The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies.

The gastrointestinal tract is lined by an epithelial monolayer responsible for selective permeability and absorption, as well as protection against harmful luminal contents. Recognition of foreign or aberrant DNA within these epithelial cells is, in part, regulated by pattern recognition receptors such as cyclic GMP-AMP synthase (cGAS). cGAS binds double-stranded DNA from exogenous and endogenous sources, resulting in the activation of stimulator of interferon genes (STING) and a type 1 interferon response. cGAS is also implicated in non-canonical pathways involving the suppression of DNA repair and the upregulation of autophagy via interactions with PARP1 and Beclin-1, respectively. The importance of cGAS activation in the development and progression of inflammatory bowel disease and gastrointestinal cancers has been and continues to be explored. This review delves into the intricacies of the complex role of cGAS in intestinal epithelial inflammation and gastrointestinal malignancies, as well as recent therapeutic advances targeting cGAS pathways.

Predictors of recurrence and long-term patient reported outcomes following surgical repair of anal fistula, a retrospective analysis.

PURPOSE: Surgery for anal fistulas can result in devastating complications, including reoperations and fecal incontinence. There is limited contemporary evidence comparing outcomes since the adoption of the ligation of intersphincteric fistula tract procedure into mainstream practice. The purpose of this study is to compare recurrence rates and long-term outcomes of anal fistula following repair. METHODS: Data was collected from the electronic medical records or patient reported outcomes from patients aged 18 or older with a primary or recurrent cryptoglandular anal fistula. Primary outcome was recurrence defined as the identification of at least one fistula os or a high clinical suspicion of anal fistula. Secondary outcomes included fecal incontinence and postoperative quality of life. RESULTS: A total of 171 patients underwent definitive surgical repairs for their anal fistula. So 66.5% had a simple fistula, and 33.5% had a complex fistula. Of the 171 patients, 12.5% had a recurrence. The recurrence rates were 5.9% for simple fistula and 25.4% for complex fistula. Predictors of recurrence included diabetes mellitus, history of anorectal abscess, complex fistula, and sphincter sparing surgery. LIFT or plug/biologic procedures were both associated with a 50% or greater recurrence rate. No significant differences were found in fecal incontinence or associated quality of life between sphincter sparing or non-sphincter sparing surgical resections. CONCLUSION: The study provides insights into the long-term outcomes of surgical repair for anal fistula. We demonstrate that sphincter sparing operations are associated with increased recurrence, meanwhile, non-sphincter sparing surgeries did not increase the risk of fecal incontinence or worsen quality of life.

Cyclic GMP-AMP synthase contributes to epithelial homeostasis in intestinal inflammation via Beclin-1-mediated autophagy.

Inflammatory bowel disease (IBD) represents a set of idiopathic and chronic inflammatory diseases of the gastrointestinal tract. Central to the pathogenesis of IBD is a dysregulation of normal intestinal epithelial homeostasis. cGAS is a DNA-sensing receptor demonstrated to promote autophagy, a mechanism that removes dysfunctional cellular components. Beclin-1 is a crucial protein involved in the initiation of autophagy. We hypothesized that cGAS plays a key role in intestinal homeostasis by upregulating Beclin-1-mediated autophagy. We evaluated intestinal cGAS levels in humans with IBD and in murine colonic tissue after performing a 2% dextran sulfate sodium (DSS) colitis model. Autophagy and cell death mechanisms were studied in cGAS KO and WT mice via qPCR, WB analysis, H&E, IF, and TUNEL staining. Autophagy was measured in stimulated intestinal epithelial cells (IECs) via WB analysis. Our data demonstrates cGAS to be upregulated during human and murine colitis. Furthermore, cGAS deficiency leads to worsened colitis and decreased levels of autophagy proteins including Beclin-1 and LC3-II. Co-IP demonstrates a direct binding between cGAS and Beclin-1 in IECs. Transfection of cGAS in stimulated HCT-116 cells leads to increased autophagy. IECs isolated from cGAS KO have diminished autophagic flux. cGAS KO mice subjected to DSS have increased cell death and cleaved caspase-3. Lastly, treatment of cGAS KO mice with rapamycin decreased the severity of colitis. Our data suggest that cGAS maintains intestinal epithelial homeostasis during human IBD and murine colitis by upregulating Beclin-1-mediated autophagy and preventing IEC death. Rescue of autophagy can attenuate the severity of colitis associated with cGAS deficiency.

