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Background: Metabolic and transcriptomic differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments, particularly in the context of obesity, may play a role in colorectal carcinogenesis. We investigated the differential functions of their metabolic compositions. Objectives: Biochemical differences between adipose tissues (VAT compared with SAT) in patients with colorectal carcinoma (CRC) were investigated by using mass spectrometry metabolomics and gene expression profiling. Metabolite compositions were compared between VAT, SAT, and serum metabolites. The relation between patients’ tumor stage and metabolic profiles was assessed. Design: Presurgery blood and paired VAT and SAT samples during tumor surgery were obtained from 59 CRC patients (tumor stages I–IV) of the ColoCare cohort. Gas chromatography time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were used to measure 1065 metabolites in adipose tissue (333 identified compounds) and 1810 metabolites in serum (467 identified compounds). Adipose tissue gene expression was measured by using Illumina’s HumanHT-12 Expression BeadChips. Results: Compared with SAT, VAT displayed elevated markers of inflammatory lipid metabolism, free arachidonic acid, phospholipases (PLA2G10), and prostaglandin synthesis–related enzymes (PTGD/PTGS2S). Plasmalogen concentrations were lower in VAT than in SAT, which was supported by lower gene expression of FAR1, the rate-limiting enzyme for ether-lipid synthesis in VAT. Serum sphingomyelin concentrations were inversely correlated (P = 0.0001) with SAT adipose triglycerides. Logistic regression identified lipids in patients’ adipose tissues, which were associated with CRC tumor stage. Conclusions: As one of the first studies, we comprehensively assessed differences in metabolic, lipidomic, and transcriptomic profiles between paired human VAT and SAT and their association with CRC tumor stage. We identified markers of inflammation in VAT, which supports prior evidence regarding the role of visceral adiposity and cancer. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT02328677","term_id":"NCT02328677"}}NCT02328677.

Current evidence on the association between smoking and colorectal cancer (CRC) prognosis after diagnosis is heterogeneous and few have investigated dose-response effects or outcomes other than overall survival. Therefore, the association of smoking status and intensity with several prognostic outcomes was evaluated in a large population-based cohort of CRC patients; 3,130 patients with incident CRC, diagnosed between 2003 and 2010, were interviewed on sociodemographic factors, smoking behavior, medication and comorbidities. Tumor characteristics were collected from medical records. Vital status, recurrence and cause of death were documented for a median follow-up time of 4.9 years. Using Cox proportional hazards regression, associations between smoking characteristics and overall, CRC-specific, non-CRC related, recurrence-free and disease-free survival were evaluated. Among stage I-III patients, being a smoker at diagnosis and smoking ≥15 cigarettes/day were associated with lower recurrence-free (adjusted hazard ratios (aHR): 1.29; 95% confidence interval (CI): 0.93-1.79 and aHR: 1.31; 95%-CI: 0.92-1.87) and disease-free survival (aHR: 1.26; 95%-CI: 0.95-1.67 and aHR: 1.29; 95%-CI: 0.94-1.77). Smoking was associated with decreased survival in stage I-III smokers with pack years ≥20 (Overall survival: aHR: 1.40; 95%-CI: 1.01-1.95), in colon cancer cases (Overall survival: aHR: 1.51; 95%-CI: 1.05-2.17) and men (Recurrence-free survival: aHR: 1.51; 95%-CI: 1.09-2.10; disease-free survival: aHR: 1.49; 95%-CI: 1.12-1.97), whereas no associations were seen among women, stage IV or rectal cancer patients. The observed patterns support the existence of adverse effects of smoking on CRC prognosis among nonmetastatic CRC patients. The potential to enhance prognosis of CRC patients by promotion of smoking cessation, embedded in tertiary prevention programs warrants careful evaluation in future investigations.

Die metformininduzierte Laktatacidose ist ein seltenes, aber fur den einzelnen Patienten schwerwiegendes Krankheitsbild. Anhand des vorliegenden Fallberichts einer 64-jahrigen Patientin mit einem Diabetes mellitus Typ 2 werden die klinische Diagnosestellung, die Pathophysiologie und die Therapie dieses Krankheitsbilds detailliert aufgearbeitet. Daruber hinaus wird in einem Exkurs auf die aktuellen Empfehlungen zur Handhabung der perioperativen Metformineinnahme fokussiert.

