Immunological Checkpoint Blockade in Anal Squamous Cell Carcinoma: Dramatic Responses Tempered By Frequent Resistance.

PURPOSE OF REVIEW: Squamous cell carcinoma of the anus (SCCA) is an HPV-associated malignancy that has limited treatment options. Immunotherapy has expanded these options and here we review current and emerging immunotherapeutic approaches. RECENT FINDINGS: Multiple studies of single-agent anti-PD1/PD-L1 immunotherapy have demonstrated a modest response rate of approximately 10% to 15%. While a minority of patients (~5%) with SCCA experience durable complete responses, most advanced SCCAs are resistant to anti-PD1/PD-L1 monotherapy. Given the need for more broadly effective immunotherapies, novel strategies, such as adaptive cell therapies and therapeutic vaccination, are being explored. To reduce the recurrence risk of localized high-risk SCCA, strategies combining immunotherapy with chemoradiation are also being investigated. While a small subset of patients with SCCA have prolonged responses to PD1-directed immunotherapy, the majority do not derive clinical benefit, and new immunotherapeutic strategies are needed. Better understanding of the immune microenvironment and predictive biomarkers could accelerate therapeutic advances.

Disparities in ovarian cancer treatment and overall survival according to race: An update.

OBJECTIVE: To determine whether guideline non-adherence is associated with Black race. METHODS: A retrospective review of National Cancer Database records of women diagnosed with epithelial ovarian cancer from 2012 to 2016 who identified as "White" or "Black" was performed. Exposure was adherence or non-adherence to National Comprehensive Cancer Network guidelines for treatment. Outcomes were differences in disease characteristics and overall survival in months. RESULTS: Of the 29,948 eligible patients, 93% (n = 27,744) were White and 7% (n = 2204) were Black. Having stage IV disease (OR 1.45, 95% CI 1.23-1.70; P < 0.001) and treatment in a comprehensive (OR 1.58, 95% CI 1.16-2.15; P = 0.0039) or academic (OR 2.30, 95% CI 1.70-3.12; P < 0.001) treatment facility were associated with Black race. Adherence to guidelines did not predict Black race (OR for adherence 1.0021, 95% CI 0.89-1.13; P = 0.97). Median survival for White patients with adherent care was 63.4 months and 51.4 months for Black patients (P = 0.0001). Median survival for White patients with non-adherent care was 60.5 months and 47.2 months for Black patients (P < 0.0001). Median overall survival was 61.1 months in White patients and 49.3 months in Black patients (P < 0.0001). CONCLUSIONS: Our data suggest that while Black patients and patients who receive non-NCCN guideline directed care have worse survival outcomes, guideline adherence is not independently associated with Black race. We must consider other socioeconomic, environmental and system factors that are contributing to the survival discrepancy in Black patients with ovarian cancer.

Morbidity of curative cancer surgery and suicide risk.

IMPORTANCE: Curative cancer operations lead to debility and loss of autonomy in a population vulnerable to suicide death. The extent to which operative intervention impacts suicide risk is not well studied. OBJECTIVE: To examine the effects of morbidity of curative cancer surgeries and prognosis of disease on the risk of suicide in patients with solid tumors. DESIGN: Retrospective cohort study using Surveillance, Epidemiology, and End Results data from 2004 to 2011; multilevel systematic review. SETTING: General US population. PARTICIPANTS: Participants were 482 781 patients diagnosed with malignant neoplasm between 2004 and 2011 who underwent curative cancer surgeries. MAIN OUTCOMES AND MEASURES: Death by suicide or self-inflicted injury. RESULTS: Among 482 781 patients that underwent curative cancer surgery, 231 committed suicide (16.58/100 000 person-years [95% confidence interval, CI, 14.54-18.82]). Factors significantly associated with suicide risk included male sex (incidence rate [IR], 27.62; 95% CI, 23.82-31.86) and age >65 years (IR, 22.54; 95% CI, 18.84-26.76). When stratified by 30-day overall postoperative morbidity, a significantly higher incidence of suicide was found for high-morbidity surgeries (IR, 33.30; 95% CI, 26.50-41.33) vs moderate morbidity (IR, 24.27; 95% CI, 18.92-30.69) and low morbidity (IR, 9.81; 95% CI, 7.90-12.04). Unit increase in morbidity was significantly associated with death by suicide (odds ratio, 1.01; 95% CI, 1.00-1.03; P = .02) and decreased suicide-specific survival (hazards ratio, 1.02; 95% CI, 1.00-1.03, P = .01) in prognosis-adjusted models. CONCLUSIONS: In this sample of cancer patients in the Surveillance, Epidemiology, and End Results database, patients that undergo high-morbidity surgeries appear most vulnerable to death by suicide. The identification of this high-risk cohort should motivate health care providers and particularly surgeons to adopt screening measures during the postoperative follow-up period for these patients.

