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AMA Research Challenge 2022

Inflammatory Bowel Disease and its Association with Melanoma and Non-Melanoma Skin Cancers

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Ricardo Correa, MD, EdD
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Stuart M. Greenstein, MD
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Stephanie Strohbeen, MD
 
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Jessica Li, MD/PhD Candidate
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Charles Lopresto, DO

### Sponsor
AMA would like to thank Laurel Road for sponsoring a $10,000 grand prize for the winner of the AMA Research Challenge. Laurel Road is not involved in the judging or scoring process to select the winner. The winner will be announced on Dec. 7 during the AMA Research Challenge finals. Payment of the grand prize will be directly from Laurel Road. See the AMA Research Challenge Official Rules for terms and conditions.

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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


poster

Background
Inflammatory bowel disease (IBD) is complex, easily misdiagnosed and mismanaged. Multidisciplinary care improves patient outcomes. Yet, few hospitals have a multidisciplinary team approach to IBD care that consistently includes a gastrointestinal expert pathologist. This study aims to quantify the impact an expert pathologist has on a multidisciplinary team in the care of difficult IBD patients.

Methods
A retrospective chart analysis was performed on patients (N=283) discussed at the semi-monthly multidisciplinary IBD conference at Carilion Clinic, from June 1, 2013 through December 31, 2019. Each patient was presented between one and six times at the conference. Data collected: demographics, baseline clinical characteristics, diagnosis before and after conference, reason for diagnostic change, endoscopy findings, medications, surgeries, and if clinical remission was achieved within 6 months after conference.

Results
After the first conference, 42% of patients presented had a diagnostic change: 84% due to expert pathologist interpretation, 12% due to radiology, and 4% due to other reasons. Majority of diagnostic changes after the second (73%), third (67%), and fourth (100%) conferences were also attributed to pathology. Crohn disease was the most common new diagnosis after conference, and indeterminate colitis was the most commonly changed diagnosis. For patients newly diagnosed with ulcerative colitis after conference, most had moderate active colitis (54%), whereas for those newly diagnosed with Crohn disease, colitis severity was distributed similarly between none (22%), mild (26%), moderate (28%), and severe (24%). Approximately 24% to 35% of patients presented had a change in IBD medication, among which ~34% to 40% had a diagnostic change. Following the conference, ~17% to 20% of patients underwent surgical intervention, among which ~12% to 27% had a diagnostic change. A majority of these patients achieved clinical remission within 6 months of the conference.

Conclusion
The majority of diagnostic changes made at the multidisciplinary IBD conference were due to histopathologic re-interpretation. A change in diagnosis at times led to significant modifications in disease management through surgery or medication changes. Multidisciplinary care teams are essential to the best management of complex IBD patients. An expert gastrointestinal pathologist is a critical team member to the discussion of nuances of each patient’s case.



Multidisciplinary Inflammatory Bowel Disease Conference: The Contribution and Impact of Pathology on Patient Care 

Background
Ogilvie syndrome, also known as acute colonic pseudo-obstruction (ACPO), is a rare form of idiopathic colonic dilation without mechanical obstruction. It typically occurs in elderly patients who have recently been hospitalized or undergone surgery with an incidence rate of about 100 cases per 100,000 hospitalizations every year. Despite neostigmine being the treatment of choice, we highlight the importance of early management and diagnosis. 

Case Presentation
A 76-year-old male with a history of class III obesity, diabetes mellitus, systolic heart failure, and ulcerative colitis well-controlled with sulfasalazine was admitted due to acute lower back pain with radiculopathy to lower extremities after lifting heavy boxes. The hospital course was complicated by developing acute kidney injury. In addition, a gradually enlarging but painless abdominal distension was noted, along with severe constipation. Serum measurements reflected persistent hypokalemia, leukocytosis, and elevated creatinine. Abdominal imaging revealed a markedly dilated colon with a cecal diameter of 12.8 cm but without signs of inflammation or perforation. Although neostigmine, correction of electrolytes, and rectal tube placement initially alleviated his condition, the abdominal distention continued to worsen. On day 16 of his stay, a repeat abdominal computed tomography showed pneumoperitoneum and the patient required emergent surgery. A 4cm perforation was appreciated in the transverse colon resulting in a total colectomy with end ileostomy. The patient recovered without complications after the surgery. 

