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Background The optimal treatment in patients with gastric cancer and peritoneal disease remains controversial. Some guidelines indicate palliative treatment only, while others consider surgical treatment in case of positive lavage cytology (CY+) or limited peritoneal disease. Here, we analyzed the role of peritoneal disease in patients with gastric cancer, and the prognostic relevance of response to neoadjuvant therapy. Methods In this retrospective cohort analysis, we analyzed patients with adenocarcinoma of the stomach or esophago-gastric junction from a single center operated between 2011 and 2019. According to histology and lavage cytology, patients were classified into four risk groups: (A) no peritoneal disease, (B) CY+ who converted to negative lavage cytology (CY−) after neoadjuvant chemotherapy, (C) CY+ without conversion after chemotherapy, and (D) patients with visible peritoneal metastasis. Results Overall, n = 172 patients were included. At initial presentation, n = 125 (73%) had no peritoneal disease, and about a third of patients (n = 47, 27%) had microscopic or macroscopic peritoneal disease. Among them, n = 14 (8%) were CY+ without visible peritoneal metastasis, n = 9 converted to CY− after chemotherapy, and in n = 5 no conversion was observed. Median overall survival was not reached in patients who had initially no peritoneal disease and in patients who converted after chemotherapy, resulting in 3-year survival rates of 65% and 53%. In contrast, median overall survival was reduced to 13 months (95% CI 8.7–16.7) in patients without conversion and was 16 months (95% CI 12–20.5) in patients with peritoneal metastasis without difference between the two groups (p = .364). The conversion rate from CY+ to CY− was significantly higher after neoadjuvant treatment with FLOT (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel) compared to ECF (epirubicin, cisplatin, and 5-fluorouracil) (p = 0.027). Conclusion Conversion of CY+ to CY− after neoadjuvant chemotherapy with FLOT is a significant prognostic factor for a better overall survival. Surgical treatment in well-selected patients should therefore be considered. However, peritoneal recurrence remains frequent despite conversion, urging for a better local control.

INTRODUCTION Over the past two decades, cytoreductive surgery and HIPEC has improved outcomes for selected patients with peritoneal metastasis from various origins. This is a cross-sectional study with descriptive analyses of HIPEC trials registered on ClinicalTrials.gov. This study aimed to characterize clinical trials on HIPEC registered on ClinicalTrials.gov with the primary objective of identifying a trial focus and to examine whether trial results were published. METHODS The search included trials registered from 1 January 2001 to 14 March 2022. We examined the associations of exposure variables and other trial features with two primary outcomes: therapeutic focus and results reporting. RESULTS In total, 234 clinical trials were identified; 26 (11%) were already published, and 15 (6%) trials have reported their results but have not been published as full papers. Among ongoing nonpublished trials, 81 (39%) were randomized, 30 (14%) were blinded, n = 39 (20%) were later phase trials (i.e., phases 3 and 4), n = 152 (73%) were from a single institution, and 91 (44%) had parallel groups. Most of the trials were recruiting at the time of this analysis (75, 36%), and 39 (20%) were completed but had yet to publish results. In total, 68% of the trials focused on treatment strategies, and 53% investigated the oncological outcome. The most studied neoplasms for HIPEC trials were peritoneally metastasized colorectal cancer (32%), gastric cancer (29%), and ovarian cancer (26%). Twenty different drugs were analyzed in these clinical trials. CONCLUSIONS Many study results are awaited from ongoing HIPEC trials. Most HIPEC trials focused on gastric, colorectal, or ovarian cancer. Many clinical trials were identified involving multiple entities and chemotherapeutic agents.

Introduction: The PRODIGE 7-trial investigated the additional value of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to cytoreductive surgery (CRS) for patients with colorectal peritoneal metastases (CPM). The results of PRODIGE 7 were presented at the 2018 ASCO meeting showing that 30 min oxaliplatin-based HIPEC did not improve overall survival. The current study investigated the impact of PRODIGE 7 on the worldwide practice of CRS and HIPEC. Materials and methods: CRS-HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning the current CRS-HIPEC practice in their hospital and country, and were asked to appraise the effect of PRODIGE 7. Results: The survey was completed by 18/19 experts. Although their personal opinions of CRS-HIPEC were barely influenced by PRODIGE 7, they reported a substantial impact on daily practice. This included a switch towards Mitomycin-C based HIPEC-regimens and prolongation of HIPEC perfusion time, a reduction in the number of referrals from non-HIPEC centers, a reduction in national consensus, the removal of HIPEC from national guidelines, and a reduced reimbursement rate. Conclusion: The PRODIGE 7 has had a major impact on the practice of CRS-HIPEC for CPM worldwide. HIPEC remains an attractive option with potential for control and eradication of disease and further studies into the optimal HIPEC-regimen are urgently needed. Meanwhile, given the complexity of the treatment of patients with CPM, and the proven benefits of optimal CRS, referral of patients with potentially resectable CPM to expert centers is recommended whilst the precise role of HIPEC is further evaluated. (c) 2021 Published by Elsevier Ltd.