Age-based disparities in treatment and outcomes of retroperitoneal rhabdomyosarcoma.

BACKGROUND: Elderly patients (EPs) suffering from retroperitoneal rhabdomyosarcoma (RRMS) carry a considerably poorer prognosis compared to younger patients (YPs). We hypothesized that EPs received less aggressive and comprehensive treatment than YPs, resulting in poorer survival outcomes. MATERIALS AND METHODS: All patients diagnosed with RRMS since 1998 in the National Cancer Data Base (NCDB) were reviewed for patient demographics, tumor characteristics, treatment modalities and survival outcomes. RESULTS: Of the 100 patients identified, 35 % were ≥65 years of age. EPs (aged ≥65 years), when compared to YPs (aged <65), were less likely to receive systemic chemotherapy (20 % EPs vs 71 % YPs, p < 0.001) and treatment at an academic center (34 % EPs vs 60 % YPs, p = 0.05), although the frequency of radiation (23 % EPs vs 31 % YPs, p = 0.40) and radical surgery (26 % EPs vs 22 % YPs, p = 0.55) were similar. EPs received treatment more frequently at comprehensive community cancer programs (57 %) and had a shorter median distance of travel for care (6.4 vs 13 miles, p = 0.009). After adjusting for gender and tumor size, EPs had a hazard ratio of 3.6 (95 % CI 1.8-7.2, p < 0.001), with a median survival of 2 months (interquartile range [IQR] 1-8 months) versus 17 months for YPs (IQR 8-43 months). CONCLUSION: Altered practice patterns exist for EPs and include reduced use of systemic chemotherapy which may contribute to poorer outcomes for RRMS patients. Although regionalization of care poses challenges, this may offer benefit to the EP group.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis.

BACKGROUND: Due to the increased adoption of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients with malignant peritoneal mesothelioma (MPM) have seen improved outcomes. We aimed to evaluate and synthesize the recent published literature. METHODS: The review was conducted according to the recommendation of the Meta-Analysis of Observational Studies in Epidemiology group with prespecified inclusion and exclusion criteria. The DEALE method was used to combine mortality rates, and imputation techniques were used to calculate standard errors. Meta-regression techniques were used to synthesize data. Publication bias was assessed using funnel plots. RESULTS: Of 6,528 citations collected, 20 articles reporting on 1,047 patients were included in the analysis. The median age was 51 years (interquartile range 49-55), with 59 % (54-67) female. The median peritoneal carcinomatosis index score was 19 (16-23). Complete cytoreduction (CC0, 1) was performed in 67 % (46-93 %) of patients. Pooled estimates of survival yielded a 1-, 3- and 5-year survival of 84, 59, and 42 %, respectively. Patients receiving early postoperative intraperitoneal chemotherapy [EPIC] (44 %) and those receiving cisplatin intraperitoneal chemotherapy alone (48 %) or in combination (44 %) had an improved 5-year survival. CONCLUSIONS: While CRS + HIPEC has led to an improved survival for patients with MPM compared to historic data, heterogeneity of studies precludes generalizable inferences. EPIC chemotherapy and cisplatin chemoperfusion may infer survival benefit.

Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Hepatic artery based therapies (HAT) are offered for patients with unresectable intrahepatic cholangiocarcinoma (ICC). We aimed to evaluate the comparative effectiveness of HAT -hepatic arterial infusion (HAI), transcatheter arterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), and Yttrium(90) radioembolization (Y-90) for unresectable ICC. METHODS: A meta-analysis was performed using a prospectively registered search strategy at PROSPERO (CRD42013004830) that utilized PubMed (2003-2013). Primary outcome was median overall survival (OS), and secondary outcomes were tumor response to therapy and toxicity. RESULTS: A total of 20 articles (of 793, n=657 patients) were selected for data extraction. Highest Median OS was observed for HAI (22.8, 95% CI 9.8-35.8) months versus Y90 (13.9, 9.5-18.3) months versus TACE (12.4, 10.9-13.9) months versus DEB-TACE (12.3, 11-13.5) months. Response to therapy (complete and partial) was highest for HAI (56.9%, 95%CI 41.0-72.8) versus Y90 (27.4%, 17.4-37.5) versus TACE (17.3%, 6.8-27.8). The grade III/IV toxicity (Events per patient) was highest for HAI (0.35, 95% CI 0.22-0.48) versus TACE (0.26, 0.21-0.32) versus DEB-TACE (0.32, 0.17-0.48). CONCLUSION: For patients with unresectable ICC treated with HAT, HAI offered the best outcomes in terms of tumor response and survival but may be limited by toxicity.

Incorporation of diagnostic laparoscopy in the management algorithm for patients with peritoneal metastases: A multi-institutional analysis.

INTRODUCTION: Diagnostic laparoscopy (DL), which can predict complete cytoreduction (CC), is often considered unfeasible in patients with Peritoneal metastases (PM) due to a hostile abdomen, prior surgeries, incomplete assessment or risk of port site recurrence. We hypothesized that DL can be successfully incorporated into the management of patients with PM. METHODS: Retrospective review and data analysis of prospectively maintained databases from two high volume institutions was performed between 2007 and 2013. RESULTS: DL was successfully completed in 211/217 (92.6%) patients with PM. The technique for entry was the Hasson in 57%, optical trocar in 38% and Veress needle in 5%. Serosal injury from DL occurred in one patient (0.4%). Predominant histology included appendiceal (40%) and colorectal primaries (34%). Exclusion from cytoreduction by DL occurred in 68 (31.3%). Among those excluded, 7 (of 68, 10.3%) subsequently underwent CRS + HIPEC after receiving systemic chemotherapy. Overall survival (from laparoscopy) for those that underwent CRS + HIPEC at the original operation was 36 versus 12.7 months among those who were excluded by laparoscopy. There were no cases of port site recurrence. CONCLUSION: Diagnostic laparoscopy can be safely incorporated in the management of patients with peritoneal metastases, and can be especially beneficial in excluding patients from attempted incomplete cytoreduction.

Is local resection adequate for T1 stage ampullary cancer?

BACKGROUND: Concerns for morbidity after a pancreaticoduodenectomy (PD) has led to practitioners adopting endoscopic resection or ampullectomy in the treatment of T1 ampullary cancer (AC). It was hypothesized that survival for patients undergoing local resection of AC was inferior to those undergoing a PD. METHODS: All the data of patients with AC reported in the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2010 were collected. Five-year survival rates according to nodal disease and histological type were compared. RESULTS: There were 1916 cases of AC; 421 (22%) had T1 disease. Among those with T1 disease, 217 (51%) received endoscopic surveillance, 21 (5%) underwent local resection/ampullectomy, 20 (5%) underwent ampullectomy with regional lymphadenectomy and 163 (39%) underwent PD. For patients with complete nodal staging (PD, n = 163), 35 (22%) had metastatic disease in the nodes. Grade was significantly associated with node positivity (P = 0.007). In multivariate models, survival was improved with either an ampullectomy with regional lymphadenectomy [hazard ratio (HR) 0.19; 95% confidence interval (CI) 0.05-0.61, P < 0.005] or a PD (HR 0.23; 95% CI 0.15-0.36, P < 0.001). CONCLUSION: Patients with T1 AC have a high risk for nodal metastases especially if they are higher-grade lesions. Nodal clearance with a lymphadenectomy or a PD is essential for long-term survival in these patients.

Diagnostic laparoscopy should be performed before definitive resection for pancreatic cancer: a financial argument.

OBJECTIVES: Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). METHODS: Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50,000/quality-adjusted life year). RESULTS: Base case costs were US$34,921 for ExLap and US$33,442 for DL in SF patients, and US$39,633 for ExLap and US$39,713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10,695/QALM in SF and US$4158/QALM in NAT patients. CONCLUSIONS: The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT.