Discussion
Although the etiology remains unclear, our patient’s advanced age and renal and cardiac comorbidities potentially precipitated the onset of Ogilvie syndrome, causing a perforated colon. The risk of perforation is increased when the cecal diameter is larger than 12cm, and the colonic distension lasts greater than 6 days, both of which were observed in our patient. Management of Ogilvie syndrome is primarily focused on urgent bowel decompression and correction of electrolyte abnormalities. Although neostigmine has been shown to rapidly alleviate Ogilvie syndrome, our patient did not respond accordingly. The mortality rate in Ogilvie syndrome increases with surgical management, regardless of the presence of perforation, and can reach up to 40% following a perforated colon. Therefore, early diagnosis and conservative management of Ogilvie syndrome are important to prevent serious complications.

Perforated Colon Caused by Neostigmine Refractory Ogilvie Syndrome

Background: Children with inflammatory bowel disease (IBD) are at risk of venous thromboembolic events (VTE). The efficacy of low molecular-weight heparin (LMWH) in preventing VTE in pediatrics is undetermined, but it is used for VTE prophylaxis. We offered prophylaxis to high-risk inpatients based on risk-stratification. We aimed to assess the efficacy of prophylactic LMWH in preventing VTE in high-risk pediatric IBD inpatients.

Methods: We performed a retrospective chart review at Seattle Children’s Hospital from 2012–2021. We included IBD patients aged 0-18 hospitalized with colitis flares. Patients admitted for surgery, perianal abscess, or non-IBD colitis were excluded. VTE risk factors were personal or family history of VTE, thrombophilia, thrombogenic medication use, smoking, obesity, or central venous line (CVL). Serious events were pulmonary embolus, stroke, or cerebral sinus venous thrombosis. The index case, first admission during the study period or with VTE, was used for analysis.

Results: 415 patients were included. Mean age was 13 ± 4, with 52.8% male. 239 (57.6%) had Crohn’s disease and 170 (41.0%) ulcerative colitis. Common risk factors were CVL (45, 10.8%) and obesity (19, 4.6%). 25 patients received prophylaxis (6.0%). There were 10 VTE events (2.4%), 3/25 (12.0%) in patients on LMWH and 7/383 (1.8%) without. There was one serious event of left middle cerebral artery thrombus and stroke in a patient not on LMWH with no risk factors. There were no serious events in patients on LMWH. The incidence of VTE was significantly higher in patients on LWMH (p=0.001, 95% CI 0.039-0.165) with RR 6.7 (p=0.0039, 95% CI 1.84-24.3). Of the 7 VTE in patients not on prophylaxis, 3 occurred in patients with no risk factors, 2 in patients with 1 risk factor, and 2 in patients with 2 risk factors.

Conclusion: Prophylactic LMWH did not prevent VTE in high-risk pediatric IBD patients. However, our population at a tertiary hospital may be sicker than the baseline. An alternative prophylaxis regimen may be needed for high-risk patients. Further data is required to identify other risk factors for VTE, and randomized control trials are needed to establish the true efficacy of LMWH in this population.

Prophylactic enoxaparin fails to prevent thrombosis in high-risk pediatric inflammatory bowel disease

Background: COVID-19 has been accompanied by a 34% increase in revenue from the sale of alcohol largely attributed to young adults, households with children, and minority groups. From 2007-2014 hospitalizations due to alcoholic hepatitis and cirrhosis increased. As alcoholic liver disease is the leading cause for liver transplant in the U.S. and nearly 50% of liver related deaths, it is vital to better understand the pathophysiology of alcoholic cirrhosis and to identify biomarkers that predict which patients will progress to fibrosis.

