Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Informing Decision-making for Transected Margin Reresection in Intraductal Papillary Mucinous Neoplasm-derived PDAC: An International Multicenter Study.

OBJECTIVE: To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section. SUMMARY BACKGROUND DATA: The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable. METHODS: Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002-2022) from six international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival (RFS). RESULTS: Overall, 832 patients with IPMN-derived PDAC were included with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared to those with an R1 status (65.8 vs. 26.3 mo P<0.001). Patients without dysplasia at the pancreatic neck margin had similar OS compared to those with low-grade dysplasia (mOS: 78.8 vs. 66.8 months, P=0.344). However, high-grade dysplasia (mOS: 26.1 mo, P=0.001) and invasive cancer (mOS: 25.0 mo, P<0.001) were associated with significantly worse OS compared to no or low-grade dysplasia. Patients who underwent conversion of high-risk margins (high-grade or invasive cancer) to a low-risk margin (low-grade or no dysplasia) after intraoperative frozen section had significantly superior OS compared to those with a high-risk neck margin on final pathology (mOS: 76.9 vs. 26.1 mo P<0.001). CONCLUSIONS: In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible.

Towards a Standardization of Learning Curve Assessment in Minimally Invasive Liver Surgery.

OBJECTIVE: The aim was to analyze the learning curves of minimal invasive liver surgery(MILS) and propose a standardized reporting. SUMMARY BACKGROUND DATA: MILS offers benefits compared to open resections. For a safe introduction along the learning curve, formal training is recommended. However, definitions of learning curves and methods to assess it lack standardization. METHODS: A systematic review of PubMed, Web of Science, and CENTRAL databases identified studies on learning curves in MILS. The primary outcome was the number needed to overcome the learning curve. Secondary outcomes included endpoints defining learning curves, and characterization of different learning phases(competency, proficiency and mastery). RESULTS: 60 articles with 12'241 patients and 102 learning curve analyses were included. The laparoscopic and robotic approach was evaluated in 71 and 18 analyses and both approaches combined in 13 analyses. Sixty-one analyses (60%) based the learning curve on statistical calculations. The most often used parameters to define learning curves were operative time (n=64), blood loss (n=54), conversion (n=42) and postoperative complications (n=38). Overall competency, proficiency and mastery were reached after 34 (IQR 19-56), 50 (IQR 24-74), 58 (IQR 24-100) procedures respectively. Intraoperative parameters improved earlier (operative time: competency to proficiency to mastery: -13%, 2%; blood loss: competency to proficiency to mastery: -33%, 0%; conversion rate (competency to proficiency to mastery; -21%, -29%), whereas postoperative complications improved later (competency to proficiency to mastery: -25%, -41%). CONCLUSIONS: This review summarizes the highest evidence on learning curves in MILS taking into account different definitions and confounding factors. A standardized three-phase reporting of learning phases (competency, proficiency, mastery) is proposed and should be followed.

Total versus Partial Pancreatectomy in Patients with Pancreatic Cancer Arising from Multifocal or Diffuse Intraductal Papillary Mucinous Neoplasia - A Multicenter Observational Study.

AIM: To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer. SUMMARY BACKGROUND DATA: Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients. METHODS: This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS. RESULTS: Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007). CONCLUSION: Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence.

Semaphorin 3C exacerbates liver fibrosis.

BACKGROUND AND AIMS: Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-ß is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can modulate TGF-ß signaling during liver fibrosis. Expression of the axon guidance molecules semaphorins (SEMAs), which signal through plexins and neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. APPROACH AND RESULTS: We analyzed publicly available patient databases and liver biopsies. We used transgenic mice, in which genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the semaphorin family in liver samples from patients with cirrhosis. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis, or HBV-induced hepatitis discriminates those with a more profibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs on activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-ß-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained on activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. CONCLUSION: SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.

Prognostic Relevance of the Proximal Resection Margin Distance in Distal Gastrectomy for Gastric Adenocarcinoma.