Perioperative Komplikationen nach chirurgischen Eingriffen am unteren Gastrointestinaltrakt stellen nach wie vor ein relevantes Problem dar. Die perioperative Morbiditat kann sowohl den unmittelbaren als auch langfristigen Therapieerfolg des einzelnen Patienten negativ beeinflussen. Zudem fuhrt die entsprechend notwendige Diagnostik und Therapie zu zusatzlichen Kosten, die das Gesundheitssystem belasten. Idealerweise sollten Komplikationen durch praventive Masnahmen verhindert werden. Im Falle einer Komplikation ist eine fruhzeitige Erkennung derselben zur Einleitung der notwendigen Therapie essenziell.

Background and Objectives Only limited data exist investigating the outcome of patients older than 75 years after resection of colorectal liver metastases (CLM). Therefore, the present study aims to evaluate clinical and oncological outcome of elderly patients. Methods A cohort of 405 patients was divided into three age-groups: (1) 75 years of age. Patients' data were prospectively collected and retrospectively analyzed. We performed survival analysis and added age-correction. Univariate and multivariate analysis was performed to determine independent prognostic risk factors. Results The 5-year survival rate of the >75 years age-group was distinctly decreased, compared to the other age-groups. After age-correction, the 5-year survival rates and the survival curves increased to the greatest extent in patients older than 75 years. The MSKCC score proved to be a sufficient independent prognostic factor in the total patient cohort, patients

Die Nutzenbewertung operativer Masnahmen bildet die Grundlage fur das Konzept der evidenzbasierten Chirurgie. Jedoch sind gerade im Bereich der operativen Medizin viele Interventionen nicht durch qualitativ hochwertige klinische Studien untersucht. Deshalb ist eine strukturierte Nutzenbewertung chirurgischer Interventionen in der Zukunft unumganglich. Dabei ist zu beachten, dass der Nutzen und das Risiko einer Masnahme eine unterschiedliche Bedeutung haben konnen, je nachdem, ob sie aus der Perspektive von Patienten, Chirurgen, der Industrie oder der Kostentrager im Gesundheitswesen betrachtet werden. Je nachdem welche Masnahmen im Rahmen chirurgischer Studien verglichen werden, sind unterschiedliche regulative Rahmenbedingungen einzuhalten. Zusatzlich stellt die Nutzenbewertung operativer Masnahmen einige spezifische Herausforderungen an klinische Forscher, beginnend bei der Wahl eines geeigneten Endpunkts bis hin zu Fragen der Standardisierung der Interventionen und dem Einfluss von Lernkurven. Als Zukunftskonzept fur die Entwicklung und Bewertung von Innovationen in der operativen Medizin dient das IDEAL-Concept, das im Jahr 2009 durch eine internationale Expertengruppe entwickelt wurde. Beispielhaft zeigen das Studienzentrum der Deutschen Gesellschaft fur Chirurgie (SDGC) und das chirurgische Studiennetzwerk (CHIR-Net), dass es durch Kooperationen von Klinikern und Methodikern moglich ist, eine kompetente, chirurgische Studienstruktur zur effektiven Nutzenbewertung operativer Masnahmen zu schaffen. Solche Netzwerke mussen zukunftig dazu dienen, die bestehenden Evidenzlucken zu schliesen und Innovationen effizient zu evaluieren.

Oxygen is essential for metazoans to generate energy. Upon oxygen deprivation adaptive and protective pathways are induced, mediated by hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain-containing enzymes (PHDs). Both play a pivotal role in various conditions associated with prolonged ischemia and inflammation, and are promising targets for therapeutic intervention. This review focuses on aspects of therapeutic PHD modulation in surgically relevant disease conditions such as hepatic and intestinal disorders, wound healing, innate immune responses, and tumorigenesis, and discusses the therapeutic potential and challenges of PHD inhibition in surgical patients.