Readmission After Surgical Resection and Transplantation for Hepatocellular Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Liver resections and transplantations have increasingly become feasible options for potential cure. These complex surgeries are inherently associated with increased rates of readmission. In the meanwhile, hospital readmission rates are rapidly becoming an important quality of care metric. Therefore, it is very important to understand the effect of 30-day readmission on mortality and the factors associated with increased 30- and 90-day mortality rates. METHODS: This is a retrospective cohort study utilizing data from the National Cancer Database. Patients included were 18 years or older who underwent liver resection or liver transplantation for HCC between 2003 and 2011. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission. RESULTS: 16 658 patients underwent either a liver resection or transplantation for HCC between 2003 and 2011. For patients with liver transplantations, increased readmission rates were associated with lower risks of 30-day mortality (P = .012) but a trend toward higher 90-day mortality (P = .057). Patients who underwent liver resection for HCC also demonstrated increased readmission rates to be associated with lower risk of 30-day mortality (P = .014) but higher 90-day mortality (P ≤ .001). CONCLUSION: This is the only study to utilize a national database to investigate the association between readmission rates and mortality rates of both liver transplantations and resections for patients with HCC. We demonstrate 30-day readmission to show no increase in 30-day mortality, but rather higher 90-day mortality.

Readmission After Surgical Resection for Colon and Rectal Cancers: A Retrospective Cohort Study.

BACKGROUND: Colorectal adenocarcinoma is a leading cause of cancer mortality worldwide, often requiring patients to undergo anatomy-altering surgical interventions leading to increased postoperative readmission. Hospital readmission rates have been correlated with increased mortality. Therefore, it is important to understand the association between 30-day readmission rates and mortality as well as the factors associated with increased readmission rates. STUDY DESIGN: This is a retrospective review utilizing data from the National Cancer Database. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission. RESULTS: Between 2010 and 2016, 207 299 patients underwent surgery for rectal cancer and 754 895 for colon cancer. The readmission rates within 30 days of discharge were 5.4% and 5.5% for patients after surgery for rectal or colon cancer, respectively. 30-day readmission was not associated with 30-day mortality, but it was independently associated with increased 90-day mortality and inferior long-term survival for both cohorts (P = .001). Independent risk factors significantly associated with increased readmission included race, non-private insurance, and low income. CONCLUSION: This study provides a large, up-to-date, and comprehensive analysis of readmission rates for colon and rectal cancers. We demonstrate that socioeconomic factors are associated with increased 30-day readmission. 30-day readmission is also independently associated with increased 90-day mortality as well as lower overall survival rates. Our study supports the need for implementation of programs that support patients of lower socioeconomic status undergoing surgery to further decrease readmission rates and mortality.

The Use of Machine Learning to Create a Risk Score to Predict Survival in Patients with Hepatocellular Carcinoma: A TCGA Cohort Analysis.

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver malignancies and is currently the fourth most common cause of cancer-related death worldwide. Due to varying underlying etiologies, the prognosis of HCC differs greatly among patients. It is important to develop ways to help stratify patients upon initial diagnosis to provide optimal treatment modalities and follow-up plans. The current study uses Artificial Neural Network (ANN) and Classification Tree Analysis (CTA) to create a gene signature score that can help predict survival in patients with HCC. Methods: The Cancer Genome Atlas (TCGA-LIHC) was analyzed for differentially expressed genes. Clinicopathological data were obtained from cBioPortal. ANN analysis of the 75 most significant genes predicting disease-free survival (DFS) was performed. Next, CTA results were used for creation of the scoring system. Cox regression was performed to identify the prognostic value of the scoring system. Results: 363 patients diagnosed with HCC were analyzed in this study. ANN provided 15 genes with normalized importance >50%. CTA resulted in a set of three genes (NRM, STAG3, and SNHG20). Patients were then divided in to 4 groups based on the CTA tree cutoff values. The Kaplan-Meier analysis showed significantly reduced DFS in groups 1, 2, and 3 (median DFS: 29.7 months, 16.1 months, and 11.7 months, p < 0.01) compared to group 0 (median not reached). Similar results were observed when overall survival (OS) was analyzed. On multivariate Cox regression, higher scores were associated with significantly shorter DFS (1 point: HR 2.57 (1.38-4.80), 2 points: 3.91 (2.11-7.24), and 3 points: 5.09 (2.70-9.58), p < 0.01). Conclusion: Long-term outcomes of patients with HCC can be predicted using a simplified scoring system based on tumor mRNA gene expression levels. This tool could assist clinicians and researchers in identifying patients at increased risks for recurrence to tailor specific treatment and follow-up strategies for individual patients.