Methods: Subjects were recruited with alcoholic cirrhosis at stage F4 of fibrosis (n = 11) and heavy drinkers without cirrhosis at stages F0-F3 of fibrosis (n = 11). Fibrosis was assessed by elastography, and alcohol consumption with the Alcoholic Use Disorders Identification Test-Concise (AUDIT-C) questionnaire. Untargeted LC-MS was performed on serum by Metabolon. Significance was assessed by Welch’s two sample t-test.

Results: There were no differences in age, gender, BMI, or AUDIT-C scores. Overall, 122 metabolites were upregulated and 127 downregulated in subjects with scores of F4 versus F0-F3. Pathway analysis revealed diacylgycerols, androgenic steroids, dihydroceramides, and glutathione metabolites were increased in non-cirrhotic subjects, while cirrhotic subjects showed increases in sterol metabolism, hemoglobin and porphyrin metabolism, and bile acid (primary and secondary) metabolism. Additionally, thymine and uracil pyrimidine metabolism were upregulated in cirrhotic subjects (F4), uncovering novel pathways for future biomarker studies. Specifically, cirrhotic subjects demonstrated increases in abundance of 5,6-dihydrothymine, 2’-O-methyluridine, 3-ureidopropionate, 5,6-dihydrouracil, and uracil. With respect to tryptophan metabolites, our analysis showed significant upregulation in circulating levels of kynurenine, oxindolylalanine, tryptophan, as well as significant decreases in 3-indoxyl sulfate, serotonin, and xanthurenate in F4 subjects compared to F0-F3. The suggests an increase in IDO-1 activity during cirrhosis, shunting tryptophan away from serotonin synthesis towards kynurenine. We also identified metabolites with significant associations with fibrosis score such as 5,6-dihydrothymine (r = 0.88), taurochenodeoxycholic acid 3-sulfate (r = 0.84), leucine (r = -0.8), and retinol (r = -0.8)

Conclusion: Our findings elucidate metabolic alterations in alcoholic liver fibrosis with the identification of several pyrimidine and tryptophan metabolites that may be used for the assessment of alcoholic liver disease.

Serum Metabolome of Alcoholic Cirrhosis Patients Reveal Changes in Pyrimidine and Tryptophan Metabolites

We present the rare case of a 40-year-old male who was found to have a scrotal leiomyoma. Leiomyomas are benign tumors of smooth muscles. Very rarely, they can affect the smooth muscle layers of the scrotum (dartos and cremasters). In a review of 11,0000 scrotal tumors, only 11 cases were found to be leiomyomas.

A Leiomyoma Presenting as an Enlarging Scrotal Mass in a 40-year-old Male

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination elicits a variable, often suboptimal immune response among solid organ transplant recipients (SOTRs), who are at increased risk of severe COVID-19 compared to immunocompetent individuals. An accurate prediction model for lack of immune response to SARS-CoV-2 vaccination could provide for a more tailored approach to antibody testing, risk stratification, and clinical decision making. The objective was to create a prediction model for failure to generate an antibody response to threedose
SARS-CoV-2 vaccination in SOTRs.
Methods
782 thrice-vaccinated COVID-naïve SOTRs were recruited for this national prospective observational study. Participants underwent serologic antibody testing (Roche Elecsys antireceptor binding domain [RBD] or Euroimmun anti-spike enzyme immunoassays) before and 1 month after receiving a third dose of vaccine (D3). A machine learning model for predicting antibody response was created using the extreme gradient boosting (XGBoost) algorithm and validated using bootstrap validation.
Results
634 (82.3%) SOTRs were seropositive for antibodies against the spike protein before and after D3. Shorter time since transplant, mycophenolate use, corticosteroid use, and older age were key risk factors, collectively attributing to 86.6% of the model’s predictive ability. In the bootstrap validation, we observed a C-statistic of 0.80 (95% CI; 0.75, 0.83) and Brier score of 0.14 (95% CI; 0.13, 0.15), representing a good prediction performance and an 11.7% (95% CI; 7.6%,
14.4%) improvement in calibration over the non-informative model. A second model predicting antibody response after the second vaccine was created and assessed on its ability to predict antibody response after the third dose; this model showed a similarly high C-statistic (0.78 [95% CI; 0.74, 0.82]), suggesting that SOTRs with higher risk of negative antibody response to two doses remain at high risk for non-response even after subsequent doses.
Conclusion
Failure to generate an antibody response to SARS-CoV-2 vaccination in SOTRs can be predicted accurately. We created an online calculator for predicting lack of antibody response to D3 based off this model, enabling transplant professionals to perform more personalized risk assessments, therefore helping to identify which SOTRs may warrant prioritization for additional vaccine doses, antibody monitoring, and other protective measures.

