Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids (SCFAs) were depleted in SARS-CoV-2-infected patients. We aimed to characterize a functional profile of the gut microbiome in patients with COVID-19 before and after disease resolution. METHODS: We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (at up to 6 times points) during hospitalization and beyond 1 month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. RESULTS: Compared with non-COVID-19 controls, patients with COVID-19 with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for SCFA and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in patients with COVID-19. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in patients with COVID-19 before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT- proB-type natriuretic peptide, and C-reactive protein (all P < .05). CONCLUSIONS: Gut microbiome of patients with COVID-19 displayed impaired capacity for SCFA and L-isoleucine biosynthesis that persisted even after disease resolution. These 2 microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.

Adoption of cytoreductive surgery in the management of peritoneal malignancies-Global trends.

Cytoreductive surgery (CRS) has now been accepted as an integral component in the management of gastrointestinal and gynecological cancers with peritoneal metastases. Since the adoption of CRS is influenced by access to advanced medical facilities, trained multidisciplinary teams, and funding, there is wide variability in incorporation of CRS into routine clinical practice between high- versus low- and middle-income countries. This review highlights the global trends in the adoption of CRS for peritoneal malignancies with a specific focus on the establishment of CRS programs and barriers to incorporate CRS into routine clinical care in low- and middle-income countries.

Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome.

BACKGROUND: Long-term complications after COVID-19 are common, but the potential cause for persistent symptoms after viral clearance remains unclear. OBJECTIVE: To investigate whether gut microbiome composition is linked to post-acute COVID-19 syndrome (PACS), defined as at least one persistent symptom 4 weeks after clearance of the SARS-CoV-2 virus. METHODS: We conducted a prospective study of 106 patients with a spectrum of COVID-19 severity followed up from admission to 6 months and 68 non-COVID-19 controls. We analysed serial faecal microbiome of 258 samples using shotgun metagenomic sequencing, and correlated the results with persistent symptoms at 6 months. RESULTS: At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months. CONCLUSION: These findings provided observational evidence of compositional alterations of gut microbiome in patients with long-term complications of COVID-19. Further studies should investigate whether microbiota modulation can facilitate timely recovery from post-acute COVID-19 syndrome.

Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial.

OBJECTIVE: The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM). DESIGN: In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24. RESULTS: Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in Bifidobacterium and Lactobacillus compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05). CONCLUSION: Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness. TRIAL REGISTRATION NUMBER: NCT03127696.

More Than an ERAS Pathway is Needed to Meet Target Length of Stay After Pancreaticoduodenectomy.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols have been successfully instituted for pancreaticoduodenectomy (PD). This study evaluates reasons patients fail to meet length of stay (LOS) and areas for pathway improvement. MATERIALS AND METHODS: A multidisciplinary team developed and implemented an ERAS protocol for open PD in 2017. The study includes a medical record review of all patients who were perioperatively managed with the ERAS protocol and failed to meet LOS after PD procedures. Target LOS was defined as 7 d. RESULTS: From 2017 to 2020, 44% (93 of 213) of patients using ERAS protocol after PD procedures failed to meet target LOS. The most common reason to fail target LOS was ileus or delayed gastric emptying (47 of 93, LOS 11). Additional reasons included work-up of leukocytosis or pancreatic leak (17 of 93, LOS 14), additional "night" of observation (14 of 93, LOS 8), and orthostatic hypotension (3 of 93, LOS 10). Of these additional 46 patients, 19 patients underwent computed tomography (on or after POD 7) and only four patients received additional inpatient intervention. CONCLUSIONS: The most common reason for PD pathway failure included slow return of gastrointestinal function, a known complication after PD. The remaining patients were often kept for observation without additional intervention. This group represents an actionable cohort to target for improving LOS through surgeon awareness rather than protocol modification.

Characterizing gastrointestinal dysfunction after pancreatic resection: a single-center retrospective study.