Association Between Helicobacter pylori Infection and Serum Iron Profile.

INTRODUCTION: Helicobacter pylori (H. pylori) infection is reported to be the most frequent cause of morbidity and mortality in cases of upper gastrointestinal (GI) diseases. There is paucity of research between the possible association of H. pylori and iron stores and iron deficiency anemia (IDA). In this study, we will determine if there is an association between serum total iron-binding capacity (TIBC), serum iron and ferritin levels, and H. pylori infection. METHODS: This case-control study was conducted in the gastroenterology ward of a major hospital in Pakistan from December 2020 to April 2021. Three hundred patients diagnosed with H. pylori were enrolled along with 300 participants in the control group. H. pylori was confirmed or excluded with the help of Giemsa stained gastric biopsy specimens. Blood was sent to the laboratory to test for ferritin, serum iron, and TIBC. Each sample was drawn in the morning to avoid any fluctuations. RESULTS: The mean serum iron level was significantly lower in participants with H. pylori infection compared to those who did not have H. pylori infection (110.72 ± 28.38 ug/dL vs. 162.5 ± 21.18 ug/dL; p-value: <0.0001). Serum ferritin level was significantly higher in participants with H. pylori infection (536.82 ± 117.0 ng/dL vs. 391.31 ± 101.54 ng/dL; p-value: <0.0001). CONCLUSION:  In comparison with the control group, TIBC and serum iron levels were found to be lower in the case group.

Frequency of Cutaneous Disorders in Patients With Celiac Disease.

Background and objective Celiac disease is an autoimmune multisystem disorder that is triggered by dietary gluten sensitivity in genetically susceptible individuals. It presents with extraintestinal cutaneous manifestations including dermatitis herpetiformis (DH), atopic dermatitis, psoriasis, urticaria, and alopecia areata. Due to the insufficient availability of data, this study aimed to estimate the frequency of cutaneous manifestation in a Pakistani population with celiac disease. Methods This cross-sectional study was conducted from January 2020 to July 2021, and 300 patients with a confirmed diagnosis of celiac disease were enrolled in the study from the internal medicine department of a tertiary care hospital in Pakistan. Celiac disease was confirmed by the presence of immunoglobulin A (IgA) endomysial antibody and IgA tissue transglutaminase antibody. The presence of cutaneous manifestations was assessed with the assistance of a qualified dermatologist and noted in a self-structured questionnaire. Results Overall, the most common cutaneous manifestation was DH (16.0%), whereas the second most common cutaneous manifestation was psoriasis (13.8%). DH was most commonly found among males (18.9%), while psoriasis was more common among females (14.12%). Conclusion Among the various cutaneous presentations in patients with celiac disease, the most common dermatological manifestation was DH. Therefore, patients with cutaneous manifestations should undergo screening for celiac disease.

Search for safer and potent natural inhibitors of Parkinson's disease.

After Alzheimer's disease, Parkinson's disease (PD) has taken second place in becoming one of the most commonly occurring neurological diseases being responsible for a number of disabling motor symptoms ranging from bradykinesia, akinesia, tremors to rigidity, that mostly targets the elderly population and severely disrupts their quality of life. The true underlying pathology of PD yet remains a mystery, however, recent advances in the field have pointed towards the production of α-synuclein aggregates, oxidative stress, and an imbalance between levels of acetylcholine and dopamine neurotransmitters in the brain that have been shown to result in loss of coordinated movement. Current treatments of PD include the gold standard dopamine precursor L-dopa, dopamine agonists pergolide and bromocriptine, catechol-o-methyl transferases inhibitors, entacapone and tolcapone and monoamine oxidase inhibitors such as Selegine and Rasagiline amongst several other drugs. While these drugs are successful in treating motor symptoms of the disease, they do so with a plethora of side effects that are especially debilitating to the elderly. In the recent years, a considerable amount of attention has been shifted towards phytocompounds such as flavonoids and green tea catechins due to promising experimental results. In this review, we have compiled phytocompounds that have shown potent activity against some of the most important targets for antiparkinsonian therapy. These compounds have exhibited activities that transcend the limits of simply attenuating mitochondrial oxidative stress and have opened doors to the discovery of novel lead compounds for newer, efficacious antiparkinsonian therapies with wider therapeutic windows.

