Survival Outcomes for Malignant Peritoneal Mesothelioma at Academic Versus Community Hospitals.

BACKGROUND: Malignant peritoneal mesothelioma is a rare disease with poor outcomes. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the cornerstone of therapy. We aim to compare outcomes of malignant peritoneal mesothelioma treated at academic versus community hospitals. METHODS: This was a retrospective cohort study using the National Cancer Database to identify patients with malignant peritoneal mesothelioma from 2004 to 2016. Patients were divided according to treating facility type: academic or community. Outcomes were assessed using log-rank tests, Cox proportional-hazard modeling, and Kaplan-Meier survival statistics. RESULTS: In total, 2682 patients with malignant peritoneal mesothelioma were identified. A total of 1272 (47.4%) were treated at an academic facility and 1410 (52.6%) were treated at a community facility. Five hundred forty-six (42.9%) of patients at academic facilities underwent debulking or radical surgery compared to 286 (20.2%) at community facilities. Three hundred sixty-six (28.8%) of patients at academic facilities received chemotherapy on the same day as surgery compared to 147 (10.4%) of patients at community facilities. Unadjusted 5-year survival was 29.7% (95% CI 26.7-32.7) for academic centers compared to 18.3% (95% CI 16.0-20.7) for community centers. In multivariable analysis, community facility was an independent predictor of increased risk of death (HR: 1.19, 95% CI 1.08-1.32, p = 0.001). CONCLUSIONS: We demonstrate better survival outcomes for malignant peritoneal mesothelioma treated at academic compared to community facilities. Patients at academic centers underwent surgery and received chemotherapy on the same day as surgery more frequently than those at community centers, suggesting that malignant peritoneal mesothelioma patients may be better served at experienced academic centers.

The Effect of Facility Volume on Survival Following Proctectomy for Rectal Cancer.

BACKGROUND: Prior studies assessing colorectal cancer survival have reported better outcomes when operations are performed at high-volume centers. These studies have largely been cross-sectional, making it difficult to interpret their estimates. We aimed to assess the effect of facility volume on survival following proctectomy for rectal cancer. METHODS: Using data from the National Cancer Database, we included all patients with complete baseline information who underwent proctectomy for non-metastatic rectal cancer between 2004 and 2016. Facility volume was defined as the number of rectal cancer cases managed at the treating center in the calendar year prior to the patient's surgery. Overall survival estimates were obtained for facility volumes ranging from 10 to 100 cases/year. Follow-up began on the day of surgery and continued until loss to follow-up or death. RESULTS: A total of 52,822 patients were eligible. Patients operated on at hospitals with volumes of 10, 30, and 50 cases/year had similar distributions of grade, clinical stage, and neoadjuvant therapies. 1-, 3-, and 5-year survival all improved with increasing facility volume. One-year survival was 94.0% (95% CI: 93.7, 94.3) for hospitals that performed 10 cases/year, 94.5% (95% CI: 94.2, 94.7) for 30 cases/year, and 94.8% (95% CI: 94.5, 95.0) for 50 cases/year. Five-year survival was 68.9% (95% CI: 68.0, 69.7) for hospitals that performed 10 cases/year, 70.8% (95% CI: 70.1, 71.5) for 30 cases/year, and 72.0% (95% CI: 71.2, 72.8) for 50 cases/year. CONCLUSIONS: Treatment at a higher volume facility results in improved survival following proctectomy for rectal cancer, though the small benefits are less profound than previously reported.

The Association Between Sex and Survival for Anal Squamous Cell Carcinoma.