Background Multimodal treatment, including systemic treatment and surgery, improved the prognosis of peritoneal metastasis (PM). Despite all efforts, recurrence rates remain high, and little data are available about clinical behavior or molecular patterns of PM in comparison to hematogenous metastasis. Here, we aimed to analyze recurrence patterns after multimodal treatment for PM from colorectal cancer. Methods Patients with colorectal PM undergoing multimodal treatment including systemic chemotherapy and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 2005 and 2017 at 4 centers were analyzed retrospectively. Results A total of 505 patients undergoing CRS/HIPEC were analyzed. Of the patients, 82.1% received preoperative chemotherapy. Median peritoneal cancer index was 6 (interquartile range = 3-11). Median disease-free and overall survival was 12 (95% confidence interval [CI] = 11 to 14) months and 51 (95% CI = 43 to 62) months, respectively. Disease recurred in 361 (71.5%) patients, presenting as isolated peritoneal recurrence in 24.6%, isolated hematogenous recurrence in 28.3%, and mixed recurrence in 13.9% of patients. Recurrence to the peritoneum was associated with an impaired time from recurrence to death of 21 (95% CI = 18 to 31) months for isolated peritoneal and 22 (95% CI = 16 to 30) months for mixed recurrence, compared with 43 (95% CI = 31 to >121) months for hematogenous recurrence (hazard ratio [HR] = 1.79, 95% CI = 1.27 to 2.53; P = .001; and HR = 2.44, 95% CI = 1.61 to 3.79; P Conclusions This study highlights the heterogeneity of peritoneal metastasis in patients with colorectal cancer. Recurrent peritoneal metastasis after radical treatment represents a more aggressive subset of metastatic colorectal cancer.

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients.

Simple Summary Surgical and locoregional treatments of peritoneal metastasis, e.g., from colorectal cancer, has gained increasing acceptance after the publication of excellent patient outcomes from many groups around the world. Apart from systemic chemotherapy and surgical removal of the tumor, locoregional therapies such as HIPEC or PIPAC may improve tumor control. Understanding the molecular characteristics of peritoneal metastasis is crucial to evolve future therapeutic strategies for peritoneal metastasis. This includes the genetic background of PM, which is often different from other sites of metastasis, and promotes peritoneal dissemination and the growth of tumor cells. Growing knowledge and insight into the physiology of the peritoneal tumor microenvironment and the specific role of the immune system in this compartment may provide a critical step to move locoregional therapy to the next level. This review summarizes the current knowledge and highlights the molecular characteristics of peritoneal metastasis. Abstract Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. The advent of better systemic treatment, a better understanding of prognostic factors, and finally, the advent of novel loco-regional therapies, has opened the door for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged survival of patients with peritoneal metastasis. This has triggered a significant body of research, leading to the molecular characterization of PM, which may further help in the development of novel treatments. This review summarizes current evidence on peritoneal metastasis and explores potential novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis.

Background CRS/HIPEC gained acceptance as a treatment for selected patients with peritoneal metastasis. However, the pathophysiology behind HIPEC is poorly understood, and a variety of regimens are currently in use. In this study, we describe for the first-time changes in the postoperative systemic inflammatory reaction, highly different among HIPEC treatment protocols. Methods HIPEC was performed with three protocols, different with regard to perfusion times and drugs: (mitomycinC/doxorubicin, 90min), (cisplatin, 90min) (oxaliplatin, 30min). Serial blood samples were assessed for C-reactive protein (CRP), white blood cells (WBC), pancreatic stone protein (PSP) and bacterial component (16s rDNA). The study was approved by the local ethics committee and registered at clinicaltirals.gov (NCT02741167). Results Overall, 140 patients from two European centers were included. In patients without postoperative complications, a secondary peak of inflammatory parameters, CRP (p = 0.015) and PSP (p = 0.004) was observed after HIPEC for 90 min with mitomycinC/doxorubicin or cisplatin but not after 30 min oxaliplatin. In patients after 90 min HIPEC, postoperative serum bacterial 16srDNA level were 2.1 times higher (95% CI 0.646–3.032, p = 0.015) compared to 30 min oxaliplatin. Discussion In conclusion, we identified a secondary inflammatory reaction after 90 min HIPEC, either with mitomycinC/doxorubicin or cisplatin, not observed after short course HIPEC with oxaliplatin. This protocol dependent physiology of acute phase proteins should be known in the clinical management of patients after HIPEC.

Background The perforated duodenal diverticulum remains a rare clinical entity, the optimal management of which has not been well established. Historically, primary surgery has been the preferred treatment modality. This was called into question during the last decade, with the successful application of non-operative therapy in selected patients. The aim of this systematic review is to identify cases of perforated duodenal diverticula published over the past decade and to assess any subsequent evolution in treatment. Methods A systematic review of English and non-English articles reporting on perforated duodenal diverticula using MEDLINE (2008–2020) was performed. Only cases of perforated duodenal diverticula in adults (> 18 years) that reported on diagnosis and treatment were included. Results Some 328 studies were identified, of which 31 articles met the inclusion criteria. These studies included a total of 47 patients with perforated duodenal diverticula. This series suggests a trend towards conservative management with 34% (16/47) of patients managed non-operatively. In 31% (5/16) patients initially managed conservatively, a step-up approach to surgical intervention was required. Conclusion Conservative treatment of perforated duodenal diverticula appears to be an acceptable and safe treatment strategy in stable patients without signs of peritonitis under careful observation. For patients who fail to respond to conservative treatment, a step-up approach to percutaneous drainage or surgery can be applied. If surgery is required, competence in techniques ranging from simple diverticulectomy to Roux-en-Y gastric diversion or even Whipple’s procedure may be required depending on tissue friability and diverticular collar size.