BACKGROUND: There are many well-described potential gastrointestinal (GI) side effects of pancreatic resection that can cause patients to suffer from chronic malabsorption, diarrhea, and persistent nausea. These GI symptoms can affect postoperative recovery, initiation of adjuvant therapy, and overall quality of life (QOL). The purpose of this study is to quantify the incidence of post-procedural complications and identify patients at higher risk for experiencing GI dysfunction after pancreatectomy. METHODS: A retrospective review of patients who underwent pancreatic resection at a single institution between January 2014 and December 2019 was performed. Demographics, operative factors, and postoperative gastrointestinal symptomatology and treatments were obtained by chart review. Significance tests were performed to compare GI dysfunction between patient subgroups. RESULTS: A total of 545 patients underwent pancreatic resection; within the cohort 451 patients (83%) underwent a pancreaticoduodenectomy (PD) and the most common indication was pancreatic adenocarcinoma. Two-thirds of patients (67%) reported gastrointestinal symptoms persisting beyond hospitalization. Only 105 patients (20%) were referred to gastroenterology for evaluation with 30 patients (5.5%) receiving a formal diagnosis. Patients who underwent PD were more likely to report GI symptoms and patients who identified as Caucasian were more likely to be referred to gastroenterology for evaluation. CONCLUSIONS: Gastrointestinal dysfunction after pancreatic resection occurs frequently yet only a small percentage of patients are referred for formal testing and diagnosis. There also appears to be a racial difference in referral patterns. Patients would benefit if earlier attention was dedicated to the diagnosis and corresponding treatment for postoperative digestive health disorders to optimize treatment planning and QOL.

Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization.

BACKGROUND & AIMS: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects gastrointestinal tissues, little is known about the roles of gut commensal microbes in susceptibility to and severity of infection. We investigated changes in fecal microbiomes of patients with SARS-CoV-2 infection during hospitalization and associations with severity and fecal shedding of virus. METHODS: We performed shotgun metagenomic sequencing analyses of fecal samples from 15 patients with Coronavirus Disease 2019 (COVID-19) in Hong Kong, from February 5 through March 17, 2020. Fecal samples were collected 2 or 3 times per week from time of hospitalization until discharge; disease was categorized as mild (no radiographic evidence of pneumonia), moderate (pneumonia was present), severe (respiratory rate ≥30/min, or oxygen saturation ≤93% when breathing ambient air), or critical (respiratory failure requiring mechanical ventilation, shock, or organ failure requiring intensive care). We compared microbiome data with those from 6 subjects with community-acquired pneumonia and 15 healthy individuals (controls). We assessed gut microbiome profiles in association with disease severity and changes in fecal shedding of SARS-CoV-2. RESULTS: Patients with COVID-19 had significant alterations in fecal microbiomes compared with controls, characterized by enrichment of opportunistic pathogens and depletion of beneficial commensals, at time of hospitalization and at all timepoints during hospitalization. Depleted symbionts and gut dysbiosis persisted even after clearance of SARS-CoV-2 (determined from throat swabs) and resolution of respiratory symptoms. The baseline abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi correlated with COVID-19 severity; there was an inverse correlation between abundance of Faecalibacterium prausnitzii (an anti-inflammatory bacterium) and disease severity. Over the course of hospitalization, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus, which downregulate expression of angiotensin-converting enzyme 2 (ACE2) in murine gut, correlated inversely with SARS-CoV-2 load in fecal samples from patients. CONCLUSIONS: In a pilot study of 15 patients with COVID-19, we found persistent alterations in the fecal microbiome during the time of hospitalization, compared with controls. Fecal microbiota alterations were associated with fecal levels of SARS-CoV-2 and COVID-19 severity. Strategies to alter the intestinal microbiota might reduce disease severity.

Laparoscopic hepatic lobectomy for symptomatic polycystic liver disease.