A Machine Learning Model for Predicting Antibody Response After ThreeDoses of Vaccine Against SARS-CoV-2 in Solid Organ Transplant Recipients

Objective
This study examines trends in racial and gender diversity of trainees within Complex General Surgical Oncology fellowships. Further, this study compares the racial and gender proportions of trainees across different fields to assess potential barriers to increasing diversity within surgical oncology training programs.

Methods
Deidentified Accredited Council for Graduate Medical Education data were queried to identify surgical trainees between 2013-2021. Trainees were identified based on self-reported race and gender and were stratified based on residency type (i.e., general surgery and the overall trainee workforce, composed of all trainees in every program) and fellowship program if applicable. Chi-squared tests were used to assess differences between groups and trends.

Results
A significantly lower proportion of individuals who are underrepresented in medicine (URMs) trained in surgical oncology fellowships (8.9%) compared with both the overall trainee pool (12.8%) and general surgery residency programs (13.1%) (p < 0.05). There was no significant increase in URM representation in surgical oncology fellowships across the study period. In addition, there was a significantly lower proportion of females training in surgical oncology fellowships (38.6%) compared with the overall trainee pool (45.6%) (p < 0.05). Despite a significant increase in female representation in general surgery residency and other surgical fellowships, there was no significant increase in female representation in surgical oncology fellowships across the study period.

Conclusions
This study identifies disparities in gender and racial minority representation within ACGME-accredited Complex General Surgical Oncology fellowship training programs. While steps have been taken to expand diversity, more needs to be done to combat the systemic barriers that both racial minorities and women face during their training.

Analysis of Racial/Ethnic Minority and Female Representation in theSurgical Oncology Training Pathway

Introduction: Risk calculators to predict post-operative surgical site infections (SSI) often rely on logistic regression (LR) analysis. Machine learning models are able incorporate a greater number of input variables by identifying non-linear relationships. Automated machine learning (AutoML) processes regularly outperform regular machine learning (ML) and LR methods for predictive accuracy outside of healthcare settings. AutoML systems have not yet been applied to predict post-operative surgical site infections. 

Methods: We used an AutoML system developed and released by Amazon in 2020, AutoGluon v0.3.1, to predict post-operative SSI in the 2019 ACS NSQIP database. A total of 3,049,617 patients and 79 pre-operative variables were included. Post-operative SSI was defined as a superficial, deep or organ-space infection that occurred within 30 days of the surgery and was not present prior to surgery. Models were trained for four hours to optimize performance on the Brier score, with lower being better. Validation of all performance metrics was done using the 2019 ACS NSQIP database. 

Results: 2.41% of the patients (n = 73,581) developed post-operative SSI. Brier scores were calculated for each model with the top performing model being an ensembled XGBoost model having a Brier score of 0.00287 on the validation set. The corresponding AUROC and AUC-PR was 0.768 and 0.110 respectively (Figure).

Conclusions: Automated machine learning models offer similar discriminatory characteristics to existing postoperative SSI calculators. Future post-operative SSI models may benefit from AutoML analysis.