BACKGROUND: The risk for recurrence in patients with distal gastric cancer can be reduced by surgical radicality. However, dispute exists about the value of the proposed minimum proximal margin distance (PMD). Here, we assess the prognostic value of the safety distance between the proximal resection margin and the tumor. PATIENTS AND METHODS: This is a single-center cohort study of patients undergoing distal gastrectomy for gastric adenocarcinoma (2001-2021). Cohorts were defined by adequacy of the PMD according to the European Society for Medical Oncology (ESMO) guidelines (≥ 5 cm for intestinal and ≥ 8 cm for diffuse Laurén's subtypes). Overall survival (OS) and time to progression (TTP) were assessed by log-rank and multivariable Cox-regression analyses. RESULTS: Of 176 patients, 70 (39.8%) had a sufficient PMD. An adequate PMD was associated with cancer of the intestinal subtype (67% vs. 45%, p = 0.010). Estimated 5-year survival was 63% [95% confidence interval (CI) 51-78] and 62% (95% CI 53-73) for adequate and inadequate PMD, respectively. Overall, an adequate PMD was not prognostic for OS (HR 0.81, 95% CI 0.48-1.38) in the multivariable analysis. However, in patients with diffuse subtype, an adequate PMD was associated with improved oncological outcomes (median OS not reached versus 131 months, p = 0.038, median TTP not reached versus 88.0 months, p = 0.003). CONCLUSION: Patients with diffuse gastric cancer are at greater risk to undergo resection with an inadequate PMD, which in those patients is associated with worse oncological outcomes. For the intestinal subtype, there was no prognostic association with PMD, indicating that a distal gastrectomy with partial preservation of the gastric function may also be feasible in the setting where an extensive PMD is not achievable.

Educational challenges and opportunities for the future generation of surgeons: a scoping review.

PURPOSE: Surgery offers exciting opportunities but comes with demanding challenges that require attention from both surgical program administrators and aspiring surgeons. The hashtag #NoTrainingTodayNoSurgeonsTomorrow on 𝕏 (previously Twitter) underscores the importance of ongoing training. Our scoping review identifies educational challenges and opportunities for the next generation of surgeons, analyzing existing studies and filling gaps in the literature. METHODS: Following the PRISMA guidelines, MEDLINE/PubMed was searched in February 2022, using the MeSH terms "surgeons/education," for articles in English or German on general, abdominal, thoracic, vascular, and hand surgery and traumatology targeting medical students, surgical residents, future surgeons, and fellows. RESULTS: The initial search yielded 1448 results. After a step-by-step evaluation process, 32 publications remained for complete review. Three main topics emerged: surgical innovations and training (n = 7), surgical culture and environment (n = 19), and mentoring (n = 6). The articles focusing on surgical innovations and training mainly described the incorporation of structured surgical training methods and program initiatives. Articles on surgical culture examined residents' burnout, well-being, and gender issues. Challenges faced by women, including implicit bias and sexual harassment, were highlighted. Regarding mentoring, mentees' needs, training challenges, and the qualities expected of both mentors and mentees were addressed. CONCLUSION: At a time of COVID-19-driven surgical innovations, the educational and working environment of the new generation of surgeons is changing. Robotic technology and other innovations require future surgeons to acquire additional technological and digital expertise. With regard to the cultural aspects of training, surgery needs to adapt curricula to meet the demands of the new generation of surgeons, but even more it has to transform its culture.

Hepatic Artery Infusion Chemotherapy for Primary and Secondary Malignancies of the Liver: State of the Art and Current High-Level Evidence.

BACKGROUND: Hepatic artery infusion chemotherapy (HAI) has been proposed as a valuable adjunct for multimodal therapy of primary and secondary liver malignancies. This review provides an overview of the currently available evidence of HAI, taking into account tumor response and long-term oncologic outcome. SUMMARY: In colorectal liver metastases (CRLM), HAI in combination with systemic therapy leads to high response rates (85-90%) and conversion to resectablity in primary unresectable disease in up to 50%. HAI in combination with systemic therapy in CRLM in the adjuvant setting shows promising long-term outcomes with up to 50% 10-year survival in a large, non-randomized single-center cohort. For hepatocellular carcinoma patients, response rates as high as 20-40% have been reported for HAI and long-term outcomes compare well to other therapies. Similarly, survival for patients with unresectable intrahepatic cholangiocarcinoma 3 years after treatment with HAI is reported as high as 34%, which compares well to trials of systemic therapy where 3-year survival is usually below 5%. However, evidence is mainly limited by highly selected, heterogenous patient groups, and outdated chemotherapy regimens. The largest body of evidence stems from small, often non-randomized cohorts, predominantly from highly specialized single centers. KEY MESSAGE: In well-selected patients with primary and secondary liver malignancies, HAI might improve response rates and, possibly, long-term survival. Results of ongoing randomized trials will show whether a wider adoption of HAI is justified, particularly to increase rates of resectability in advanced malignant diseases confined to the liver.