Cost effectiveness of routine laparoscopic ultrasound for assessment of resectability of gallbladder cancer.

BACKGROUND: In addition to a diagnostic laparoscopy (DL), a routine laparoscopic ultrasound (LUS) has been proposed to identify undetected hepatic metastases and/or anatomically advanced disease in patients with T2 or higher gall bladder cancer (GBC) patients planned for surgical resection. It was hypothesized that a routine LUS is not a cost-effective strategy for these patients. METHODS: Decision tree modeling was undertaken to compare DL-LUS vs. DL at the time of definitive resection of GBC (with no prior cholecystectomy). Costs in US dollars (payer's perspective), quality-adjusted life weeks (QALWs), and incremental cost-effectiveness ratios (ICER) were calculated (horizon: 6 weeks, willingness-to-pay: $1,000/QALW or $50,000/QALY). RESULTS: DL-LUS was cost effective at the base case scenario (costs: $30,838 for DL vs. $30,791 for DL-LUS and effectiveness 3.81 QALWs DL vs. 3.82 QALW DL-LUS), resulting in a cost reduction of $9,220 per quality-adjusted life week gained (or $479,469 per QALY). DL-LUS became less cost effective as the cost of ultrasound increased or the probability of exclusion from resection decreased. CONCLUSIONS: Routine LUS with DL for the assessment of resectability and exclusion of metastases is cost effective for patients with GBC. Until improvements in preoperative imaging occur to decrease the probability of exclusion, this appears to be a feasible strategy.

Review of the impact of antineoplastic therapies on the risk for cholelithiasis and acute cholecystitis.

BACKGROUND: Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients. METHODS: A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies. RESULTS: Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis. CONCLUSIONS: There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.

Effect of the experience of surgical chairpersons on departmental National Institutes of Health funding.

BACKGROUND: Experience and application of recruitment packages can be critical in leadership efforts of surgical chairpersons in promoting research, although attrition of these efforts can happen over time due to lack of new resources. We aimed to examine the impact of experience of surgical chairpersons on departmental National Institutes of Health (NIH) funding. METHODS: Experience as a chairperson defined as the number of years spent as an interim or permanent chair was abstracted from the department Web site (US medical schools only). The NIH funding (US dollars) of the departments were obtained from the Blue Ridge Medical Institute (www.brimr.org). The change in NIH funding from the immediate previous financial year (2010-2009 and 2011-2010) was used to classify chairpersons into four groups: group 1 (-/-), group 2 (-/+), group 3 (+/+), and group 4 (+/-) for analysis. RESULTS: Median NIH funding were $1.9 (0.7-6) million, $1.8 (0.6-5) million, and $1.7 (0.7-5) million for 2009, 2010, and 2011, respectively, and the median experience as a surgical chairperson was 6 y (3-10). Recent chairpersons (<1 y) inherited departments that usually lost NIH funding (62%) and were frequently unable to develop a positive trend for growth over the next fiscal year ([-/-] n = 4 and [+/-] n = 2, 75%). Chairpersons who held their positions for 4-6 y were most likely to be associated with trends of positive funding growth, whereas chairpersons >10 y were most likely to have lost funding (66%, P = 0.07). CONCLUSIONS: Provision of new development dollars later in their tenure and retention of chairpersons might lead to more positive trends in increase in NIH funding.

Surgical management of bowel obstruction in patients with peritoneal carcinomatosis.

BACKGROUND: Due to low life expectancy, treatment strategies for malignant bowel obstruction (MBO) due to peritoneal carcinomatosis (PC) emphasize improved quality of life and symptom relief. Currently, the value of palliative surgery to treat obstructive PC is unclear. METHODS: A prospectively registered search strategy (PROSPERO) was utilized to identify articles examining outcomes of patients undergoing surgical palliation for MBO from PC in PubMed (2003-2013). Primary outcomes of interest were median overall survival (OS) and treatment complications. RESULTS: Of 730 articles screened, 64 were selected for full-text review and 5 were quantitatively synthesized. This comprised 313 patients with MBO, of which 249 (79.5%) presented with PC. The mean age was 61.4 years (range 51-67). The OS for surgical patients was 6.4 months (2.8-19.7, n = 190). Stratification by surgical technique suggested an OS of resection, ostomy, and enteral bypass as 7.2 months (n = 174), 3.4 months (n = 9), and 2.7 months (n = 7), respectively. Major complications occurred in 37.0% of patients that underwent resection. CONCLUSIONS: This study supports surgical resection over surgical bypass to treat obstructive PC, as it offered better OS with fewer complications. Higher quality studies are needed to conclusively assess the role of surgery in patients with obstructive PC.

