the Department of Pathology. 141

The Center for Surgery & Public Health (CSPH) Data Support Services Core Director: Melissa Poleo, MS The mission of the CSPH Data Support Services Core is to promote and advance health services research by providing data infrastructure support to CSPH researchers and surgeon scientists. Established in 2021, the core provides data handling and data analysis services. Data handling is accomplished by storing data on a secure server and accessing it via a virtual computing environment with multi-use licenses for common statistical software. Data analysis is accomplished by the provision of statistical support, scientific review and methods guidance for investigators. The CSPH Data Support Services Core offers access to a secure server to store and work with data in a secure computing environment. Security and compliance measures include physically securing the server and the data backup site, in addition to data encryption. The core serves as a central resource for databases, database administration, information retrieval, and provides biostatistical methodology consultation to faculty and researchers. The CSPH data manager ensures access to the server meets all compliance requirements, including data encryption, physical safeguards and offsite data backup. Data available through the CSPH server includes 18 different sources, including nationwide and state- level longitudinal hospital care data through the Healthcare Cost and Utilization Project (HCUP), the American College of Surgeons National Surgical Quality Improvement Program and Medicare claims. The CSPH data core acquires new data as appropriate to support the CSPH mission and makes data available to all researchers as allowed. Investigators can also store project-specific data on the CSPH server. D. CLINICAL RESEARCH As of October 2021, the DOS manages over 200 active clinical research protocols, including more than 50 active clinical trials. The clinical trials are funded by federal agencies, industry, foundation and departmental funds. Given the volume of ongoing clinical research, the DOS created a senior clinical research manager position in 2021. This individual oversees the clinical trial portfolio to include reviewing and negotiating clinical trial agreements and budgets, assisting with submission of regulatory documents with the IRB and assisting with monitoring studies. 142

Exhibit 20: Department of Surgery Federally Funded Clinical Trials (2016-2021) PI Name Title Sponsor Dr. Aranki Network for Cardiothoracic Surgical Investigations in NIH via the Icahn Dr. Bueno Cardiovascular Medicine: Anticoagulation for New Onset School of Dr. Carty Postoperative Atrial Fibrillation after CABG Medicine NIH via New York Dr. Carty The EDRN Mesothelioma Biomarker Discovery Laboratory University Dr. Carty A Novel Approach to Lower Extremity Amputation to Department of Augment Volitional Motor Control and Restore Defense Dr. Kibel Proprioception Dr. Kibel A Novel Approach to Upper Extremity Amputation to Department of Dr. Menard Augment Volitional Motor Control and Restore Defense Dr. Preston Proprioception A Novel Approach to Lower Extremity Residual Limb Department of Dr. Swanson Revision to Augment Volitional Motor Control, Restore Defense Dr. Wolfe Proprioception and Reverse Limb Atrophy NIH-NCI via the EDRN Prostate MRI Biomarker Study and Reference Set University of Michigan Pilot Study of an Implantable Microdevice to Test Multiple Drug Responses in Prostate Cancer Patients NIH-NCI BEST-CLI Trial A Phase II Multi-Institutional Trial to Evaluate Prostate NIH-NHLBI Specific Membrane Antigen (PSMA)-Based PET Imaging of High-Risk Prostate Cancer NIH via Westat, Comparative Effectiveness of Limited Resection vs. Inc. Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer NIH via the Icahn Prevalence Effects in Visual Search: Theoretical and School of Practical Implications Medicine NIH-NEI 143

Alliance for Clinical Trials in Oncology Since 2011, the DOS has overseen the Alliance for Clinical Trials in Oncology (Alliance). Under the leadership of Monica Bertagnolli, MD, the Alliance is a multi-institutional, international cancer clinical trials consortium. The goal of the Alliance is to design studies that bring the greatest possible benefit to patients with cancer and to make these trials available to everyone who needs them. Dr. Bertagnolli has led the Alliance as its group chair since its inception in 2011, when the organization was created by a merger of three legacy clinical trials groups: Cancer and Leukemia Group B, the North Central Cancer Treatment Group and the American College of Surgeons Oncology Group. Other DOS members who currently hold significant roles in the Alliance include: • Steven Piantadosi, MD, PhD, associate group chair for Strategic Initiatives and Innovation • Anna Weiss, MD, Alliance executive officer, Breast Cancer Clinical Research and Patient- Centered Outcomes Research Institute (PCORI) Programs • Jiping Wang, MD, PhD, study chair, Gastrointestinal Cancers Committee trials for gastric and hepatocellular cancer Department members with leadership roles in the past five years include: • Elizabeth Mittendorf, MD, PhD, co-chair, Alliance Immuno-Oncology Committee (2017-2020) • Mark Fairweather, MD, Alliance executive officer, ICAREdata Initiative (2018-2020) Alliance research has expanded considerably over the past 10 years, maintaining a portfolio of 100-120 active clinical trials at any one time, approximately half of which represent actively enrolling trials. The remainder are trials either in development or with enrollment completed and awaiting endpoint reporting. In the United States, Alliance consortium members represent 70 community oncology programs and 48 academic medical centers. International trials are conducted in collaboration with clinical trials groups in Australia, Austria, China, France, Germany, Italy and Spain. Alliance enrolls approximately 3,600-4,400 patients per year and produces an average of 61 scientific publications per year, 25% of which are published in journals with an impact factor greater than 10. Funding for Alliance research comes from the National Cancer Institute, the U.S. Food and Drug Administration (FDA), the Patient-Centered Outcomes Research Institute, multiple pharmaceutical industry sponsors and a number of oncology- focused nonprofit foundations. 144