// Christoph Kahlert 1, * , Maria Fiala 1, * , Gabriel Musso 2, 3 , Niels Halama 4 , Sophia Keim 4 , Massimiliano Mazzone 5, 6 , Felix Lasitschka 7 , Mathieu Pecqueux 8 , Fee Klupp 1 , Thomas Schmidt 1 , Nuh Rahbari 8 , Sebastian Scholch 8 , Christian Pilarsky 8 , Alexis Ulrich 1 , Martin Schneider 1 , Juergen Weitz 8 , Moritz Koch 8 1 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg 69120, Germany 2 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA 3 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA 4 Medical Oncology, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Germany 5 Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven 3000, Belgium 6 Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU, Leuven 3000, Belgium 7 Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany 8 Department of General, Visceral and Thoracic Surgery, University of Dresden, Dresden 01307, Germany * These authors contributed equally to this work Correspondence to: Christoph Kahlert, e-mail: christoph.kahlert.079@googlemail.com Keywords: Pancreatic cancer, stroma, angiogenic cytokines, expression profile Received: August 05, 2014 Accepted: October 27, 2014 Published: December 30, 2014 ABSTRACT Pancreatic cancer consists of a heterogenous bulk of tumor cells and stroma cells which contribute to tumor progression by releasing angiogenic factors. Those factors can be detected as circulating serum factors. We performed a compartment-specific analysis of tumor-derived and stroma-derived angiogenic factors to identify biomarkers and molecular targets for the treatment of pancreatic cancer. Kryo-frozen tissue from primary ductal adenocarcinomas ( n = 51) was laser-microdissected to isolate tumor and stroma tissue. Expression of 17 angiogenic factors (angiopoietin-2, follistatin, GCSF, HGF, interleukin-8, leptin, PDGF-BB, PECAM-1, VEGF, matrix metalloproteinase -1, -2, -3, -7, -9, -10, -12, and -13) was analyzed using a multiplex elisa assay for tissue-derived proteins and corresponding serum. Our study reveals a compartment-specific expression profile for several angiogenic factors and matrix metalloproteinases. ROC analysis of corresponding serum samples reveals MMP-7 and MMP-12 as strong classifiers for the diagnosis of patients with pancreatic cancer vs. healthy control donors. High expression of tumor-derived PDGF-BB and MMP-1 correlates with prolonged survival in univariate and multivariate analysis. In conclusion, a distinct expression patterns for angiogenic cytokines and MMPs in pancreatic cancer and surrounding stroma may implicate them as novel targets for cancer treatment. Tumor-derived PDGF-BB and MMP-1 are significant and independent prognostic markers for poor survival.

The aims of this study are to compare the 30-day rate of bowel obstruction for stapled vs. handsewn closure of loop ileostomy, and to further assess efficacy and safety for each technique by secondary endpoints such as operative time, rates of anastomotic leakage, and other post-operative complications within 30 days. A systematic literature search (MEDLINE, The Cochrane Library, EMBASE and ISI Web of Science) was performed to identify randomized controlled trials (RCTs) comparing stapled and handsewn closure of loop ileostomy after low anterior resection. Random effects meta-analyses were calculated and presented as risk ratio (RR) and mean difference (MD) with corresponding 95 % confidence intervals. Forty publications were retrieved and 4 RCTs (649 patients) were included. There was methodological and clinical heterogeneity of included trials, but statistical heterogeneity was low for most endpoints. Stapler use significantly reduced the rate of bowel obstruction compared to hand-sewn closure (RR 0.53 [0.32, 0.88]; P = 0.01). The operation time was significantly lower for stapling compared to hand suture (MD −15.5 min [−18.4, 12.6]; P

miRNAs are crucial in cellular processes and have been shown to be abnormally expressed in cancer tissue and the circulation. Circulating miRNAs may serve as a novel class of minimally invasive biomarkers for prognosis. Within a first methodologic study, we evaluated the miRNA profile kinetics in the plasma of patients with colorectal cancer after surgical tumor removal to identify potential suitability as prognostic biomarkers. This pilot study is based on the ColoCare Study, a cohort study of newly diagnosed patients with stage I–IV colorectal cancer. Colorectal cancer pre- and postsurgical blood (2–7 days after surgery) and 6 months follow-up blood from 35 patients were examined and candidate miRNAs were investigated in the plasma. miRNA levels were measured by two-step qRT-PCR. Statistical analysis was performed using log-transformed normalized CT values using SAS 9.3. Comparing pre- and postsurgical miRNA levels revealed a statistically significant decrease of nine circulating miRNAs after surgery (miR92a, miR18a, miR320a, miR106a, miR16-2, miR20a, miR223, miR17, and miR143). Analyses of plasma levels over all three time points demonstrated a statistically significant decrease from presurgery to postsurgery and re-increase from postsurgery to the six months follow-up time point of four circulating miRNAs (miR92a, miR320a, miR106a, and miR18a). We were able to show for the first time that in plasma miRNA profiles change within days after colorectal cancer surgery. Our results underscore the role of the investigated miRNAs in colorectal cancer and their potential utility as prognostic biomarkers. See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.” Cancer Epidemiol Biomarkers Prev; 23(12); 2632–7. ©2014 AACR.