Evidence mapping on how to perform an optimal surgical repair of large hiatal hernias.

BACKGROUND: Symptomatic and large hiatal hernia (HH) is a common disorder requiring surgical management. However, there is a lack of systematic, evidence-based recommendations summarizing recent reviews on surgical treatment of symptomatic HH. Therefore, this systematic review aimed to create evidence mapping on the key technical issues of HH repair based on the highest available evidence. METHODS: A systematic review identified studies on eight key issues of large symptomatic HH repair. The literature was screened for the highest level of evidence (LE from level 1 to 5) according to the Oxford Center for evidence-based medicine's scale. For each topic, only studies of the highest available level of evidence were considered. RESULTS: Out of the 28.783 studies matching the keyword algorithm, 47 were considered. The following recommendations could be deduced: minimally invasive surgery is the recommended approach (LE 1a); a complete hernia sac dissection should be considered (LE 3b); extensive division of short gastric vessels cannot be recommended; however, limited dissection of the most upper vessels may be helpful for a floppy fundoplication (LE 1a); vagus nerve should be preserved (LE 3b); a dorso-ventral cruroplasty is recommended (LE 1b); routine fundoplication should be considered to prevent postoperative gastroesophageal reflux (LE 2b); posterior partial fundoplication should be favored over other forms of fundoplication (LE 1a); mesh augmentation is indicated in large HH with paraesophageal involvement (LE 1a). CONCLUSION: The current evidence mapping is a reasonable instrument based on the best evidence available to guide surgeons in determining optimal symptomatic and large HH repair.

Gastric Bypass Resolves Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Low-BMI Patients: A Prospective Cohort Study.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) reflects the multifactorial pathogenesis of fatty liver disease in metabolically sick patients. The effects of metabolic surgery on MAFLD have not been investigated. This study assesses the impact of Roux-en-Y gastric bypass (RYGB) on MAFLD in a prototypical cohort outside the guidelines for obesity surgery. METHODS: Twenty patients were enrolled in this prospective, single-arm trial investigating the effects of RYGB on advanced metabolic disease (DRKS00004605). Inclusion criteria were an insulin-dependent type 2 diabetes, body mass index of 25 to 35 kg/m 2 , glucagon-stimulated C-peptide of >1.5 ng/mL, glycated hemoglobin >7%, and age 18 to 70 years. A RYGB with intraoperative liver biopsies and follow-up liver biopsies 3 years later was performed. Steatohepatitis was assessed by expert liver pathologists. Data were analyzed using the Wilcoxon rank sum test and a P value <0.05 was defined as significant. RESULTS: MAFLD completely resolved in all patients 3 years after RYGB while fibrosis improved as well. Fifty-five percent were off insulin therapy with a significant reduction in glycated hemoglobin (8.45±0.27% to 7.09±0.26%, P =0.0014). RYGB reduced systemic and hepatic nitrotyrosine levels likely through upregulation of NRF1 and its dependent antioxidative and mitochondrial genes. In addition, central metabolic regulators such as SIRT1 and FOXO1 were upregulated while de novo lipogenesis was reduced and ß-oxidation was improved in line with an improvement of insulin resistance. Lastly, gastrointestinal hormones and adipokines secretion were changed favorably. CONCLUSIONS: RYGB is a promising therapy for MAFLD even in low-body mass index patients with insulin-treated type 2 diabetes with complete histologic resolution. RYGB restores the oxidative balance, adipose tissue function, and gastrointestinal hormones.

The Problem of Appetite Loss After Major Abdominal Surgery: A Systematic Review.