ICAREdata Project In 2018, Dr. Bertagnolli and Dr. Piantadosi began a collaboration with the goal of modernizing clinical data collection for oncology research. Together with colleagues from MITRE Corporation (a federally funded research and development center), they launched an initiative within the Alliance known as the Integrating Clinical Trials and Real-World Endpoints data (ICAREdata) Initiative. The primary goals of this project are to develop the infrastructure required to collect research data directly from the electronic health record (EHR) of treating institutions, to use this data to conduct clinical research of sufficient quality for use in therapy development, and to support the approval of new therapies by the FDA and other regulators. A secondary but equally important goal tier is to increase the quality of data collected from the routine clinical care environment so it can be aggregated at scale to better inform care delivery and health policy development. Accomplishments to date include the launch of an HL7-approved data standard, known as minimum Oncology Data Elements (mCODE) that permits cross-institutional data interoperability and electronic data transfer (via FHIR) sufficient to meet basic requirements of cancer clinical research. Working with the EHR vendor, EPIC, the mCODE developers introduced the mCODE data structure into the EPIC EHR, so that every institution using EPIC can deliver data in this format. To promote mCODE use, an FHIR accelerator, known as Codex, was developed under the direction of MITRE Corporation. In 2019, the Alliance launched the ICAREdata Initiative as a clinical research use case within Codex. Funding from the FDA is currently supporting Alliance ICAREdata clinical trials (N=6) that collect research data via the EHRs of member institutions, including the Brigham, MGH and DFCI. A special project, led by Dr. Piantadosi, is underway in collaboration with the FDA to add the collection of treatment-related adverse events. A team led by Selina Chow, MD (Alliance Foundation), is implementing radiographic image collection for Alliance trials. Within the next two to three years, it is anticipated that the ICAREdata infrastructure will be in operation across most Alliance institutions, greatly facilitating multi-institutional clinical trials, cancer care delivery research and therapeutic agent post-market surveillance. Importantly, the use of this resource is not restricted to the Alliance, but will be available to the entire HMS community for use in clinical research of all types. 145

E. RESEARCH CENTERS The DOS houses three research centers: The Center for Surgery and Public Health (CSPH), The Gillian Reny Stepping Strong Center for Trauma Innovation, and the Patient-Reported Outcomes, Value, and Experience (PROVE) Center. The Center for Surgery & Public Health Directors: Zara Cooper, MD, and Melissa Poleo, MS One of the founding programs in surgical health services research, the CSPH is a national leader in the science of surgical care delivery, producing research that informs policy and program development for the delivery of safe, high quality and equitable patient-centered care. Founded in 2005 as a joint initiative of Harvard Medical School, the Harvard T.H. Chan School of Public Health and the Brigham, CSPH has trained more than 100 surgical health services researchers. From national data sets to patient focus groups, CSPH leverages the power of data and integrates the voices of patients and providers to transform how health care is delivered. Exploring surgery through a public health lens, research at CSPH expands beyond the operating room, examining interactions within the health care system and the social determinants and lived experiences of patients. Locally, CSPH researchers are working with multidisciplinary providers to address the equity gap in telemedicine for patients with limited English proficiency. Leading a growing multi-institutional research collaboration of Boston-area hospitals, the Functional Outcomes and Recovery after Trauma Emergencies (FORTE) project collects, analyzes and interprets long-term patient-centered outcomes after traumatic injury in the United States. With the largest database of long-term trauma outcomes, the FORTE project continues to produce novel research showing how a patient’s age, gender, race and education impacts their recovery far more than the severity of their injury. CPSH researchers are also working to improve surgical outcomes for patients that are not well-served by existing health care practices, including older and seriously ill patients, patients with dementia, and sex and gender minorities. They are studying how to improve interactions between patients, their caregivers and health professionals, and implementing new care pathways that are better adapted to patient 146