BACKGROUND: The incidence of anal squamous cell carcinoma (SCC) is rising, despite the introduction of a vaccine against human papillomavirus (HPV), the most common etiology of anal SCC. The rate of anal SCC is higher among women and sex-based survival differences may exist. We aimed to examine the association between sex and survival for stage I-IV anal SCC. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with stage I-IV anal SCC from 2004-2016. Outcomes were assessed utilizing log rank tests, Kaplan-Meier statistics, and Cox proportional-hazard modeling. Subgroup analyses by disease stage and by HPV status were performed. Outcomes of interest were median, 1-, and 5-year survival by sex. RESULTS: There were 31,185 patients with stage I-IV anal SCC. 10,714 (34.3%) were male and 20,471 (65.6%) were female. 1- and 5- year survival was 90.2% (95% CI 89.8 - 90.7) and 67.7% (95% CI 66.9 - 68.5) for females compared to 85.8% (95% CI 85.1 - 86.5) and 55.9% (95% CI 54.7 - 57.0) for males. In subgroup analysis, females demonstrated improved unadjusted and adjusted survival for all stages of disease. Female sex was an independent predictor of improved survival (HR 0.68, 95% CI 0.65 - 0.71, P < 0.001). CONCLUSIONS: We demonstrate better overall survival for females compared to males for stage I-IV anal SCC. It is not clear why women have a survival advantage over men, though exposure to prominent risk factors may play a role. High-risk men may warrant routine screening for anal cancer.

Management of Nonoperative Diverticulitis : Is Surgical Admission Always Best?

BACKGROUND: Institutional pathways (IPs) allow efficient utilization of health care resources. Recent literature reports decreased hospital length of stay (LOS), complications, and costs with the admittance of surgical disease to surgical services. Our study aimed to demonstrate that admission to surgery for nonoperative, acute diverticulitis reduces hospital LOS, and cost, with comparable complication rates. METHODS: In January 2017, we defined IPs for diverticulitis, mandating emergency department admission to a surgical service. Patients admitted from October 2015 to June 2016 (pre-protocol, control cohort) were compared with those admitted January 2017-September 2018 (post-protocol, IP cohort). Primary outcomes included hospital LOS, direct cost, indirect cost, total cost, and 30-day readmission. Student's 2-tailed t-test and chi-square analysis were utilized, with statistical significance P < .05. RESULTS: Nonoperative management of acute diverticulitis occurred in 62 (74%) patients in the control cohort. One hundred and eleven patients (85%) were admitted to the IP cohort. Patient characteristics were similar, except for a higher percentage of surgical patients utilizing private insurance and younger in age. Interestingly, no difference in hospital LOS (3.8 vs 4.7 days; P = 0.07), direct cost ($2639.44 vs $3251.52; P = .19), or overall cost ($5968.67 vs $6404.08, P = .61) was found between cohorts. Thirty-day readmission rates were comparable at 8% and 11% (P = .59). CONCLUSION: Institutional policy mandating admissions for patients receiving nonoperative management of diverticulitis to surgical services does not reduce hospital LOS or cost. This argues that admission to medical services may be an acceptable practice. This raises the question, is acute diverticulitis always a surgical issue?

IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon.

During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a-/- mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation.NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.

DNA damage response genes mark the early transition from colitis to neoplasia in colitis-associated colon cancer.

Chronic intestinal inflammation predisposes patients with Inflammatory Bowel Disease (IBD) to Colitis-Associated Cancer (CAC). In the setting of chronic inflammation, microsatellite instability (MSI) results from early loss of DNA damage response (DDR) genes, ultimately leading to tumor formation. Despite continued efforts to improve early detection of high risk, pre-dysplastic regions in IBD patients, current macroscopic and genetic surveillance modalities remain limited. Therefore, understanding the regulation of key DDR genes in the progression from colitis to cancer may improve molecular surveillance of CAC. To evaluate DDR gene regulation in the transition from colitis to tumorigenesis, we utilized the well-established Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) pre-clinical murine model of CAC in C57BL/6 mice. In order to assess colonic tumor burden in the setting of mutagen and intestinal irritation, tumors were visualized and graded in real time through high-resolution murine colonoscopy. Upon sacrifice, colons were opened and assessed for macroscopic tumor via high magnification surgical lenses (HMSL). Tissues were then sectioned and separated into groups based on the presence or absence of macroscopically visible tumor. Critical DDR genes were evaluated by semi-quantitative RT-PCR. Interestingly, colon tissue with macroscopically visible tumor (MVT) and colon tissue prior to observable tumor (the non-macroscopically visible tumor-developing group, NMVT) were identical in reduced mRNA expression of mlh1, anapc1, and ercc4 relative to colitic mice without mutagen, or those receiving mutagen alone. Colitis alone was sufficient to reduce colonic ercc4 expression when compared to NMVT mice. Therefore, reduced ercc4 expression may mark the early transition to CAC in a pre-clinical model, with expression reduced prior to the onset of observable tumor. Moreover, the expression of select DDR genes inversely correlated with chronicity of inflammatory disease. These data suggest ercc4 expression may define early stages in the progression to CAC.