Estimation of polymorphisms in the drug-metabolizing enzyme, cytochrome P450 2C19 gene in six major ethnicities of Pakistan.

Interindividual differences in cytochrome P450 (CYP) 2C19 activity may result in variations in the therapeutic response to drugs metabolized by this enzyme. Differences at gene level may translate into protein level with consequent impairment of the enzyme activity. As a result patients with such genetic differences might experience undesirable effects or no effect at all. The aim of the present study was to find out the prevalence of allelic and genotype frequencies of low activity variants of CYP2C19 genes in healthy individuals from six distinct ethnicities of Pakistan. Blood sample was taken from healthy volunteers following informed consent. Isolation of the DNA was followed by the PCR amplification and restriction fragment length polymorphism. Selected samples were sequenced by Sanger sequencing. The frequency of major alleles was 84.93% for CYP2C19*2 and 91.85% for CYP2C19*3, while minor allele was present at 15.06% for CYP2C19*2 and 8.14% for CYP2C19*3. For CYP2C19*2, the frequency of *1*1 genotype was 75.80%, *1*2 was 18.27%, and *2*2 was 5.92% whereas for CYP2C19*3, The frequency of *1*1 genotype was 84.19%, *1*3 was 15.30%, and *3*3 was 0.49% in the Pakistani population. A substantial variation in genotype and allelic frequencies was observed in various ethnicities. Our study demonstrates that a significant Pakistani population has at least one minor allele, which indicates a large number of patients potentially being affected by these variations. Especially, a significant genotype frequency of PM suggests implication for the treatment response and severity/frequency of adverse effects in patients receiving drugs metabolized by CYP2C19.

Comparison of Effect of Nebivolol and Bisoprolol on Sexual Function of Hypertensive Female Patients.

Introduction Male and female sexual dysfunction is frequently found in patients with hypertension. Many studies indicate that this is found more frequently in patients treated with beta-blockers rather than due to hypertension itself; however, almost all studies have been done on male population. This study aims to study the effect of two commonly used beta-blockers on sexual function of a hypertensive female patient. Methods This two-arm open-label randomized prospective study was conducted from April 1, 2019 to March 30, 2020 in a tertiary care hospital at Pakistan. One hundred and fifty participants randomized to group A were given nebivolol 5 mg once daily in addition to their current hypertensive treatment. Another 150 participants randomized to group B were given bisoprolol 5 mg once daily in addition to their hypertensive therapy. Sexual function was assessed on day 0 and day 90 using female sexual function index (FSFI). Results The mean sexual score in the nebivolol group significantly improved after day 90 in comparison to day 0 (24.16 ± 2.1 vs. 26.91 ± 2.6; p-value < 0.0001), while no difference in sexual score in bisoprolol group after day 90 was observed (24.14 ± 2.1 vs. 24.12 ± 2.0; p-value = 0.91). Conclusion In this study, nebivolol group was associated with a significant improvement in sexual function. This can be due to additional vasodilation properties and a low risk of sexual side effects associated with nebivolol.

Impact of Intravenous Vitamin C Administration in Reducing Severity of Symptoms in Breast Cancer Patients During Treatment.

Introduction Alternative medicine during treatment is often used to make the quality of life (QoL) better. Women with early-stage breast cancer, particularly the ones who possess lower QoL, are more prone to opt for complementary medicine. This study aims to explore the effects exerted by intravenous vitamin C (IVC) on symptoms and adverse events associated with breast cancer treatment. Methods This single-center, parallel-group, single-blind interventional study was conducted in the oncology ward of a tertiary care hospital in Pakistan. For this study, after informed consent was taken, breast cancer patients with Union for International Cancer Control stages IIA to IIIb were included in the study. Three hundred and fifty (n = 350) patients were randomized into two groups at a ratio of 1:1. Study group was randomized to receive 25 grams per week of IVC at a rate of 15 grams per hour for four weeks in addition to their current standard treatment, and the control group received placebo (normal saline drip with label removed) in addition to their current standard treatment. Results In patients who had received IVC, there was a significant decrease in the mean severity score after 28 days for the following symptoms: nausea (2.65 ± 0.62 vs. 2.59 ± 0.68; p-value: 0.0003), loss of appetite (2.26 ± 0.51 vs. 2.11 ± 0.52; p-value: 0.007), tumor pain (2.22 ± 0.45 vs. 1.99 ± 0.40, p-value: <0.0001), fatigue (3.11 ± 0.32 vs. 2.87 ± 0.29; p-value: <0.0001), and insomnia (2.59 ± 0.35 vs. 2.32 ± 0.36, p-value: <0.0001). Conclusion Our study showed improvement in the mean severity score of nausea, fatigue, tumor pain, loss of appetite, and fatigue. More studies are also needed to assess the long-term effects of IVC in the cancer management. This shall help incorporate the use of IVC in standard practice to make the journey of cancer management comfortable for the patients.

