Faculty Bibliography

Introduction: Non-alcoholic fatty liver disease (NAFLD) is present in 36-70% of women with polycystic ovary syndrome (PCOS). Both are highly prevalent in subjects with obesity. Androgen overproduction in PCOS promotes a pro-apoptotic environment and may contribute to NAFLD. Our objective was to examine the association between PCOS and NAFLD diagnosis and if PCOS is an independent predictor of advanced fibrosis in patients with NAFLD.
Method(s): In a single-center retrospective analysis of electronic medical records, 625 adult patients ( .18 years old) with a diagnosis of NAFLD from 2018-2019 were divided into 3 cohorts: a female study group with PCOS, female control group without PCOS, and a male control cohort, age-matched to the study group. PCOS diagnosis was based on established PCOS society criteria. Our primary outcome was to assess the stage of liver fibrosis, as defined by histology, Fibroscan, MR elastography, NAFLD fibrosis score (NFS), by the age of initial diagnosis. Additionally, demographic, laboratory and clinical parameters were analyzed to compare the three cohorts. Demographics were analyzed using ANOVA, Pearson's chi-squared, and Kruskal-Wallis methods. Linear regression modeling NAFLD score as a function of age of diagnosis was performed.
Result(s): A total of 625 subjects with NAFLD were seen. Of these, 21 met criteria for the female NAFLD/PCOS study group, 525 in the female NAFLD only control group, and 79 age-matched male subjects with NAFLD. The NAFLD/PCOS females study group were significantly younger than the other two cohorts at time of diagnosis of NAFLD, had the highest BMI of 38.4, highest AST/ALT ratio of 0.92, lowest albumin value of 4.03, highest percentage of patients with physical signs of the male cohort was associated with a 0.7 reduction in NFS compared to women with NAFLD only. Females with NAFLD demonstrate significant difference in the mean NFS and mean age of diagnosis compared to the other 2 groups, while females with both versus males with NAFLD did not (Image 1).
Conclusion(s): Females with PCOS significantly demonstrated NAFLD at an earlier age supported by positive physical and radiological signs, and worse NFS vs. males at the time of initial NAFLD diagnosis.

Introduction: Critically-ill patients with COVID-19 often require long-term enteral access due to prolonged ventilator support and slow recovery from neurologic injury. The outcomes of hospitalized patients with SARS-CoV-2 who received gastrostomy tubes (GTs) are unknown and limited guidance exists on how to safely triage GT placement in this population. The Enteral Access Team (EAT) is a multidisciplinary team led by an attending gastroenterologist (GI) hospitalist with advanced practice providers who collaborate with Palliative Care, Geriatrics, Speech-Language Pathology, and Nutrition to reduce unnecessary feeding tube placements at the end-of-life. The EAT reviews the appropriateness of GT placement and triages each case to the indicated procedural service. The EAT's multidisciplinary approach was applied for patients with COVID-19.
Method(s): We performed a retrospective study of 135 hospitalized patients with positive PCR tests for SARS-CoV-2 who received GTs between 3/2020 and 4/2021. The GTs were placed by 3 services (gastroenterology, interventional radiology and surgery) at 3 hospitals within 1 health system in New York. One of the hospitals employed the multidisciplinary EAT approach to its triage of GT placement. Outcomes were compared between the EAT site and control sites where GT placement was decided through direct consultation by the primary team with one of the procedural services.
Result(s): Demographics for the two groups, including overall numbers of COVID-19 admissions, can be seen in Table 1. At the EAT site (n =43) 5% of patients expired prior to discharge following GT placement compared with 25% at the control sites (P <0.05). Patients at the EAT site were older with a mean age of 70 years compared to the control sites with a mean age of 63 years (P=0.01). There was no significant difference in the percentage of COVID-19 patients who received GTs, length-ofstay, or time from gastrostomy to discharge or death. Multivariable analysis showed the odds of in hospital mortality were 10.1 times greater with the standard workflow than with the EAT workflow (OR 10.1, [95% CI: 1.7-60.6], P <0.05).