BACKGROUND: Laparoscopic fenestration has largely replaced open fenestration of liver cysts. However, most hepatectomies for polycystic liver disease (PCLD) are performed open. Outcomes data on laparoscopic hepatectomy for PCLD are lacking. METHODS: Patients who underwent surgery for PCLD at a single institution between 2010 and 2019 were reviewed and grouped by operative approach. Pre- and post-operative volumes were calculated for patients who underwent resection. Primary outcomes were: volume reduction, re-admission and postoperative complications. RESULTS: Twenty-six patients were treated for PCLD: 13 laparoscopic fenestration, nine laparoscopic hepatectomy, three open hepatectomy and one liver transplantation. Median length of stay for patients after laparoscopic resection was 3 days (IQR 2-3). The only complication was post-operative atrial fibrillation in one patient. There were no readmissions. Overall volume reduction was 51% (range 22-69) for all resections, 32% (range 22-46) after open resection and 56% (range 39-69) after laparoscopic resection. CONCLUSION: Volume reduction achieved through laparoscopic approach exceeded open volume reduction at this institution and is comparable to volume reduction in previously published open resection series. Adequate volume reduction can be accomplished by laparoscopic means with acceptable postoperative morbidity.

Regional lymph node sampling in hepatoma resection: insight into prognosis.

BACKGROUND: The importance of regional lymph node sampling (LNS) during resection of hepatocellular carcinoma (HCC) is poorly understood. This study sought to ameliorate this knowledge gap through a nationwide population-based analysis. METHODS: Patients who underwent liver resection (LR) for HCC were identified from Surveillance, Epidemiology and End Results (SEER-18) database (2003-2015). Cohort-based clinicopathologic comparisons were made based on completion of regional LNS. Propensity-score matching reduced bias. Overall and disease-specific survival (OS/DSS) were analyzed. RESULTS: Among 5395 patients, 835 (15.4%) underwent regional LNS. Patients undergoing LNS had larger tumors (7.0vs4.8 cm) and higher T-stage (30.9 vs. 17.6% T3+, both p < 0.001). Node-positive rate was 12.0%. Median OS (50 months for both) and DSS (28 vs. 29 months) were similar between cohorts, but node-positive patients had decreased OS/DSS (20/16 months, p < 0.01). Matched patients undergoing LNS had equivalent OS (46 vs. 43 months, p = 0.869) and DSS (27 vs. 29 months, p = 0.306) to non-LNS patients. The prognostic impact of node positivity persisted after matching (OS/DSS 24/19 months, p < 0.01). Overall disease-specific mortality were both independently elevated (overall HR 1.71-unmatched, 1.56-matched, p < 0.01; disease-specific HR 1.40-unmatched, p < 0.01, 1.25-matched, p = 0.09). CONCLUSION: Regional LNS is seldom performed during resection for HCC, but it provides useful prognostic information. As the era of adjuvant therapy for HCC begins, surgeons should increasingly consider performing regional LNS to facilitate optimal multidisciplinary management.

Prognostic impact of postoperative low platelet count after liver transplantation.

BACKGROUND: The positive impact of platelets has been recently implicated in liver transplantation (LT). The aim of this study was to determine the risk factors for graft loss and mortality after LT, focusing on perioperative platelet counts. METHODS: We reviewed all deceased donor LT from 2000 to 2012 and enrolled 975 consecutive recipients. The risk factors for graft loss and mortality were analyzed by multivariate analysis, using Cox's regression model. RESULTS: Using cutoff values acquired by receiver operating characteristics curve analysis, multivariate analyses determined that viral hepatitis C (hazard ratio [HR]=1.32), donor age >40 (HR=1.33), higher peak serum alanine aminotransferase (HR=1.01), reoperation within 30 days (HR=1.51), and platelet count <72 500/µL on postoperative day (POD) 5 (HR=1.30) were independent risk factors for graft loss. Viral hepatitis C (HR=1.33), reoperation within 30 days (HR=1.35), and platelet count <72 500/µL on POD 5 (HR=1.38) were independent risk factors for mortality. CONCLUSION: A low platelet count on POD 5 was associated with graft loss and mortality after LT. Platelet count <72 500/µL on POD 5 can be a predictor of poor graft and overall survival. Maintaining higher postoperative platelet counts could potentially improve graft and overall survival rates.

Prediction of biliary anastomotic stricture after deceased donor liver transplantation: the impact of platelet counts - a retrospective study.