Prognostic differences between pTN- and ypTN-categories and the prognostic accuracy of the 8th edition UICC-pTNM- and AJCC-ypTNM-staging-system for esophageal and gastric adenocarcinoma are unclear.We retrospectively analyzed data of 740 patients with esophagogastric adenocarcinoma, who underwent curative surgery (344 after neoadjuvant treatment [NT]) at our institution. Survival analyses were performed according to Kaplan-Meier (log-rank test). Multivariate analyses were performed using the Cox proportional hazard model.Low ypT-categories did not discriminate overall survival (ypT0: reference; ypT1: HR1.0/p = 0.909; ypT2: HR0.9/p = 0.845; ypT3: HR1.5/p = 0.184; ypT4: HR2.8/p = 0.004) and no difference was found between ypN1- and ypN2-disease (ypN0: HR0.4/p 0.001; ypN1: reference; ypN2: HR1.1/p = 0.653; ypN3: HR1.7/p = 0.014). In esophageal adenocarcinoma the UICC-TNM- and AJCC-ypTNM-staging-system was able to predict survival for patients after NT, while in gastric cancer it failed to provide sufficient prognostic information. A simplified staging system provided better stratification after NT and was an independent prognosticator for both esophageal and gastric adenocarcinoma (stage I: reference; stage II: HR2.2/p = 0.005; stage III: HR4.1/p 0.001).Prognostic value of ypTN-categories seems limited. After NT the current UICC/AJCC-staging-system is able to predict survival in esophageal adenocarcinoma, but needs to be reevaluated in gastric cancer patients and modified if needed. A novel simplified staging system might be more practicable for patients after NT.

Summary Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference −2·3, 95% CI −6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. Funding German Research Foundation (DFG).

Background: The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of various solid tumors, its role in colorectal cancer remains unknown. We aimed to assess the prognostic significance of EMX2 expression in stage III colorectal adenocarcinoma. Methods: Expression levels of EMX2 in human colorectal cancer and adjacent mucosa were assessed by qRT-PCR technology, and results were correlated with clinical and survival data. siRNA-mediated knockdown and adenoviral delivery-mediated overexpression of EMX2 were performed in order to investigate its effects on the migration of colorectal cancer cells in vitro. Results: Compared to corresponding healthy mucosa, colorectal tumor samples had decreased EMX2 expression levels. Furthermore, EMX2 down-regulation in colorectal cancer tissue was associated with distant metastasis (M1) and impaired overall patient survival. In vitro knockdown of EMX2 resulted in increased tumor cell migration. Conversely, overexpression of EMX2 led to an inhibition of tumor cell migration. Conclusions: EMX2 is frequently down-regulated in human colorectal cancer, and down-regulation of EMX2 is a prognostic marker for disease-free and overall survival. EMX2 might thus represent a promising therapeutic target in colorectal cancer.

There is limited information regarding the impact of anastomotic leakage on oncologic outcome in exclusively colon cancer patients.The colorectal database of the Department of Surgery of the University of Heidelberg was used to assess the impact of anastomotic leakage on oncologic outcome in patients undergoing curative resection for Stage I-III colon cancer. Risk-adjusted Cox regression analysis and propensity score methods were used to assess overall, disease-free, and relative survival.628 patients of which 26 (4.1%) experienced anastomotic leakage were analysed. Anastomotic leakage was associated with significantly worse overall, disease-free and relative survival in univariate and multivariate analysis. The analysis after exact propensity score matching confirmed the negative impact of anastomotic leakage on overall (HR 2.62, 95% CI 1.33-5.18, p = .011), disease-free (HR 2.28, 95% CI 1.16-4.47, p = .027) and relative survival (HR 3.70, 95% CI 1.82-7.52, p .001). 5-year overall survival was 51.6% (95% CI 34.5-77.2%) for patients with anastomotic leakage compared to 77.7% (95% CI 73.0-82.8%) for patients without anastomotic leakage.All conceivable efforts should be made to avoid anastomotic leakage after colon resection for cancer not only to evade short-term consequences but also to allow for adequate long-term outcome.