OBJECTIVE: To systematically review the problem of appetite loss after major abdominal surgery. SUMMARY OF BACKGROUND DATA: Appetite loss is a common problem after major abdominal surgery. Understanding of etiology and treatment options is limited. METHODS: We searched Medline, Cochrane Central Register of Controlled Trials, and Web of Science for studies describing postoperative appetite loss. Data were extracted to clarify definition, etiology, measurement, surgical influence, pharmacological, and nonpharmacological treatment. PROSPERO registration ID: CRD42021224489. RESULTS: Out of 6144 articles, we included 165 studies, 121 of which were also analyzed quantitatively. A total of 19.8% were randomized, controlled trials (n = 24) and 80.2% were nonrandomized studies (n = 97). The studies included 20,506 patients undergoing the following surgeries: esophageal (n = 33 studies), gastric (n = 48), small bowel (n = 6), colon (n = 27), rectal (n = 20), hepatobiliary (n = 6), and pancreatic (n = 13). Appetite was mostly measured with the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC QLQ C30, n = 54). In a meta-analysis of 4 randomized controlled trials gum chewing reduced time to first hunger by 21.2 hours among patients who had bowel surgery. Other reported treatment options with positive effects on appetite but lower levels of evidence include, among others, intravenous ghrelin administration, the oral Japanese herbal medicine Rikkunshito, oral mosapride citrate, multidisciplin-ary-counseling, and watching cooking shows. No studies investigated the effect of well-known appetite stimulants such as cannabinoids, steroids, or megestrol acetate on surgical patients. CONCLUSIONS: Appetite loss after major abdominal surgery is common and associated with increased morbidity and reduced quality of life. Recent studies demonstrate the influence of reduced gastric volume and ghrelin secretion, and increased satiety hormone secretion. There are various treatment options available including level IA evidence for postoperative gum chewing. In the future, surgical trials should include the assessment of appetite loss as a relevant outcome measure.

Mechanical stretching and chemical pyloroplasty to prevent delayed gastric emptying after esophageal cancer resection-a meta-analysis and review of the literature.

BACKGROUND: Delayed gastric emptying (DGE) occurs in up to 40% of patients after esophageal resection and prolongs recovery and hospital stay. Surgically pyloroplasty does not effectively prevent DGE. Recently published methods include injection of botulinum toxin (botox) in the pylorus and mechanical interventions as preoperative endoscopic dilatation of the pylorus. The aim of this study was to investigate the efficacy of those methods with respect to the newly published Consensus definition of DGE. METHODS: A systematic literature search using CENTRAL, Medline, and Web of Science was performed to identify studies that described pre- or intraoperative botox injection or mechanical stretching methods of the pylorus in patients undergoing esophageal resection. Frequency of DGE, anastomotic leakage rates, and length of hospital stay were analyzed. Outcome data were pooled as odd's ratio (OR) or mean difference using a random-effects model. Risk of bias was assessed using the Robins-I tool for non-randomized trials. RESULTS: Out of 391 articles seven retrospective studies described patients that underwent preventive botulinum toxin injection and four studies described preventive mechanical stretching of the pylorus. DGE was not affected by injection of botox (OR 0.87, 95% confidence interval [CI] 0.37-2.03, P = 0.75), whereas mechanical stretching resulted in significant reduction of DGE (OR 0.26, 95% CI 0.14-0.5, P < 0.0001). CONCLUSION: Mechanical stretching of the pylorus, but not injection of botox reduces DGE after esophageal cancer resection. A newly developed consensus definition should be used before the conduction of a large-scale randomized-controlled trial.

Transrectal rigid-hybrid NOTES cholecystectomy can be performed without peritoneal contamination: a controlled porcine survival study.

BACKGROUND AND STUDY AIMS: The risk of infectious complications due to peritoneal contamination is a major concern and inhibits the widespread use of transrectal NOTES. A standardized rectal washout with a reversible colon occlusion device in situ has previously shown potential in reducing peritoneal contamination. The aim of this study was to compare the peritoneal contamination rate and inflammatory reaction for transrectal cholecystectomy after ideal rectal preparation (trCCE) and standard laparoscopic cholecystectomy (lapCCE) in a porcine survival experiment. METHODS: Twenty pigs were randomized to trCCE (n = 10) or lapCCE (n = 10). Before trCCE, rectal washout was performed with saline solution. A colon occlusion device was then inserted and a second washout with povidone-iodine was performed. The perioperative course and the inflammatory reaction (leukocytes, C-reactive protein) were compared. At necropsy, 14 days after surgery the abdominal cavity was screened for infectious complications and peritoneal swabs were obtained for comparison of peritoneal contamination. RESULTS: Peritoneal contamination was lower after trCCE than after lapCCE (0/10 vs. 6/10; p = 0.003). No infectious complications were found at necropsy in either group and postoperative complications did not differ (p = 1.0). Immediately after the procedure, leukocytes were higher after lapCCE (17.0 ± 2.7 vs. 14.6 ± 2.3; p = 0.047). Leukocytes and C-reactive protein showed no difference in the further postoperative course. Intraoperative complications and total operation time (trCCE 114 ± 32 vs. 111 ± 27 min; p = 0.921) did not differ, but wound closure took longer for trCCE (31.5 ± 19 vs. 13 ± 5 min; p = 0.002). CONCLUSIONS: After standardized rectal washout with a colon occlusion device in situ, trCCE was associated without peritoneal contamination and without access-related infectious complications. Based on the findings of this study, a randomized controlled clinical study comparing clinical outcomes of trCCE with lapCCE should be conducted.