Management of acute cholecystitis in cancer patients: a comparative effectiveness approach.

BACKGROUND: Host factors and therapy characteristics predispose cancer patients to a high risk of acute cholecystitis. Management of cholecystitis is often difficult given complex decision making involving the underlying cancer, possible interruption of treatment, and surgical fitness of the patient. METHODS: A management pathway was developed for cholecystitis in cancer patients which incorporated patient-specific survival and risks of recurrence. Estimates were obtained from a multistage systematic review. A decision tree with a lifetime horizon was constructed to compare conventional strategies [conservative treatment (CT), percutaneous cholecystostomy (PC) and definitive cholecystectomy (DC)] with the new pathway (NP). The decision tree was optimized for highest estimated survival. Sensitivity analyses were performed. RESULTS: In low surgical risk patients with cancer-specific survival of 12 months, the NP yielded estimated survivals of 11.9 versus 11.8 (CT) versus 11.8 (PC) versus 11.9 months for the DC arm. For high-risk patients, the estimated survival was 11.6 (NP), 9.9 (DC), 11.4 (PC), and 11 (CT) months, respectively. The decision to perform a DC at 6 weeks after a PC was optimum in patients expected to survive 24 months (23.2 months from the NP) or with a shorter expected survival but a high recurrence risk (>20 %). Model estimates were robust in sensitivity analyses. CONCLUSIONS: Incorporation of the surgical risk and the risk of recurrent cholecystitis, while balancing the patient-specific survival and the impact of antineoplastic therapy in the management of cholecystitis yields improved survival. This work provides measures to evaluate surgical judgment, and can augment the physician-patient decision making.

Role of laparoscopy in patients with peritoneal metastases considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: We hypothesized that diagnostic laparoscopy (DL) was feasible for the evaluation of patients with peritoneal carcinomatosis (PC) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: A retrospective review of PC patients treated from January 2010 to April 2013 was conducted. Data on tumor characteristics, treatment details and survival outcomes were extracted and analyzed. RESULTS: Of the 101 PC patients (mean age 52.9 ± 14.1 years), 73 diagnostic laparoscopies DL (61 concurrent with CRS + HIPEC) were performed in 70 patients whereas 31 patients underwent direct exploratory laparotomy (EL). Complete laparoscopic assessment was possible in 63 cases (86.3%), resulting in 18 exclusions (27.7%) while 10 cases were converted to open due to inadequate laparoscopic visualization. Subsequently, CRS + HIPEC was performed in 85.4% (of 55 selected for HIPEC, DL) versus 74.2% (EL, P value = 0.20). Among those excluded from HIPEC at the initial operation, delayed HIPEC after conversion chemotherapy was achieved in 6 (of 11 with extensive disease, DL). The incidence of grade 3 to 5 complications was 0% DL versus 10% EL (P value = 0.2). There were no port site recurrences at mean follow up of 9.1 ± 8 months. CONCLUSIONS: Laparoscopy is a feasible technique for selecting patients with PC for CRS + HIPEC, and can help select patients for conversion chemotherapy in the setting of high peritoneal carcinomatosis index (PCI) score.

Gut Microbiome-Colorectal Cancer Relationship.