Background: Surgical site infections (SSIs) represent an economic burden to healthcare systems. The use of negative pressure wound therapy (NPWT) for SSI prophylaxis remains uncertain. Methods: A s...

Platelet-derived peripheral serotonin has pleiotropic effects on coagulation, metabolism, tissue regeneration, and cancer growth; however, the effect of serotonin on the tumor microenvironment remains understudied. Peripheral serotonin–deficient (

Background Donation after circulatory death (DCD) represents up to 40% of used kidney grafts. While studies have shown similar outcomes compared with donation after brain death (DBD) in the short term and mid-term, no data on long-term outcomes exist. Methods We retrospectively analysed patients transplanted at our institution between January 1985 and March 2000. All DCD recipients were matched one-to-one with patients transplanted with DBD grafts during this period according to sex, age and year of transplantation and followed up until December 2020. During this period, 1133 kidney transplantations were performed, of which 122 were with a DCD graft. Results The median graft survival after 35 years of follow-up was 23 years [277 months {95% confidence interval (CI) 182–372}] in DBD recipients and 24.5 years [289 months (95% CI 245–333)] in DCD recipients (P = 0.65; hazard ratio 0.91). Delayed graft function occurred in 47 patients in the DCD group compared with 23 in the DBD group (P < 0.001), albeit without a significant long-term outcome difference in graft or patient survival. We could not show any difference in graft function in terms of creatinine levels (133 versus 119 µmol/L), proteinuria (370 versus 240 mg/24 h) and glomerular filtration rate slope (–0.6 versus –0.3 mL/min/year) between the two groups for graft survival >20 years. Conclusions This is the first study to show similar graft survival and function in DCD kidneys compared with DBD kidneys after 35 years of follow-up. DCD grafts are a valuable resource and can be utilized in the same way as DBD grafts.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined treatment option for well-selected patients with peritoneal carcinomatosis (PC). The study aimed to identify factors influencing cancer-specific survival (CSS) and disease-free survival (DFS). Data of 113 patients with colorectal or appendicular carcinomatosis from a single center operated between 2009 and 2014 were retrospectively collected and analyzed. Patients with high-grade tumors received standard perioperative chemotherapy, and patients with low-grade appendix tumors were directly operated. HIPEC was performed after radical CRS. Patients had carcinomatosis from appendix neoplasms in 63% (71/113), including low-grade and high-grade tumors, and colorectal cancer in 37% (42/113). Complete cytoreduction and HIPEC were possible in 67% of patients. Major morbidity occurred in 10.6% of patients, and mean follow-up was 28 months. For colorectal PC, median CSS and DFS were 40 and 12 months, respectively. Median DFS was 19 months for high-grade appendix tumors, while median CSS has not been reached. All patients with diffuse peritoneal adenomucinosis were still alive at time of analysis; rate of DFS was 96% for these patients after 3 years. Major postoperative complications (Clavien-Dindo IIIB or higher) and positive nodal state were associated with impaired CSS and DFS, while a peritoneal cancer index score of >10 was independently associated with impaired CSS. CRS/HIPEC offers a survival benefit in well-selected patients with PC. Major postoperative complications affect long-term oncologic outcome of these patients.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) offer survival benefits in well-selected patients with peritoneal tumors. The complexity of CRS/HIPEC requires surgical specialization. In contrast, limited data are available regarding the impact of anesthesia management. We assessed the role of standard operating procedures (SOPs) for anesthesia on perioperative patient outcomes after CRS/HIPEC. Between 2009 and 2015, 112 CRS/HIPEC were performed at the University Hospital of Zurich. Procedures were grouped in an “early or late” group before (n = 57) and after (n = 55) the introduction of SOPs, which defined management of fluids, serum albumin, hemostasis, and body temperature. Introduction of SOPs significantly changed patient management. Patients received in total less colloids (p = 0.03) and less diuretics (p = 0.007). We noticed an increased substitution of albumin (p = 0.001) and coagulation factors (p = 0.008). Body temperatures were higher at the end of the operation (p = 0.005), and more patients were extubated in the operating room (66% vs. 42%, p = 0.02). The rate of major complications (p = 0.003) and reoperations (p = 0.01) was reduced after the introduction of SOPs. On multivariate analysis, two independent prognostic factors were identified. The use of > 2000 mL of colloids [odds ratio (OR) 5.31 (1.06–26.56), p = 0.042] was associated with major morbidity. In contrast, substitution of albumin [OR 0.12 (0.01–0.96), p = 0.046] was associated with better outcomes. SOPs for perioperative anesthesia management have a major impact on outcomes of patients after CRS/HIPEC. Management of colloid administration was an independent prognostic factor for perioperative outcomes. This highlights the role of the anesthesiologist and the need for specialization beyond the surgical team.