Gastric bypass simultaneously improves adipose tissue function and insulin-dependent type 2 diabetes mellitus.

OBJECTIVE: The underlying causes of type 2 diabetes (T2DM) remain poorly understood. Adipose tissue dysfunction with high leptin, inflammation, and increased oxidative stress may play a pivotal role in T2DM development in obese patients. Little is known about the changes in the adipose tissue after Roux-Y gastric bypass (RYGB) in non-severely obese patients (BMI < 35 kg/m2) and since these patients have more T2DM-associated complications than obese patients ("obesity paradox"), we investigated changes in adipose tissue function in a cohort of BMI <35 kg/m2 with insulin-dependent T2DM after RYGB surgery which resolves T2DM. METHODS: Twenty patients with insulin-dependent T2DM and BMI <35 kg/m2 underwent RYGB. Insulin-resistance, leptin, oxidative stress, and cytokines were determined over 24 months. Expression of cytokines and NF-kappaB pathway genes were measured in leukocytes (PBMC). Adipose tissue inflammation was examined histologically preoperatively and 24 months after RGYB in subcutaneous adipose tissue. RESULTS: Insulin-resistance, leptin, oxidative stress as well as adipose tissue inflammation decreased significantly after RYGB. Similarly, systemic inflammation was reduced and peripheral blood mononuclear cells (PBMCs) were reprogrammed towards an M2-type inflammation. Loss of BMI correlated with leptin levels (r = 0.891, p < 0.0001), insulin resistance (r = 0.527, p = 0.003), and oxidative stress (r = 0.592, p = 0.016). Leptin correlated with improved insulin resistance (r = 0.449, p = 0.032) while reduced leptin showed a strong association with improved oxidative stress (r = 0.809, p = 0.001). Lastly, reduced oxidative stress correlated strongly with improved insulin-resistance (r = 0.776, p = 0.001). CONCLUSIONS: RYGB improves adipose tissue function and inflammation. Leptin as marker for adipose tissue dysfunction may be the mediating factor between insulin resistance and oxidative stress and thereby likely improving T2DM.

Warming to 39°C but Not to 37°C Ameliorates the Effects on the Monocyte Response by Hypothermia.

OBJECTIVE: To investigate whether warming to normal body temperature or to febrile range temperature (39°C) is able to reverse the detrimental effects of hypothermia. BACKGROUND: Unintentional intraoperative hypothermia is a well-described risk factor for surgical site infections but also sepsis. We have previously shown that hypothermia prolongs the proinflammatory response whereas normothermia and especially febrile range temperature enhance the anti-inflammatory response. METHODS: Primary human monocytes were isolated from healthy volunteers. After stimulation with LPS (Lipopolysaccharide), the monocytes were exposed to 32°C for 3  hours or 6  hours and then warmed at either 37°C or 39°C for the remaining 33  hours or 36  hours, respectively. Tumor necrosis factor α, interleukin 10, and the expression of miR-155 and miR-101 were assessed at 24  hours and 36  hours. RESULTS: Warming to 37°C does not normalize monocyte cytokine secretion within 36  hours, whereas warming to 39°C partially reverses the effects of hypothermia on monocyte function. Both miR-155 and miR-101 were suppressed after the warming episode. However, 39°C had a stronger suppressive effect than 37°C. The duration of hypothermia and the warming temperature seem to be critical for a full reversibility of the effects of hypothermia. CONCLUSION: Warming to normal body temperature (37°C) does not restore normal monocyte function in vitro. These data suggest that hypothermic patients should be warmed to febrile range temperatures. Furthermore, febrile range temperatures should be investigated as a means to modulate the inflammatory response in patients with systemic infections.