Revisiting endotracheal self-extubation in the surgical and trauma intensive care unit: Are they all fine?

OBJECTIVES: Endotracheal self-extubation (ESE) is a serious health care concern. We designed this study to test our hypothesis that not all patients with ESE are successful in spontaneous breathing and reintubation has negative impact on outcomes. METHODS: Data on all 39 patients of ESE in our surgical and trauma intensive care unit (ICU) in 2012 were prospectively collected and retrospectively analyzed. RESULTS: There were 42 episodes of ESE in 39 of 939 intubated patients (frequency, 4.0%), with 54% of events requiring reintubation. Pre-ESE positive end-expiratory pressure was higher and Pao2/fraction of inspired oxygen ratio was lower, and the post-ESE respiration rate was higher in the reintubated group. On univariate analysis, weaning and spontaneous breathing trial before ESE were favorable predictors for nonreintubation. Multivariate regression analysis demonstrated that agitation before ESE was an independent predictor of reintubation. The need for reintubation was associated with increased risk of pulmonary infectious complications, ventilator days, the need for tracheostomy, and ICU and hospital LOS. The financial costs for ventilator days and ICU rooms were significantly higher in patients with reintubation. CONCLUSION: Not all patients were fine after ESE. We have not decreased the frequency of ESE or improved outcomes if the patients were reintubated. The need for reintubation was not only associated with a high pulmonary complication rate but also prolonged duration on mechanical ventilation and hospital/ICU stay and increased the hospital costs.

The coenzyme A disulphide reductase of Borrelia burgdorferi is important for rapid growth throughout the enzootic cycle and essential for infection of the mammalian host.

In a microarray analysis of the RpoS regulon in mammalian host-adapted Borrelia burgdorferi, bb0728 (cdr) was found to be dually transcribed by the sigma factors σ(70) and RpoS. The cdr gene encodes a coenzyme A disulphide reductase (CoADR) that reduces CoA-disulphides to CoA in an NADH-dependent manner. Based on the abundance of CoA in B. burgdorferi and the biochemistry of the enzyme, CoADR has been proposed to play a role in the spirochaete's response to reactive oxygen species. To better understand the physiologic function(s) of BbCoADR, we generated a B. burgdorferi mutant in which the cdr gene was disrupted. RT-PCR and 5'-RACE analysis revealed that cdr and bb0729 are co-transcribed from a single transcriptional start site upstream of the bb0729 coding sequence; a shuttle vector containing the bb0729-cdr operon and upstream promoter element was used to complement the cdr mutant. Although the mutant was no more sensitive to hydrogen peroxide than its parent, it did exhibit increased sensitivity to high concentrations of t-butyl-hydroperoxide, an oxidizing compound that damages spirochetal membranes. Characterization of the mutant during standard (15% oxygen, 6% CO(2)) and anaerobic (< 1% O(2) , 9-13% CO(2)) cultivation at 37°C revealed a growth defect under both conditions that was particularly striking during anaerobiosis. The mutant was avirulent by needle inoculation and showed decreased survival in feeding nymphs, but displayed no survival defect in unfed flat nymphs. Based on these results, we propose that BbCoADR is necessary to maintain optimal redox ratios for CoA/CoA-disulphide and NAD(+) /NADH during periods of rapid replication throughout the enzootic cycle, to support thiol-disulphide homeostasis, and to indirectly protect the spirochaete against peroxide-mediated membrane damage; one or more of these functions are essential for infection of the mammalian host by B. burgdorferi.