Automated machine learning (AutoML) with AutoGluon to predict post-operative surgical site infection (SSI) using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database

In the United States, >30 million people (10.5% of the population) have diabetes, both diagnosed and undiagnosed. Many of these patients go on to develop diabetes related complications, such as peripheral neuropathy; these patients are also prone to foot injury. The purpose of this study is to determine the outcome of an isolated foot burn in the diabetic patient. A retrospective chart review of adult (>18yo) patients admitted to a major metropolitan burn center at a safety-net hospital from 2008-2020 with an isolated burn to the lower extremity and a diagnosis of diabetes mellitus. The primary outcome was Hospital length of stay, The secondary outcome was infection, number of operations, amputations, and mortality. Subgroup analysis was done to see how HbA1C affect patient’s outcome. A total of 136 patients were included for evaluation. 79% of the patient were male. 84% of the patients were <65yo and the mean age was 54.1yo and HbA1C of 8.99. Scald injury was most common (54%). The average burn size was 2.29% TBSA. 54.5% of the patients had neuropathy. The average hospital length of stay was 15 days ± 14.5 SD. Mean length of stay for all patients at our burn center is 6.55 days/% TBSA burned (internal data). 73.5% of the patients underwent surgical excision. 22% of the patients underwent an amputation and 3.7% were admitted to the intensive care unit with an average ICU length of stay of 7 Additionally, there was 1 inpatient mortality. The study revealed that scald burn was the most common mechanism of burn. Diabetic patients delay seeking medical attention and have extended hospital length of stay, High rate of infection and amputation. Most of these burn injuries and outcomes are preventable with improved education of diabetic patient on foot burn and glycemic control.

DFB: Tiny burn, big problem - The implications of a diabetic foot burn  

Abstract Title: Efficiency of IES device in facilitating distraction enterogenesis for treating short gut syndrome.

Background
Short gut syndrome (SGS) is intestinal failure because of inadequate intestinal length often encountered by pediatric surgeons. In SGS, gut adaptation and enteral absorption is low, often requiring long term parenteral nutrition for adequate development. This poses increased risk for complications including line sepsis, necrotizing enterocolitis, and liver failure. Surgical options like small bowel implantation pose significant risks and often provide limited gut expansion. We aim to experimentally evaluate the efficiency of the intestinal expansion sleeve (IES) in determining lengthening of the native bowel. We hypothesize that intestinal expansion commensurate to the IES compression can be achieved already at time of surgery.

Methods
IES devices were made using proprietary cylindrical material with helicoid trusses and isometric ends measuring 30mm in length. Ends of the device were coated with a barium-sealant mixture preventing distress and improved visualization after placement. IES devices were pre-contracted over a dilator, leading to diametric expansion. Mechanical characterization of IES devices and native small intestine segments were performed using an Instron 8874 Biaxial servo hydraulic fatigue testing system. IES devices were implanted in ex vivo intestinal segments of Sprague Dawley rats. Post-deployment gut expansion was measured using calipers. Lastly, histological analysis of the gut tissue was performed for native and experimental tissue following IES removal.

Results
IES devices deployed in rat small intestine immediately produced lengthening of 2.17 ± .17cm to 2.75 ± .22cm (p<.001, n=11). Mechanical characterization demonstrated IES exerted longitudinal forces of 0.13 ± 0.01 N to 0.22 ± 0.01 N upon expansion to post deployment length. Mechanical characterization of native small bowel demonstrated that forces greater than 1.88 ± .21 N produced rupturing of the tissue. The data proves IES devices provide significant expansion without risk of small intestinal failure. Histological examination showed significantly decreased thickness of serosal, muscular, and mucosal layers of the small intestine. 

Conclusion
This study shows that distraction enterogenesis and intestinal lengthening can be achieved using novel IES devices without the risk of mechanical failure. The findings of this study ex-vivo specimens need further corroboration in vivo for long term outcomes.

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Inflammatory Bowel Disease and its Association with Melanoma and Non-Melanoma Skin Cancers

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