Conclusion(s): The EAT's novel multidisciplinary team-based approach helps to appropriately select hospitalized patients with SARs-CoV-2 for long-term enteral access leading to reduced in-hospital mortality following GT placement. Additionally, this approach may help to mediate the national shortage of GTs and reduce the risk of exposure to providers involved in GT placement

Introduction: Cytotoxic drugs are hampered by limited efficacy. Hence, a personalized treatment approach matching chemotherapy with appropriate patients remains an unmet need. Genomic heterogeneity creates an opportunity to discern key genomic aberrations and pathways that confer resistance and response to standard treatment options. We conducted a study using the Cellworks Computational Omics Biology Model (CBM) to identify novel genomic biomarkers associated with response among Non-Small Cell Lung Cancer (NSCLC) patients receiving platinum-based treatments.
Method(s): 104 NSCLC patients who received platinum-based chemotherapy were selected from TCGA: platinum-etoposide (N=18), platinum-gemcitabine (N=20), platinum-vinorelbine (N=31), platinum-paclitaxel (N=21), and platinum-docetaxel (N=14). Mutation and CNV from each case served as input for the CBM to generate a patient-specific protein network-map based on PubMed and other resources. Biomarkers unique to each patient were identified within protein network-maps. Drug impact on the disease network was biosimulated to determine efficacy score by measuring the effect of chemotherapy on the cell growth score, a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. Effectively, the mechanism of action of each drug was mapped to each patient's genome and biological consequences determined response.
Result(s): Among the 104 patients, 74 were responders (R) and 30 non-responders (NR), determined using compete and partial response based on RECIST criteria (Figure 1). The CBM predicted clinical response with 73% sensitivity and 77% specificity. Cellworks CBM identified novel biomarkers responsible for platinum-based combination therapy response as mentioned below. +Etoposide: 13q-del, RB1-del, MBD1-del, LIG4-del, ERCC5-del, ATP7B-del +Gemcitabine: AKT3-amp, MAPKAP2-amp, TAP1-del +Vinorelbine: TET2-del/LOF, TRIB3-amp, SLX4-del +Paclitaxel: KLF4-del, SNCG-del, RAC1-amp/GOF +Docetaxel: BCL2L1-amp, HMGA1-amp, NSD1-del, SLC22A7-amp, FSIP1-del These genes contributed to drug efficacy by impacting various pathways, including DNA repair, oxidative-stress, methylation machinery, spindle formation, and mitotic-catastrophe. The aberration frequency of these genes was high among the responders within each subgroup and was very low in non-responders. Additionally, a model of clinical outcome versus the linear and quadratic function of efficacy score, drug combination and the interaction of both showed that efficacy score provides predictive information above and beyond the choice of drug combination alone (likelihood ratio chi-sq = 35.56, df=13, p-value = 0.0007). [Formula presented]
Conclusion(s): This pilot study highlights how the Cellworks CBM biosimulation platform can help identify patients for therapy response prediction. By using novel biomarkers, a CBM-informed decision tree can be employed to identify the optimal drug combination for platinum-based therapy. We suggest that this approach be validated prospectively in a larger patient cohort. Keywords: Cancer Therapy Biosimulation, Multi-omics Therapy Biosimulation, Personalized Cancer Therapy
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Introduction: Crohn's disease (CD) carries a major healthcare burden, costing over $10 billion a year in the United States. Strictures are a common complication of CD, emerging in over half of patients after 20 years from diagnosis, and requiring invasive interventions such as surgery which further increases healthcare costs. Endoscopic balloon dilation (EBD) has emerged as an alternative intervention in managing CD strictures. We determined the cost-effectiveness of EBD versus resection surgery for patients with short (<4-5cm) anastomotic or primary small or large bowel strictures.