Obesity-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are two main causes of end-stage liver disease requiring a liver transplantation. Studies exploring bariatric surgery in the liver transplantation setting have increased in recent years; however, a systematic analysis of the topic is lacking to date. This meta-analysis was conducted to explore the perioperative and long-term outcomes of bariatric surgery in obese patients undergoing liver transplantation. Electronic databases were systematically searched for studies reporting bariatric surgery in patients undergoing liver transplantation. The primary outcomes were postoperative complications and mortality. We also extracted data about excess weight loss, body mass index, and improvement of comorbidities after bariatric surgery. A total of 96 patients from 8 articles were included. Bariatric surgery–related morbidity and mortality rates were 37% (95% CI 0.27–0.47) and 0.6% (95% CI 0.02–0.13), respectively. Body mass index at 24 months was 31.02 (95% CI 25.96–36.09) with a percentage excess weight loss at 12 and 24 months of 44.08 (95% CI 27.90–60.26) and 49.2 (95% CI 31.89–66.66), respectively. After bariatric surgery, rates of improvement of arterial hypertension and diabetes mellitus were 61% (95% CI 0.45–0.75) and 45% (95% CI 0.25–0.66), respectively. In most patients, bariatric surgery was performed after liver transplant and the most frequent technique was sleeve gastrectomy. Bariatric surgery can be performed safely in the setting of liver transplantation resulting in improvement of obesity-related comorbidities. The optimal timing and technique require further studies.

Eine limitierte Metastasierung des nichtkleinzelligen Lungenkarzinoms (NSCLC) wird in der 8. Version des TNM-Systems als eigenstandiges Tumorstadium definiert. Prospektive Studien ergaben einen Uberlebensvorteil lokal ablativer Therapie der Oligometastasen zusatzlich zur obligatorischen Systemtherapie. Lungen- und Nebennierenmetastasen sind auch im Stadium der Oligometastasierung charakteristisch. Zur Wahl der lokaltherapeutischen Modalitat existieren keine randomisierten oder prospektiven Studien. Es wird eine Ubersicht der klinischen Evidenz strahlentherapeutischer und chirurgischer Optionen bei Oligometastasen der Lunge und Nebenniere gegeben. Radioonkologisch ist eine ausreichend hoch dosierte Korperstereotaxie (SBRT) erforderlich. Die SBRT ermoglicht die unterbrechungsfreie Kombination von Lokal- und Systemtherapie sowie zeitgleiche Therapie mehrerer Oligometastasen. Chirurgisch erlauben minimal-invasive oder robotische Verfahren eine Morbiditatsreduktion, ohne die Wahrscheinlichkeit einer R0-Resektion zu beeintrachtigen. Die Chirurgie ermoglicht die histopathologische Analyse der resezierten Oligometastasen sowie ein systematisches pathologisches Staging. Die Evidenz zur SBRT beruht auf prospektiven, teils randomisierten Studien; chirurgische Studien sind meist retrospektive Fallserien. Grose der Oligometastasen sowie deren anatomische Lokalisation sollten im interdisziplinaren Tumorboard zur Entscheidung uber die optimale Lokaltherapie berucksichtigt werden. Die Patienten sind umfassend zu informieren und deren Wunsche in einer gemeinsamen Entscheidung zu berucksichtigen. Sowohl chirurgische als auch strahlentherapeutische Verfahren konnen eine sichere und effektive Behandlung von Oligometastasen der Lunge und Nebenniere erzielen.

OBJECTIVES Abdominal surgery after lung transplantation is an important factor for major morbidity and mortality. Herein, we describe the incidence and outcome of abdominal surgery occurring early or late after transplantation. METHODS Overall, 315 patients who underwent lung transplantation between January 2000 and December 2013 at our institution were included in a prospective database. Perioperative parameters were assessed, and complications were graded according to the Clavien-Dindo Classification. RESULTS Among 315 patients after lung transplantation, 52 patients underwent abdominal surgery, 16 during the early postoperative phase and 42 at later time points. Bowel ischaemia and perforation of the right colon were the most common reason for early surgery, with a median interval of 7 days after lung transplantation. The median survival time for patients with early abdominal surgery was 31 months compared to 40 and 90 months for patients with no or late abdominal surgery (P = 0.001 and P = 0.002, respectively). The most common late indications for surgery were perforated diverticulitis, ileus and hernia, with a median interval of 37.9 months after lung transplantation and a median survival comparable with patients without any abdominal surgery (P = 0.9). However, prior hospitalization due to a non-abdominal disease was associated with increased morbidity (P = 0.006) after late surgery. CONCLUSIONS Early abdominal surgeries after lung transplantation are associated with a significant mortality risk. Abdominal operations at late time points have a favourable outcome unless patients were hospitalized prior to the abdominal complication. Clinical trial registration number ZH-KEK-Nr. 2014-0244.

Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.