Biliary stricture is a common cause of morbidity after liver transplantation (LT). This study aimed to determine the risk factors for post-transplant biliary anastomotic strictures (BAS), focusing on perioperative platelet counts. We enrolled 771 consecutive recipients who underwent ABO-identical/compatible deceased donor LT with duct-to-duct biliary reconstruction from January 2000 to June 2012. BAS was identified in 142 cases. The median time for stricture development was 176 days. Preoperative and postoperative platelet counts within 5 days after LT were significantly lower in patients with BAS than those without BAS. Using cutoff values acquired by the receiver operating characteristic curve analysis, persistent postoperative thrombocytopenia was defined as platelet counts <41 × 1000/µl and <53 × 1000/µl on postoperative day (POD) 3 and POD 5, respectively. Multivariate analysis indicated persistent postoperative thrombocytopenia (OR = 2.38) was the only independent risk factor for BAS. No significant associations were observed in terms of donor and surgical factors. Multivariate analysis demonstrated estimated blood loss (OR = 1.01, per 100 ml) was an independent contributing factor for persistent postoperative thrombocytopenia. We demonstrated low platelet count was associated with progression of post-transplant BAS. Minimizing intraoperative blood loss potentially contributes to maintain post-transplant platelet count, which may reduce incidence of BAS.

Patient-Reported Convalescence and Quality of Life Recovery: A Comparison of Open and Robotic-Assisted Radical Cystectomy.

Background Robotic-assisted radical cystectomy (RARC) is gaining traction as a surgical approach, but there are limited data on patient-reported outcomes for this technique compared to open radical cystectomy (ORC). Objective To compare health-related quality of life (HRQoL) and short-term convalescence among bladder cancer patients who underwent ORC and RARC. Methods Review of a single-institution bladder cancer database was conducted. Baseline and postoperative HRQoL was evaluated using the Bladder Cancer Index (BCI) for 324 patients who had ORC (n = 267) or RARC (n = 57) between 2008 and 2012. The BCI assesses function and bother in urinary, bowel, and sexual domains. Among 87 distinct patients (ORC n = 67, RARC n = 20), we also evaluated short-term postoperative convalescence using the Convalescence and Recovery Evaluation (CARE) questionnaire. Our primary outcomes were HRQoL within 12 months and short-term convalescence within 6 weeks following cystectomy. We fit generalized estimating equation regression models to estimate longitudinal changes in BCI scores within domains, and CARE domain score differences were tested with Wilcoxon rank-sum tests. Results Clinical characteristics and baseline BCI/CARE scores were similar between the 2 groups (all P > .05). Within 1 year after surgery, recovery of HRQoL across all BCI domains was comparable, with scores nearly returning to baseline at 1 year for all patients. CARE scores at 4 weeks revealed that patients treated with ORC had better pain (29.1 vs 20.0, P = .02) domain scores compared to RARC. These differences abated by week 6. Conclusions HRQoL recovery and short-term convalescence were similar in this cohort following ORC and RARC.

Regional Therapy Approaches for Gastric Cancer with Limited Peritoneal Disease.

PURPOSE: Despite advances in systemic therapy, outcomes of patients with gastric cancer (GC) peritoneal carcinomatosis (PC) remain poor, in part because of poor penetrance of systemic therapy into peritoneal metastasis due to the plasma-peritoneal barrier and anarchic intra-tumoral circulation. Hence, regional treatment approach with administration of chemotherapy directly into the peritoneal cavity (intraperitoneal, IP) under various conditions, combined with or without cytoreductive surgery (CRS) has remained an area of significant research interest. The purpose of this review is to provide high-level evidence for regional treatment approaches in the management of GCPC with limited peritoneal disease. METHODS: A review of the current literature and ongoing clinical trials for regional IP therapies for GCPC was performed. Studies included in this review comprise of phase III randomized controlled trials, non-randomized phase II studies, high-impact retrospective studies, and active ongoing clinical trials for each available IP modality. RESULTS: The three common IP approaches are heated intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal chemotherapy (NIPEC) and more recently introduced, pressurized intraperitoneal aerosolized chemotherapy (PIPAC). These IP approaches have been combined with systemic therapy and/or CRS with varying degrees of promising results, demonstrating evidence of improvements in survival rates and peritoneal disease control. Patient selection, optimization of systemic therapy, and completeness of cytoreduction have emerged as major factors influencing the design of contemporary and ongoing trials. CONCLUSION: IP chemotherapy has a clear role in the management of patients with GCPC, and when combined with CRS in appropriately selected patients has the potential to significantly improve survival. Ongoing and upcoming IP therapy clinical trials hold great promise to shape the treatment paradigm for GCPC.