Medicaid expansion and the management of pancreatic cancer.

BACKGROUND: Medicaid expansion under the Affordable Care Act has improved access to screening and treatment for certain cancers. It is unclear how this policy has affected the diagnosis and management of pancreatic cancer. METHODS: Using a quasi-experimental difference-in-differences (DID) approach, we analyzed Medicaid and uninsured patients in the National Cancer Data Base during two time periods: pre-expansion (2011-2012) and postexpansion (2015-2016). We investigated changes in cancer staging, treatment decisions, and surgical outcomes. RESULTS: In this national cohort, pancreatic cancer patients in expansion states had increased Medicaid coverage relative to those in nonexpansion states (DID = 17.49, p < 0.01). Medicaid expansion also led to an increase in early-stage diagnoses (Stage I/II, DID = 4.71, p = 0.03), higher comorbidity scores among surgical patients (Charlson/Deyo score 0: DID = -13.69, p = 0.02), a trend toward more neoadjuvant radiation (DID = 6.15, p = 0.06), and more positive margins (DID = 11.69, p = 0.02). There were no differences in rates of surgery, postoperative outcomes, or overall survival. CONCLUSION: Medicaid expansion was associated with improved insurance coverage and earlier stage diagnoses for Medicaid and uninsured pancreatic cancer patients, but similar surgical outcomes and overall survival. These findings highlight both the benefits of Medicaid expansion and the potential limitations of policy change to improve outcomes for such an aggressive malignancy.

Patient Factors Limit Colon Cancer Survival at Safety-Net Hospitals: A National Analysis.

BACKGROUND: Safety-net hospitals serve a vital role in society by providing care for vulnerable populations. Existing data regarding oncologic outcomes of patients with colon cancer treated at safety-net hospitals are limited and variable. The objective of this study was to delineate disparities in treatment and outcomes for patients with colon cancer treated at safety-net hospitals. METHODS: This retrospective cohort study identified 802,304 adult patients with colon adenocarcinoma from the National Cancer Database between 2004-2016. Patients were stratified according to safety-net burden of the treating hospital as previously described. Patient, tumor, facility, and treatment characteristics were compared between groups as were operative and short-term outcomes. Cox proportional hazards regression was utilized to compare overall survival between patients treated at high, medium, and low burden hospitals. RESULTS: Patients treated at safety-net hospitals were demographically distinct and presented with more advanced disease. They were also less likely to receive surgery, adjuvant chemotherapy, negative resection margins, adequate lymphadenectomy, or a minimally invasive operative approach. On multivariate analysis adjusting for patient and tumor characteristics, survival was inferior for patients at safety-net hospitals, even for those with stage 0 (in situ) disease. CONCLUSION: This analysis revealed inferior survival for patients with colon cancer treated at safety-net hospitals, including those without invasive cancer. These findings suggest that unmeasured population differences may confound analyses and affect survival more than provider or treatment disparities.

Potential therapeutic natural products against Alzheimer's disease with Reference of Acetylcholinesterase.

Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population and will be a major burden on healthcare system by the mid of the century. Despite scientific and technological breakthroughs in the last 50 years, that have expanded our understanding of the disease on a system, cellular and molecular level, therapies that could stop or slow the progression of the disease are still unavailable. The Food and Drug Administration (FDA), has approved acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, tacrine and rivastigmine) and glutamate receptor antagonist (memantine) for the treatment of AD. In this review we summarize the studies reporting phytocompounds and extracts from medicinal plants that show AChE inhibitory activities and could be of potential benefit in AD. Future research directions are suggested and recommendations made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.