INTRODUCTION The accuracy of preoperative lymph-node staging in patients with adenocarcinoma of the esophagogastric junction (AEG) or gastric cancer (GC) is low. The aim of this study was to assess the accuracy of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT) for lymph-node staging in patients with AEG or GC, with or without neoadjuvant treatment. PATIENTS AND METHODS 221 consecutive patients with GC (n = 88) or AEG (n = 133) were evaluated. Initial staging included endoscopic ultrasound (EUS), multidetector spiral CT (MDCT) and PET-CT. PET-CT was performed for restaging in patients after neoadjuvant treatment (n = 94). Systematic lymphadenectomy was routinely performed with histopathological assessment of individual mediastinal and abdominal lymph-node stations. Preoperative staging from EUS, MDCT, and PET-CT was correlated with histopathological results. RESULTS PET-CT showed a high specificity (91%) and positive predictive value (89%) for the preoperative detection of lymph-node metastases. In comparison, EUS was more sensitive (73% versus 50%, P

Background The management of patients with colorectal cancer (CRC) with peritoneal metastases is challenging, and the roles of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are unclear and debated among experts. Materials and Methods The experts of the Swiss Peritoneal Cancer Group were contacted and agreed to participate in this analysis. Experts from 9 centers in Switzerland provided their decision algorithms for CRS/HIPEC for patients with or at high risk for peritoneal metastases from CRC. Their responses were converted into decision trees on the basis of objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies. Results The final treatment algorithms included a total of 5 decision criteria (age, Peritoneal Cancer Index [PCI], extraperitoneal metastases, Peritoneal Surface Disease Severity Score, and various risk factors [RF]) and 2 treatment options (HIPEC, yes or no). HIPEC was never recommended for patients without peritoneal metastases in the absence of RF for peritoneal metastases. For patients with a PCI ≤15 without organ metastases, all centers recommended CRS/HIPEC. There was also a consensus not to perform CRS/HIPEC in elderly patients (80 years and older), those with a PCI >20, and those with unresectable metastases. For patients with a PCI = 16 to 20, there was no consensus. Conclusion Multiple decision criteria relevant to all participating centers were identified. Because patient selection for CRS/HIPEC remains difficult, uniform criteria for the term “high risk” for peritoneal metastases and systemic metastases are helpful. Future trials and guidelines should take these criteria into account.

Background Pathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known. Methods From a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by ≥35%. Major pathologic regression was defined as less than 10% residual tumor cells. Results Metabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%. Conclusion Response PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy. Trial registration The trial was registered and approved by local ethics committee PB_2016–00769.

Background Mycophenolic acid (MPA), either given as an ester pro-drug or as an enteric-coated sodium salt, is the most commonly prescribed anti-proliferative immunosuppressive agent used following organ transplantation and widely applied in immune-mediated diseases. Clinicians are well aware of common adverse reactions related to MPA treatment, in particular diarrhea, leukopenia and infections. Here we report a case of severe, persistent ascites associated with MPA treatment. The otherwise unexplained and intractable ascites, requiring repeated paracenteses for more than 8 months, rapidly ceased with stopping the MPA treatment. To our knowledge this is the first case of severe ascites associated with MPA treatment reported in the scientific literature. Case Presentation A 45-year old female with type 1 diabetes mellitus received a simultaneous kidney-pancreas transplant. The surgery was uneventful. However, post-operatively she developed severe transudative ascites requiring in total more than 40 paracenteses treatments draining in the average 2.8 l of ascites fluid. The ascites formation persisted despite exclusion of a surgical complication, fully functioning kidney and pancreas allografts, lack of any significant proteinuria, normalization of circulating albumin levels, intensive use of diuretics and deliberate attempts to increase the intervals between the paracentesis treatments. Various differential diagnoses, including infectious, hepatic, vascular and cardiac causes were ruled out. Nine months after surgery enteric-coated mycophenolate sodium was switched to azathioprine after which ascites completely resolved. When mycophenolate was recommenced abdominal fullness and weight gain reoccurred. The patient had to be switched to long-term azathioprine treatment. More than 1 year post-conversion the patient remains free of ascites. Conclusion MPA is the most widely used antimetabolite immunosuppressive agent. We suggest to consider MPA treatment in the differential diagnosis of severe and unexplained ascites in transplant and non-transplant patients.

Background & Aims Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. Methods Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro . Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively. Results Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro , Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo , Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody. Conclusions Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, HMGB1, and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.

OBJECTIVES: : To evaluate the outcome after Hartmann's procedure (HP) versus primary anastomosis (PA) with diverting ileostomy for perforated left-sided diverticulitis. BACKGROUND: : The surgical management of left-sided colonic perforation with purulent or fecal peritonitis remains controversial. PA with ileostomy seems to be superior to HP; however, results in the literature are affected by a significant selection bias. No randomized clinical trial has yet compared the 2 procedures. METHODS: : Sixty-two patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to HP (n = 30) and to PA (with diverting ileostomy, n = 32), with a planned stoma reversal operation after 3 months in both groups. Data were analyzed on an intention-to-treat basis. The primary end point was the overall complication rate. The study was discontinued following an interim analysis that found significant differences of relevant secondary end points as well as a decreasing accrual rate (NCT01233713). RESULTS: : Patient demographics were equally distributed in both groups (Hinchey III: 76% vs 75% and Hinchey IV: 24% vs 25%, for HP vs PA, respectively). The overall complication rate for both resection and stoma reversal operations was comparable (80% vs 84%, P = 0.813). Although the outcome after the initial colon resection did not show any significant differences (mortality 13% vs 9% and morbidity 67% vs 75% in HP vs PA), the stoma reversal rate after PA with diverting ileostomy was higher (90% vs 57%, P = 0.005) and serious complications (Grades IIIb-IV: 0% vs 20%, P = 0.046), operating time (73 minutes vs 183 minutes, P < 0.001), hospital stay (6 days vs 9 days, P = 0.016), and lower in-hospital costs (US $16,717 vs US $24,014) were significantly reduced in the PA group. CONCLUSIONS: : This is the first randomized clinical trial favoring PA with diverting ileostomy over HP in patients with perforated diverticulitis.