Determinants, Costs, and Consequences of Common Bile Duct Injury Requiring Operative Repair Among Privately Insured Individuals in the United States, 2003-2020.

Objective: Characterize the determinants, all-cause mortality risk, and healthcare costs associated with common bile duct injury (CBDI) following cholecystectomy in a contemporary patient population. Background: Retrospective cohort study using nationwide patient-level commercial and Medicare Advantage claims data, 2003-2019. Beneficiaries ≥18 years who underwent cholecystectomy were identified using Current Procedure Terminology (CPT) codes. CBDI was defined by a second surgical procedure for repair within one year of cholecystectomy. Methods: We estimated the association of common surgical indications and comorbidities with risk of CBDI using logistic regression; the association between CBDI and all-cause mortality using Cox proportional hazards regression; and calculated average healthcare costs associated with CBDI repair. Results: Among 769,782 individuals with cholecystectomy, we identified 894 with CBDI (0.1%). CBDI was inversely associated with biliary colic (odds ratio [OR] = 0.82; 95% confidence interval [CI]: 0.71-0.94) and obesity (OR = 0.70, 95% CI: 0.59-0.84), but positively associated with pancreas disease (OR = 2.16, 95% CI: 1.92-2.43) and chronic liver disease (OR = 1.25, 95% CI: 1.05-1.49). In fully adjusted Cox models, CBDI was associated with increased all-cause mortality risk (hazard ratio = 1.57, 95% CI: 1.38-1.79). The same-day CBDI repair was associated with the lowest mean overall costs, with the highest mean overall costs for repair within 1 to 3 months. Conclusions: In this retrospective cohort study, calculated rates of CBDI are substantially lower than in prior large studies, perhaps reflecting quality-improvement initiatives over the past two decades. Yet, CBDI remains associated with increased all-cause mortality risks and significant healthcare costs. Patient-level characteristics may be important determinants of CBDI and warrant ongoing examination in future research.

Performance of multiparametric prostate magnetic resonance imaging validated by targeted and systematic transperineal biopsies.

Objective: To measure the performance of multiparametric (mp) magnetic resonance imaging (MRI) to identify intraprostatic tumour deposits using a systematic and targeted MR-guided transperineal prostate biopsy technique. Materials and Methods: Patients underwent a combined systematic and targeted MR-guided transperineal biopsy procedure in the dorsal lithotomy position under general anaesthesia. Systematic biopsies were spaced 10 mm or less apart and additional biopsies targeted any Prostate Imaging-Reporting and Data System (PI-RADS) 3, 4 or 5 lesions identified on mpMRI. Cancer detection rates were calculated on a per patient and per lesion basis. Results: A total of 125 patients underwent the biopsy procedure. The positive predictive value (PPV) of mpMRI per patient was 59% for any cancer and 49% for Gleason score (GS) ≥ 7 cancer. The negative predictive value (NPV) of mpMRI per patient was 67% for any cancer and 88% for GS ≥ 7 cancer. On a per lesion basis, the PPV of PI-RADS 3 lesions for any and GS ≥ 7 cancer was 24% and 10%. For PI-RADS 4 lesions it was 42% and 32%. For PI-RADS 5 lesions, it was 76% and 70%. MpMRI failed to identify GS ≥ 7 cancer found on systematic biopsy in 22% of patients. Conclusion: Based on a combination of systematic and targeted transperineal prostate biopsies, mpMRI showed a high NPV and low PPV for GS ≥ 7 cancer on a per patient basis. The PPV of mpMRI on a per lesion basis increased with increasing PI-RADS score. However, there were a significant number of both false positive as well as false negative (mpMRI invisible) areas within the prostate that contained GS ≥ 7 cancer. Therefore, pathologic confirmation using both targeted and systematic mapping biopsy is necessary to accurately identify all intraprostatic tumour deposits.