Comparative Outcomes of Neoadjuvant Treatment Prior to Total Mesorectal Excision and Total Mesorectal Excision Alone in Selected Stage II/III Low and Mid Rectal Cancer.

BACKGROUND: Current guidelines advocate that all rectal cancer patients with American Joint Committee on Cancer (AJCC) stages II and III disease should be subjected to neoadjuvant therapy. However, improvements in surgical technique have resulted in single-digit local recurrence rates with surgery only. METHODS: Operative, postoperative, and oncological outcomes of patients with and without neoadjuvant therapy were compared between January 2002 and December 2013. For this purpose, all patients resected with low anterior rectal resection (LAR) and total mesorectal excision (TME) who had or had not been irradiated were identified from the authors' prospectively maintained database. Patients who were excluded were those with high rectal cancer or AJCC stage IV disease; in the surgery-only group, patients with AJCC stage I disease or with pT4Nx rectal cancer; and in the irradiated patients, patients with ypT4Nx or cT4Nx rectal cancer. RESULTS: Overall, 454 consecutive patients were included. A total of 342 (75 %) patients were irradiated and 112 (25 %) were not irradiated. Median follow-up for all patients was 48 months. Among patients with and without irradiation, pathological circumferential resection margin positivity rates (2.9 vs. 1.8 %, p = 0.5) were not different. At 5 years, in irradiated patients compared with surgery-only patients, the incidence of local recurrence was decreased (4.5 vs. 3.8 %, p = 0.5); however, systemic recurrences occurred more frequently (10 vs. 17.8 %, p = 0.2). Irradiation did not affect overall or disease-free survival (neoadjuvant treatment vs. surgery-only: 84.9 vs. 88.2 %, p = 0.9; 76 vs. 79.1 %, p = 0.8). CONCLUSIONS: The current study adds to the growing evidence that suggests a selective rather than generalized indication for neoadjuvant treatment in stages II and III rectal cancer.

Surgical versus medical treatment of type 2 diabetes mellitus in nonseverely obese patients: a systematic review and meta-analysis.

OBJECTIVE: To compare surgical versus medical treatment of type 2 diabetes mellitus (T2DM) remission and comorbidities in patients with a body mass index (BMI) less than 35 kg/m2. BACKGROUND: Obesity surgery can achieve remission of T2DM and its comorbidities. Metabolic surgery has been proposed as a treatment option for diabetic patients with BMI less than 35 kg/m2 but the efficacy of metabolic surgery has not been conclusively determined. METHODS: A systematic literature search identified randomized (RCT) and nonrandomized comparative observational clinical studies (OCS) evaluating surgical versus medical T2DM treatment in patients with BMI less than 35 kg/m2. The primary outcome was T2DM remission. Additional analyses comprised glycemic control, BMI, HbA1c level, remission of comorbidities, and safety. Random effects meta-analyses were calculated and presented as weighted odds ratio (OR) or mean difference (MD) with 95% confidence intervals (95% CI). RESULTS: Five RCTs and 6 OCSs (706 total T2DM patients) were included. Follow-up ranged from 12 to 36 months. Metabolic surgery was associated with a higher T2DM remission rate (OR: 14.1, 95% CI: 6.7-29.9, P < 0.001), higher rate of glycemic control (OR: 8.0, 95% CI: 4.2-15.2, P < 0.001) and lower HbA1c level (MD: -1.4%, 95% CI -1.9% to -0.9%, P < 0.001) than medical treatment. BMI (MD: -5.5 kg/m2, 95% CI: -6.7 to -4.3 kg/m2, P < 0.001), rate of arterial hypertension (OR: 0.25, 95% CI: 0.12-0.50, P < 0.001) and dyslipidemia (OR: 0.21, 95% CI: 0.10-0.44, P < 0.001) were lower after surgery. CONCLUSION: Metabolic surgery is superior to medical treatment for short-term remission of T2DM and comorbidities. Further RCTs should address the long-term effects on T2DM complications and mortality.