Obstructive cholestasis induces liver injury, postoperative complications, and mortality after surgery. Adaptive control of cholestasis, including bile salt homeostasis, is necessary for recovery and survival. Peripheral serotonin is a cytoprotective neurotransmitter also associated with liver regeneration. The effect of serotonin on cholestatic liver injury is not known. Therefore, we tested whether serotonin affects the severity of cholestatic liver injury. We induced cholestasis by ligation of the bile duct (BDL) in either wild-type (WT) mice or mice lacking peripheral serotonin (Tph1−/− and immune thrombocytopenic [ITP] mice). Liver injury was assessed by the levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and tissue necrosis. Bile salt–regulating genes were measured by quantitative polymerase chain reaction and confirmed by western blotting and immunohistochemistry. Tph1−/− mice displayed higher levels of plasma AST, ALT, bile salts, and hepatic necrosis after 3 days of BDL than WT mice. Likewise, liver injury was disproportional in ITP mice. Moreover, severe cholestatic complications and mortality after prolonged BDL were increased in Tph1−/− mice. Despite the elevation in toxic bile salts, expression of genes involved in bile salt homeostasis and detoxification were not affected in Tph1−/− livers. In contrast, the bile salt reabsorption transporters Ostα and Ostβ were up-regulated in the kidneys of Tph1−/− mice, along with a decrease in urinary bile salt excretion. Serotonin reloading of Tph1−/− mice reversed this phenotype, resulting in a reduction of circulating bile salts and liver injury. Conclusion: We propose a physiological function of serotonin is to ameliorate liver injury and stabilize the bile salt pool through adaptation of renal transporters in cholestasis. (HEPATOLOGY 2012;56:209–218)

Purpose Inguinal hernia repair is one of the most common procedures in visceral surgery, and an important teaching operation for residents during their first years. A variety of surgical approaches is currently available, including open surgery with or without mesh and laparoscopic surgery. Here we assessed the current clinical practice for inguinal hernia surgery in Switzerland and the impact on training of surgical residents. Methods An anonymous online survey was performed among surgical clinics of the Swiss Society of Visceral Surgery (SSVS). Results The overall response rate was 51 %. Nearly all hernia repairs are performed with prosthetic material, and only 3.2 % of the procedures use no mesh. Overall, open surgery is used for 58.5 % of hernias and 41.5 % are operated laparoscopically. In laparoscopic surgery, TEP is the first choice. Overall, the Lichtenstein repair is the classical teaching operation performed by residents in 77.3 % of cases. In contrast to open surgery, laparoscopic hernia repair is not a training operation and residents perform only 9.7 % of laparoscopic hernia repairs. Conclusion The survey confirms the use of prosthetic material as the standard, and the Lichtenstein repair as the first choice for primary inguinal hernia repair. The popularity of laparoscopic hernia surgery is increasing at the price of less teaching operations available for young residents.

Background & Aims Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant. Methods Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21. Results Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21 -/- mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx. Conclusions Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.

OBJECTIVE: We conducted a systematic review of the published literature to critically assess benefits and risks of the use of preoperative chemotherapy in patients presenting with colorectal liver metastases. BACKGROUND: In many centers, chemotherapy is used before hepatic resection of colorectal metastases, even in the presence of a single lesion. Application of chemotherapy requires clear conceptual distinction between patients presenting with resectable lesions (neoadjuvant) versus patients presenting with unresectable lesions, for which chemotherapy is used to reach a resectable situation (downsizing). METHODS: The literature (PubMed) was systematically reviewed for publications related to liver surgery and chemotherapy according to the methodology recommended by the Cochrane Collaboration. RESULTS: For unresectable liver metastases, combination regimens result in enhanced tumor response and resectability rates up to 30%, although the additional benefit from targeted agents such as bevacizumab or cetuximab is marginal. For resectable lesions, studies on neoadjuvant chemotherapy failed to convincingly demonstrate a survival benefit. Most reports described increased postoperative complications in a subset of patients due to parenchymal alterations such as chemotherapy-associated steatohepatitis or sinusoidal obstruction syndrome. CONCLUSION: Preoperative standard chemotherapy can be recommended for downsizing unresectable liver metastases, but not for resectable lesions, for which adjuvant chemotherapy is preferred.