Utilization of parenteral nutrition in major gastrointestinal surgery: An opportunity for quality improvement.

BACKGROUND & AIMS: Parenteral nutrition (PN) is commonly utilized to support patients in the perioperative period of major gastrointestinal (GI) surgeries. This study sought to evaluate PN utilization based on malnutrition status and duration of PN use in a single academic institution to evaluate baseline ASPEN recommendation concordance and identify opportunities for quality improvement. METHODS: Patients who had undergone major GI surgical oncology operations and received PN were identified over six months. The medical charts were reviewed for clinicopathologic variables, nutrition status, and the initiation and duration of PN. The cohort was stratified by PN recommendation concordance, and intergroup comparisons were made to identify factors associated with non-concordant utilization of PN. RESULTS: Eighty-one patients were identified, 38.3% of patients were initiated on PN due to dysmotility. Other indications were: intra-abdominal leak (27.2%), mechanical obstruction (18.5%), and failure to thrive (16.0%). Non-concordant PN utilization was identified in 67.9% (55/81) of patients. The most frequent reason for non-concordance was initiation outside the recommended time frame due to severity of malnutrition; well-nourished patients started "too soon" accounted for 29.0% (16/55), and 61.8% started "too late," most of whom were moderately or severely malnourished (34/55). In 16.0% (13/81) of the overall cohort, PN was administered for fewer than five days. CONCLUSIONS: PN use during the perioperative period surrounding major GI oncologic operations is clinically nuanced and frequently not concordant with established ASPEN recommendations. Quality improvement efforts should focus on reducing delayed PN initiation for nutritionally at-risk patients without increasing premature PN use in well-nourished patients.

Smac-mimetic compound SM-164 induces radiosensitization in breast cancer cells through activation of caspases and induction of apoptosis.

Radiotherapy is a treatment choice for local control of breast cancer, particularly after the removal of tumor tissues by surgery. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. Here, we determined in breast cancer cells the potential radiosensitizing activity of SM-164, a small molecule compound, that mimics the activity of SMAC, a mitochondrial protein released during apoptosis to activate caspases by inhibiting cellular inhibitor of apoptosis proteins, cIAP-1, and XIAP. We found that SM-164 at nanomolar concentrations promoted degradation of cIAP-1, disrupted the inhibitory binding of XIAP to active caspase-9, and sensitized breast cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.7-1.8. In one line of breast cancer cells resistant to SM-164 as a single agent, SM-164 radiosensitization was mediated by intrinsic apoptosis pathway through activation of caspases-9 and -3. In a line of breast cancer cells sensitive to SM-164 as a single agent, SM-164 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases-9, -8, and -3. Consistently, blockage of caspase activation, through siRNA knockdown or treatment with a pan-caspase inhibitor z-VAD-fmk, inhibited apoptosis and abrogated SM-164 radiosensitization. Our study demonstrates that IAPs are valid radiosensitizing targets in breast cancer cells and SM-164 could be further developed as a novel class of radiosensitizers for the treatment of radioresistant breast cancer.

Surgical Indications and Outcomes of Resection for Pancreatic Neuroendocrine Tumors with Vascular Involvement.

Complete surgical resection of pancreatic neuroendocrine tumors (pNETs) has been suggested as the only potentially curative treatment. A proportion of these tumors will present late during disease progression, and invade or encase surrounding vasculature; therefore, surgical treatment of locally advanced disease remains controversial. The role of surgery with vascular reconstruction in pNETs is not well defined, and there is considerable variability in the use of aggressive surgery for these tumors. Accurate preoperative assessment is critical to evaluate individual considerations, such as anatomical variants, areas and lengths of vessel involvement, proximal and distal targets, and collateralization secondary to the degree of occlusion. Surgical approaches to address pNETs with venous involvement may include thrombectomy, traditional vein reconstruction, a reconstruction-first approach, or mesocaval shunting. Although the amount of literature on pNETs with vascular reconstruction is limited to case reports and small institutional series, the last two decades of studies have demonstrated that aggressive resection of these tumors can be performed safely and with acceptable long-term survival.