Method(s): A microsimulation state-transition model simulated the benefits and risks of EBD and bowel resection surgery for patients with primary or anastomotic strictures due to CD. Our base case was a 40-year-old patient with CD who developed a stricture. Strategies included EBD or surgery as a patient's first procedure, after which they were allowed to receive either procedure based on probabilities of subsequent intervention derived from the literature. Our primary outcome was qualityadjusted life years (QALYs) over ten years, and strategies were compared using a willingness to pay of $100,000/QALY from a societal perspective. Costs (in 2021 $US) and incremental cost-effectiveness ratios (ICER) were calculated. Deterministic 1-way and probabilistic analyses assessed model uncertainty.
Result(s): The EBD strategy cost $19,822 and resulted in 6.18 QALYs while the surgery strategy cost $41,358 and resulted in 6.37 QALYs. Surgery had an ICER of $113,332 per QALY, making EBD a cost-effective strategy. The median number of EBDs was 6 in the EBD strategy and 0 in the surgery strategy. The median number of surgeries was 2 in the surgery strategy and 1 in the EBD strategy. Of individuals who initially received EBD, 50.4% underwent subsequent surgery. One-way sensitivity analyses showed that the probabilities of requiring repeated interventions, surgery mortality (, 0.6%), and quality of life after interventions were the most influential parameters in our model. Probabilistic sensitivity analyses favored EBD in 50.9% of iterations.
Conclusion(s): EBD, when feasible, is a cost-effective strategy for managing CD primary or anastomotic strictures. Sensitivity analyses show that differences in patient risk and quality of life after intervention can impact cost-effectiveness. The decision between EBD or surgery should be made considering cost-effectiveness, patient risks, and quality of life preferences

Introduction: PD-L1 is an immune checkpoint protein that mediates immune evasion. In Non-Small Cell Lung Cancer (NSCLC), its expression is used to predict the outcome of treatment targeting PD-1/L1. However, clinical benefits do not occur uniformly, and new approaches are needed to assist in selecting patients for immunotherapy.
Method(s): 26 patients with known clinical response to pembrolizumab were selected from publicly available data (PMID:25765070) (Table 1). Mutation and copy number aberrations from individual cases served as input into the Cellworks Omics Biology Model (CBM) to generate a patient-specific protein network map from PubMed and other online resources. Disease-biomarkers unique to each patient were identified within protein network maps. Digital drug biosimulations were conducted by measuring the effect of pembrolizumab on a cell growth score comprised of a composite of cell proliferation, viability, apoptosis, metastasis, and other cancer hallmarks. Drug biosimulations were conducted to identify and evaluate therapeutic efficacy.
Result(s): Among 26 patients treated with pembrolizumab, 14 were clinical responders, defined as stable disease or partial response lasting longer than 6 months, and 12 non-responders. Notably, 9/12 non-responders were PD-L1 positive (Table 1). Cellworks biosimulation predicted response with 84.6% accuracy, 75% specificity, and 92.86% sensitivity. Positive predictive value was 81.25% and negative predictive value was 90%. CBM identified that response was influenced by pathways that impacted the tumor microenvironment (TME). Deletions of adenosine pathway genes were observed in responders, whereas CNVs for these genes were enriched in non-responders (Table 1). Loss of ENPP1, and INSIG1 and SENP2 CNV aberrations, all of which regulate the STING pathway, could play a significant role in governing immune checkpoint blockade (ICB) response. Although STK11 loss appears to be a biomarker for poor ICB response, it was equally enriched in responders (n=7) and non-responders (n=7) in this dataset. Notably, responders had STK11 mutations and chromosome 6 loss, whereas non-responders had STK11 loss with chromosome 6 wild type or gain. Finally, frameshift mutations (FSM) enhance neoepitope formation and were higher in responders (average FSM = 48) vs non-responders (average FSM = 19). [Formula presented]
Conclusion(s): Alterations of the adenosine and STING pathways play key roles in determining benefit from PD-1/L1 targeting and highlight therapeutic possibilities for improving outcome in specific patient subgroups based on PD-L1 expression. The Cellworks CBM captures a holistic picture of the TME using tumor omics and improves response prediction beyond PD-L1 testing. Keywords: Multi-omics Therapy Biosimulation, Personalized Cancer Therapy, Immunotherapy Biosimulation