Background: c-radiation is an effective treatment for cancer. There is evidence that radiotherapy supports tumor-specific immunity. It was described that irradiation induces de novo protein synthesis and enhances antigen presentation, we therefore investigated whether c-radiation results in increased expression of cancer-testis (CT) antigens and MHC-I, thus allowing efficient immunological control. This is relevant because the expression of CT-antigens and MHC-I on tumor cells is often heterogeneous. We found that the changes induced by c-radiation promote the immunological recognition of the tumor, which is illustrated by the increased infiltration by lymphocytes after radiotherapy. Methods/Findings: We compared the expression of CT-antigens and MHC-I in various cancer cell lines and fresh biopsies before and after in vitro irradiation (20 Gy). Furthermore, we compared paired biopsies that were taken before and after radiotherapy from sarcoma patients. To investigate whether the changed expression of CT-antigens and MHC-I is specific for c-radiation or is part of a generalized stress response, we analyzed the effect of hypoxia, hyperthermia and genotoxic stress on the expression of CT-antigens and MHC-I. In vitro irradiation of cancer cell lines and of fresh tumor biopsies induced a higher or de novo expression of different CT-antigens and a higher expression of MHC-I in a time- and dose-dependent fashion. Importantly, we show that irradiation of cancer cells enhances their recognition by tumor-specific CD8+ T cells. The analysis of paired biopsies taken from a cohort of sarcoma patients before and after radiotherapy confirmed our findings and, in addition showed that irradiation resulted in higher infiltration by lymphocytes. Other forms of stress did not have an impact on the expression of CT-antigens or MHC-I. Conclusions: Our findings suggest that c-radiation promotes the immunological recognition of the tumor. We therefore propose that combining radiotherapy with treatments that support tumor specific immunity may result in increased therapeutic efficacy.

Objectives: To evaluate the effects of pentoxifylline (PTX) on liver regeneration in patients undergoing major liver resection. Background: Recent experimental data suggest that PTX, a tumor necrosis factor (TNF) α inhibitor, enhances liver regeneration and reduces ischemic injury through activation of the interleukin-6 (IL-6) signaling pathway. However, the clinical impact of PTX in patients undergoing major liver surgery is unknown. Methods: One hundred one consecutive noncirrhotic patients undergoing major liver surgery with inflow occlusion were included in a double-blinded, randomized, controlled trial (RCT) at a single tertiary care center (2006-2009). Fifty-one patients received intravenous administration of PTX starting 12 hours before and ending 72 hours after surgery, whereas 50 control patients received a placebo infirsion. Primary endpoint was liver regeneration as assessed by three-dimensional volumetry based on magnetic resonance (MR) tomography at postoperative day 8 compared with preoperative images. Secondary endpoints were transaminases, cytokines, and postoperative complications. Results: Both groups were comparable regarding demographics, risk score, preoperative laboratory tests, and type and extent of liver resection. Treatment with PTX resulted in significantly better volume regeneration for small remnant livers [remnant liver to body weight (RLBW) ratio ≤ 1.2%], whereas no beneficial effect was observed for RLBW ratio of more than 1.2%. There was a 3.6-fold stronger induction of IL-6 mRNA for the PTX group (P < 0.001). Postoperative alanine aminotransferase (AST) levels were significantly decreased for the PTX group on the second postoperative day (442 vs 585 U/L, P = 0.025). No significant benefit could be identified regarding the number and severity of postoperative complications and median ICU (1 vs 1 day) and hospital stay (10 vs 10 days). However, the PTX group had significantly more drug-related adverse events (23 vs 8, P = 0.007). Conclusions: This is the first RCT evaluating the effects of PTX on liver regeneration after major liver resection. The study demonstrates beneficial effects of PTX on regeneration of small remnant livers (RLBW ratio ≤ 1.2%) that seems to be mediated by IL-6.

The clinical and morphologic outcome of patients with obstructed defecation syndrome after stapled transanal rectal resection was prospectively evaluated. Twenty-four consecutive patients (22 women; median age, 61 (range, 36–74) years) who suffered from obstructed defecation syndrome and with rectal redundancy on magnetic resonance defecography were enrolled in the study. Constipation was assessed by using the Cleveland Constipation Score. Morphologic changes were determined by using closed-configuration magnetic resonance defecography before and after stapled transanal rectal resection. After a median follow-up of 18 (range, 6–36) months, Cleveland Constipation Score significantly decreased from 11 (range, 1–23) preoperatively to 5 (range, 1–15) postoperatively (P = 0.02). In 15 of 20 patients, preexisting intussusception was no longer visible in the magnetic resonance defecography. Anterior rectoceles were significantly reduced in depth, from 30 mm to 23 mm (P = 0.01), whereas the number of detectable rectoceles did not significantly change. Complications occurred in 6 of the 24 patients; however, only two were severe (1 bleeding and 1 persisting pain requiring reintervention). Clinical improvement of obstructed defecation syndrome after stapled transanal rectal resection correlates well with morphologic correction of the rectal redundancy, whereas correction of intussusception seems to be of particular importance in patients with obstructed defecation syndrome.