A National Assessment of Optimal Oncologic Surgery for Distal Pancreatic Adenocarcinomas.

OBJECTIVES: The objective of this study was to create a composite measure, optimal oncologic surgery (OOS), for patients undergoing distal pancreatectomy for pancreatic adenocarcinoma and identify factors associated with OOS. METHODS: Adult patients undergoing distal pancreatectomy were identified from the National Cancer Database between 2010 and 2016. Patients were stratified based on receipt of OOS. Criteria for OOS included 90-day survival, no 30-day readmission, length of stay ≤7 days, negative resection margins, ≥12 lymph nodes harvested, and receipt of chemotherapy. Multivariate logistic regression was performed to identify predictors of OOS. Survival curves and a Cox proportional hazards model were created to compare survival and identify risk factors for mortality. RESULTS: Three thousand five hundred forty-six patients were identified. The rate of OOS was 22.3%. Diagnosis after 2012, treatment at an academic medical center, and a minimally invasive surgical approach (MIS) were associated with OOS. Survival was superior for patients undergoing OOS. Decreasing age at diagnosis, fewer comorbidities, surgery at an academic medical center, MIS, and lower pathologic stage were also associated with improved survival on multivariate analysis. CONCLUSIONS: Rates of OOS for distal pancreatectomy are low. Time trends show increasing rates of OOS that may be related to increasing MIS, adjuvant chemotherapy, and referrals to academic medical centers.

Pathologic Complete Response Following Neoadjuvant Therapy for Gastric Adenocarcinoma: A National Cancer Database Analysis on Incidence, Predictors, and Outcomes.

INTRODUCTION: With advances in multimodal therapy, survival rates in gastric cancer have significantly improved over the last two decades. Neoadjuvant therapy increases the likelihood of achieving negative margins and may even lead to pathologic complete response (pCR). However, the impact of pCR on survival in gastric cancer has been poorly described. We analyzed the rate and predictors of pCR in patients receiving neoadjuvant therapy as well as impact of pCR on survival. METHODS: We conducted a National Cancer Database (NCDB) analysis (2004-2016) of patients with gastric adenocarcinoma who received neoadjuvant chemotherapy followed by surgical resection. RESULTS: The pCR rate was 2.2%. Following adjustment, only neoadjuvant chemoradiation, non-signet histology, and tumor grade remained as significant factors predicting pCR. pCR was a statistically significant predictor of survival. CONCLUSION: In this NCDB study, pCR was a predictor of survival. Though chemoradiation rather than chemotherapy alone was a predictor of pCR, it was not a predictor of survival. Further studies are needed to elucidate the role of radiation in the neoadjuvant setting and to discern the impact of pCR on survival.

Impact of Resection Margin Status in Patients with Pancreatic Cancer: a National Cohort Study.

AIM: To assess the predictors and influence of resection margins and the role of neoadjuvant and adjuvant therapy on survival for a national cohort of patients with resected pancreatic cancer. METHODS: Using the National Cancer Data Base between 2004 and 2016, 56,532 patients were identified who underwent surgical resection for pancreatic adenocarcinoma. Univariate and multivariate models were employed to identify factors predicting R0/R1 resection and assess the impact on survival. RESULTS: In total, 48,367 (85.6%) patients were found to have negative margins (R0) compared to 8165 (14.4%) who had microscopic residual tumor (R1). Factors predicting positive margin on univariate analysis included male gender, Medicare, advanced stage, moderately or poorly differentiated tumor, lymphovascular invasion, and tumors > 2 cm. Factors predicting R0 resection included receipt of neoadjuvant therapy and treatment at an Academic/Research Center. Following adjustment for other factors, margin status remained an independent predictor for overall survival (HR: 1.24; 95% CI 1.22-1.27, p < 0.001) (1-, 3-, and 5-year overall survival rates (R0: 77%, 37%, and 25% vs R1: 62%, 19%, and 10%). CONCLUSIONS: A positive margin predicts a poorer survival than R0 resections regardless of stage and receipt of adjuvant therapy. Several modifiable factors significantly predict the likelihood of R0 resection including neoadjuvant treatment and treatment at Academic/Research Programs. Knowledge about these factors can help guide patient management by offering neoadjuvant treatment modalities at Academic as well as Community hospitals.