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Introduction: Gastrointestinal follicular lymphoma (FL) is a rare, but distinct extra-nodal variant of non-Hodgkin's lymphoma. Its incidence has grown outside of known genetic inheritance, due to epigenetic mutations from increased toxic exposure to benzene and pesticides, expanded life spans, and widespread standardized screening efforts. Diagnosis is by colonoscopy-obtained tissue staining and can be missed if alternative CRC screening methods are used in lieu. Case Description/Methods: A 54-year-old Ukranian male with a past medical history of HTN and GERD came in for an asymptomatic screening colonoscopy. One 8 mm polyp in the transverse colon was positive for FL. IHC staining demonstrated atypical small B-lymphocytes, positive for CD451, CD201, PAX51, CD101, and BCL-21. Bloodwork, including LDH, beta-2-microglobulin, were normal. A staging PET scan was negative indicating an isolated disease within the colonic polyp. As the patient was asymptomatic, no further treatment was indicated and the patient was scheduled for regular follow-up.
Discussion(s): GI FL is a B-cell lymphoma with an incidence slightly higher in women and a median age of 65. Occurrence outside of the bone marrow, spleen, or liver is uncommon. Descending incidence within the GI tract is the duodenum, ileum, stomach, and rarely colon. Within the colon, it presents asymptomatically. Definitive diagnosis is by a colonoscopy-obtained tissue staining. Colonoscopy adherence is generally high after the age of 65, given the median age of colorectal cancer incidence is 67 and the availability of Medicare coverage. However, if alternatively approved screening modalities are utilized such as the gFOBT, FIT, FIT-DNA, or flexible sigmoidoscopy, then the diagnosis of a FL might be missed until either mass or metastatic effects become apparent. Diagnostic work-up includes IHC staining for CD-20, CD-36, a follicular cell pattern, increase in B cells, bcl-2, bcl-6, and a 14:18 translocation by FISH or PCR (85% of cases). Investigation into a primary NHL, leukemia, or MDS includes flow cytometry, bone marrow biopsy, and cytogenetics. Increased LDH indicates rapid progression with staging done by PET or pan CTs. Colonic FL have a 10-year survival rate of 80% and an indolent course, so treatment is only indicated if the patient is symptomatic. Treatment for stage 1 is radiation, stages 2-4 is CHO P-R chemotherapy. Adjuvant or refractory treatments include anti-CD20 monoclonal antibodies, such as rituximab or obinutuzumab.

OBJECTIVE:Prolactin secreting tumors respond well to medical management with a small fraction of patients requiring surgery. We conducted a systematic review and meta-analysis to study the determinants of surgical remission in these tumors. METHODS:We searched PubMed to identify eligible studies reporting postoperative remission in patients treated with transsphenoidal surgery for prolactinoma. Primary outcomes included postoperative remission, follow-up remission, and recurrence. Postoperative and follow-up remission were defined as normoprolactinemia at less than and greater than one-year post-operation respectively. Recurrence was defined as hyperprolactinemia after initial normalization of prolactin levels. Odds ratios (OR) were calculated, stratified by radiological size, tumor extension, and tumor invasion, and analyzed using a random-effects model meta-analysis. RESULTS:Thirty-five studies were included. Macroadenomas were associated with lower rates of postoperative remission OR 0.20, 95% confidence interval [CI] 0.16-0.24) and lower rates of remission at follow-up (OR 0.11, 95% CI 0.053-0.22). Postoperative remission was less likely in tumors with extra- or suprasellar extension (OR 0.16, 95% CI 0.06-0.43) and tumors with cavernous sinus invasion (OR 0.03, 95% CI 0.01-0.13). Female gender and absence of preoperative dopamine agonist (DA) treatment were also associated with higher remission rates. Across the included studies, there was considerable heterogeneity in each primary outcome (postoperative remission I2=94%, follow-up remission I2=86%, recurrence I2=68%). CONCLUSIONS:Transsphenoidal surgery for prolactinomas may be particularly effective in small, non-invasive, treatment naive tumors and may provide a viable first-line alternative to dopamine agonist therapy in such patients.