AIM: To evaluate the incidence of late biliary complications in non-resectable alveolar echinococcosis (AE) under long-term chemotherapy with benzimidazoles. METHODS: Retrospective analysis of AE patients with biliary complications occurring more than three years after the diagnosis of AE. We compared characteristics of patients with and without biliary complications, analyzed potential risk factor for biliary complications and performed survival analyses. RESULTS: Ninety four of 148 patients with AE in Zurich had non-resectable AE requiring long-term benzimidazole chemotherapy, of which 26 (28%) patients developed late biliary complications. These patients had a median age of 55.5 (35.5-65) years at diagnosis of AE and developed biliary complications after 15 (8.25-19) years of chemotherapy. The most common biliary complications during long-term chemotherapy were late-onset cholangitis (n = 14), sclerosing cholangitis-like lesions (n = 8), hepatolithiasis (n = 5), affection of the common bile duct (n = 7) and secondary biliary cirrhosis (n = 7). Thirteen of the 26 patients had undergone surgery (including 12 resections) before chemotherapy. Previous surgery was a risk factor for late biliary complications in linear regression analysis (P = 0.012). CONCLUSION: Late biliary complications can be observed in nearly one third of patients with non-resectable AE, with previous surgery being a potential risk factor. After the occurrence of late biliary complications, the median survival is only 3 years, suggesting that late biliary complications indicate a poor prognostic outcome.

The use of vascular occlusion during liver resection is still a matter of debate. The aim of this review was to assess the advantages and disadvantages of portal triad occlusion as a protective strategy during elective liver resection and liver transplantation. Newer strategies such as pharmacological preconditioning are also discussed. A systematic literature search was conducted to detect randomized controlled trials assessing the effectiveness and safety of portal triad clamping, ischaemic preconditioning and pharmacological preconditioning during liver surgery. Vascular clamping cannot be systematically recommended. When used, portal triad clamping is associated with a tendency towards reduced blood loss and blood transfusion without having an impact on morbidity. Intermittent clamping appears to be better tolerated than continuous clamping, especially in patients with chronic liver disease. Ischaemic preconditioning before continuous portal triad clamping reduces reperfusion injury after warm ischaemia, particularly in steatotic patients. Ischaemic preconditioning has unclear effects in transplantation and there is currently no evidence to support or refute the use of ischaemic preconditioning in the donor. There are emerging alternative conditioning strategies, including the use of volatile anaesthetics, which may provide new and easily applicable therapeutic options to protect the liver.

Background The aim of hyperthermic intraperitoneal chemotherapy (HIPEC) is to eradicate microscopic residual tumor after radical surgical tumor excision in patients with peritoneal carcinomatosis. The common use of antineoplastic agents such as mitomycin C, doxorubicin, or oxaliplatin with hyperthermia fails to eradicate tumors in a significant subset of patients, and alternative approaches to target chemoresistant cells are needed. The induction of reactive oxygen species (ROS) by inhibiting the critical detoxification enzyme superoxide dismutase (SOD) during hyperthermia is an appealing approach to induce death of residual cancer cells. Methods Human and murine colon cancer cell lines were subjected to mild hyperthermia (40-42°C), and treated with chemotherapy, similar to clinical protocols. ROS were induced by the SOD inhibitor diethyldithiocarbamate (DDC), a metabolite of the drug disulfiram. In mice, peritoneal carcinomatosis use C57Bl/6 was induced in C57Bl/6 by intraperitoneal injection of syngenic tumor cells (MC38). Results Hyperthermia alone failed to kill cells but induced intracellular ROS and activated protective mechanisms. Chemotherapy conferred inconsistent cytotoxicity depending on the cell line and dose. In contrast, induction of ROS by DDC consistently activated apoptotic pathways, with increased cell death in combination with mild hyperthermia. In vivo, combined treatment with DDC and hyperthermia significantly delayed tumor progression in tumor-bearing mice. In addition, hyperthermic combined treatment with chemotherapy and DDC significantly improved animal survival compared with chemotherapy alone. Conclusions Addition of DDC improves the efficacy of existing HIPEC protocols in a safe way and may open the door to a more effective, multimodal HIPEC.

Background Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a minimally invasive approach under investigation as a novel treatment for patients with peritoneal carcinomatosis of various origins. The aim was to review the available evidence on mechanisms, clinical effects and risks. Methods This was a systematic review of the literature on pressurized intraperitoneal chemotherapy published between January 2000 and October 2016. All types of scientific report were included. Results Twenty-nine relevant papers were identified; 16 were preclinical studies and 13 were clinical reports. The overall quality of the clinical studies was modest; five studies were prospective and there was no randomized trial. Preclinical data suggested better distribution and higher tissue concentrations of chemotherapy agents in PIPAC compared with conventional intraperitoneal chemotherapy by lavage. Regarding technical feasibility, laparoscopic access and repeatability rates were 83–100 and 38–82 per cent. Surgery-related complications occurred in up to 12 per cent. Postoperative morbidity was low (Common Terminology Criteria for Adverse Events grade 3–5 events reported in 0–37 per cent), and hospital stay was about 3 days. No negative impact on quality of life was reported. Histological response rates for therapy-resistant carcinomatosis of ovarian, colorectal and gastric origin were 62–88, 71–86 and 70–100 per cent respectively. Conclusion PIPAC is feasible, safe and well tolerated. Preliminary good response rates call for prospective analysis of oncological efficacy.