Traditionally, the role of gut dysbiosis was thought to be limited to pathologies like Clostridioides difficile infection, but studies have shown its role in other intestinal and extraintestinal pathologies. Similarly, recent studies have surfaced showing the strong potential role of the gut microbiome in colorectal cancer, which was traditionally attributed mainly to sporadic or germline mutations. Given that it is the third most common cancer and the second most common cause of cancer-related mortality, 78 grants totaling more than USD 28 million have been granted to improve colon cancer management since 2019. Concerted efforts by several of these studies have identified specific bacterial consortia inducing a proinflammatory environment and promoting genotoxin production, causing the induction or progression of colorectal cancer. In addition, changes in the gut microbiome have also been shown to alter the response to cancer chemotherapy and immunotherapy, thus changing cancer prognosis. Certain bacteria have been identified as biomarkers to predict the efficacy of antineoplastic medications. Given these discoveries, efforts have been made to alter the gut microbiome to promote a favorable diversity to improve cancer progression and the response to therapy. In this review, we expand on the gut microbiome, its association with colorectal cancer, and antineoplastic medications. We also discuss the evolving paradigm of fecal microbiota transplantation in the context of colorectal cancer management.

Plasma metabolomic differences in early-onset compared to average-onset colorectal cancer.

Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or  ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.

Attributes of a surgical chairperson associated with extramural funding of a department of surgery.

BACKGROUND: Chairpersons of surgery departments are key stakeholders and role models and leaders of research in academic medical institutions. However, the characteristics of surgical chairpersons are understudied. This study aimed to investigate the association between the personal academic achievement of a surgical chairperson and the National Institutes of Health (NIH) funding of the department. METHODS: We calculated the Hirsch index (H-index), a measure of research productivity, for chairpersons of surgery of the top 90 research medical schools that were ranked by U.S. News & World Report. Specialty training, y as chairperson, location, and NIH institutional and department funding were analyzed. Nonparametric tests and linear regression methods were used to compare the different groups. RESULTS: Of the 90 chairpersons, 20 positions for chairs (22%) are either recent (<1 y) or unfilled (n = 6). Only 3% of all chairpersons are women, and the median H-index for the chairpersons is 20 (Interquartile range 14-27) with a median 101 publications with 14 cites per publication. Median surgery-specific NIH funding in 2011 was $1.7 million (Interquartile range $721,042-5,085,305). The chairperson's H-index was exponentially associated with department funding in multivariate models adjusting for institution rank, except when the H-index was extreme (<4 or >49) (coefficient 0.32, P = 0.02). CONCLUSIONS: The research productivity of a chairperson is the only personal attribute of those studied that is associated with the departmental NIH funding. This suggests the important role an academically productive surgical leader may play as a champion for the academic success of the department.

Comparison of characteristics and outcomes of young-onset versus average onset pancreatico-biliary adenocarcinoma.

BACKGROUND: Young-onset gastrointestinal malignancies appear to be increasing in incidence. There are limited data on young-onset pancreaticobiliary adenocarcinoma (YO-PBA). METHODS: The study comprised patients with PBA (pancreatic adenocarcinoma, intra-, and extra-hepatic cholangiocarcinoma) and included in the National Cancer Database (NCDB) between 2004 and 2017. YO-PBA was defined as a diagnosis at age less than 50 years. Logistic regression to assess factors associated with YO-PBA status, and cox proportional hazards modeling to associate relevant factors with overall survival was performed. RESULTS: The study cohort comprised 360,764 patients, with 20,822 (5.8%) YO-PBA. YO-PBA was associated with (p-values<0.0001 for all): male sex (6.3% YO-male out of all male patients vs. 5.2% YO-female, OR 1.29, 95% CI 1.25-1.33), Black race (7.9% YO-Black vs. 5.0% YO-White, OR 1.72, 95% CI 1.64-1.80), lower income (6.4% YO-lowest household income based group vs. 5.5% highest, OR 1.08, 95% CI 1.03-1.13). YO-PBA were more likely to present with stage-IV disease (6.4% YO-Stage IV of all stage IV vs. 5.4% YO-Stage I-III, OR 1.25, 95% CI 1.21-1.29 p-value < 0.0001). Factors associated with overall survival (OS) in non-operable patients included-sex - male vs. female, HR 1.12 (95% CI 1.08-1.15); race - Black vs. White, HR 1.23 (95% CI 1.06-1.42); income group - lowest vs. highest, HR 1.33 (95% CI 1.27-1.39), and treatment center type - academic vs. nonacademic center, HR 0.87 (95% CI 0.85-0.90). CONCLUSIONS: Socioeconomic factors significantly impact incidence and outcomes for young-onset pancreaticobiliary adenocarcinoma (YO-PBA). More work is needed to help understand the mechanisms involved while addressing the disparities.