BACKGROUND:Limited research has addressed the obesity-COVID-19 severity association in paediatric patients. OBJECTIVE:To determine whether obesity is an independent risk factor for COVID-19 severity in paediatric patients and whether age modifies this association. METHODS:SARS-CoV-2-positive patients at NYU Langone Health from 1 March 2020 to 3 January 2021 aged 0-21 years with available anthropometric measurements: weight, length/height and/or body mass index (BMI). Modified log-Poisson models were utilized for the analysis. Main outcomes were 1) hospitalization and 2) critical illness (intensive care unit [ICU] admission). RESULTS:One hundred and fifteen of four hundred and ninety-four (23.3%) patients had obesity. Obesity was an independent risk factor for critical illness (adjusted risk ratio [ARR] 2.02, 95% CI 1.17 to 3.48). This association was modified by age, with obesity related to a greater risk for critical illness in adolescents (13-21 years) [ARR 3.09, 95% CI 1.48 to 6.47], but not in children (0-12 years). Obesity was not an independent risk factor for hospitalization for any age. CONCLUSION/CONCLUSIONS:Obesity was an independent risk factor for critical illness in paediatric patients, and this association was modified by age, with obesity related to a greater risk for critical illness in adolescents, but not in children. These findings are crucial for patient risk stratification and care.

BACKGROUND:The authors sought to study the risk factors associated with severe outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients with cancer. METHODS:The authors queried the New York University Langone Medical Center's records for hospitalized patients who were polymerase chain reaction-positive for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and performed chart reviews on patients with cancer diagnoses to identify patients with active cancer and patients with a history of cancer. Descriptive statistics were calculated and multivariable logistic regression was used to determine associations between clinical, demographic, and laboratory characteristics with outcomes, including death and admission to the intensive care unit. RESULTS:A total of 4184 hospitalized SARS CoV-2+ patients, including 233 with active cancer, were identified. Patients with active cancer were more likely to die than those with a history of cancer and those without any cancer history (34.3% vs 27.6% vs 20%, respectively; P < .01). In multivariable regression among all patients, active cancer (odds ratio [OR], 1.89; CI, 1.34-2.67; P < .01), older age (OR, 1.06; CI, 1.05-1.06; P < .01), male sex (OR for female vs male, 0.70; CI, 0.58-0.84; P < .01), diabetes (OR, 1.26; CI, 1.04-1.53; P = .02), morbidly obese body mass index (OR, 1.87; CI, 1.24-2.81; P < .01), and elevated D-dimer (OR, 6.41 for value >2300; CI, 4.75-8.66; P < .01) were associated with increased mortality. Recent cancer-directed medical therapy was not associated with death in multivariable analysis. Among patients with active cancer, those with a hematologic malignancy had the highest mortality rate in comparison with other cancer types (47.83% vs 28.66%; P < .01). CONCLUSIONS:The authors found that patients with an active cancer diagnosis were more likely to die from COVID-19. Those with hematologic malignancies were at the highest risk of death. Patients receiving cancer-directed therapy within 3 months before hospitalization had no overall increased risk of death. LAY SUMMARY/UNASSIGNED:Our investigators found that hospitalized patients with active cancer were more likely to die from coronavirus disease 2019 (COVID-19) than those with a history of cancer and those without any cancer history. Patients with hematologic cancers were the most likely among patients with cancer to die from COVID-19. Patients who received cancer therapy within 3 months before hospitalization did not have an increased risk of death.