Squamous cell cancer (SCC) is a rare histological subtype of rectal cancer. It is unclear whether SCC should be treated by multimodal therapy, including surgery, or by chemoradiation alone. The objective of the study was to define an optimal treatment strategy. Patients with rectal cancer and SCC histology were identified in the Surveillance Epidemiology and End Results Database between 1990 and 2013. According to treatment, three groups were defined: radiotherapy and surgery (RT/SX), radiotherapy (RT), and surgery (SX). Overall survival (OS) and disease-specific survival (DSS) for localized, regional, and distant disease were assessed using a multivariable Cox regression model. Out of 856,435 colorectal cancer patients, 1747 with SCC of the rectum were eligible. Four hundred and fifty-five were treated with RT/SX, 994 with RT, and 298 with SX. Adjusted hazard ratios (HR) did not differ for OS and DSS in localized disease. In regional disease, OS and DSS were improved for RT/SX compared to RT (HR 0.751, 95% CI 0.566–0.997, P = 0.048 and HR 0.679, 95% CI 0.478–0.966, P = 0.031). In distant disease, OS and DSS were not different. Multimodal therapy including surgery improved OS and DSS compared to receiving a treatment without surgery for regional disease in rectal SCC. No difference was observed in localized and distant disease. The findings contradict with recent reports favoring definitive chemoradiation.

Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies., The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients.

Background Neoadjuvant therapy is an important strategy for locally advanced pancreatic cancer (PDAC) as resection rates increase with modern chemotherapy regimens even in patients with arterial tumor encasement. The aim of this study is the description of technique and initial outcomes of a new type of radical and arterial-sparing resection after neoadjuvant treatment for locally advanced PDAC. Methods The surgical technique and perioperative results of a new type of operation are described, comprising radical tumor removal by sharp dissection along the celiac axis and the superior mesenteric artery with complete dissection of all soft tissue between both – arteries and superior mesenteric/portal vein (TRIANGLE operation). Results 15 patients underwent artery-preserving tumor removal without mortality, 7/15 patients showed postoperative complications and an R0 resection was achieved in 6/15 patients. Functional outcome was good in 11/15 patients despite the extended approach of dissection. Conclusion After neoadjuvant therapy for locally advanced PDAC, surgical exploration should be attempted in patients with stable disease or remission to clarify true vascular infiltration. In case of absent viable tumor, the described technique allows to perform radical surgery without arterial resection in this subgroup of patients.

To date there is no evidence that more intensive follow-up after surgery for esophagogastric adenocarcinoma translates into improved survival. This study aimed to evaluate the impact of standardized surveillance by a specialized center after resection on survival. Data of 587 patients were analyzed who underwent curative surgery for esophagogastric adenocarcinoma in our institution. Based on their postoperative surveillance, patients were assigned to either standardized follow-up (SFU) by the National Center for Tumor Diseases (SFU group) or individual follow-up by other physicians (non-SFU group). Propensity score matching (PSM) was performed to compensate for heterogeneity between groups. Groups were compared regarding clinicopathological findings, recurrence, and impact on survival before and after PSM. Of 587 patients, 32.7% were in the SFU and 67.3% in the non-SFU group. Recurrence occurred in 39.4% of patients and 92.6% within the first 3 years; 73.6% were treated, and of those 17.1% underwent resection. In recurrent patients overall and post-recurrence survival (OS/PRS) was influenced by diagnostic tools (p

Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.

To investigate the association of serum 25-hydroxyvitamin D (25(OH)D

Rezidive nach kurativer Resektion eines Magenkarzinoms sind mit einem schlechten Langzeituberleben der Patienten assoziiert. Bei einem limitierten Lokalrezidiv ohne gleichzeitige Fernmetastasen oder Peritonealkarzinose besteht in einer stark selektionierten Subgruppe von Patienten die Moglichkeit, durch eine erneute chirurgische Resektion das Uberleben zu verbessern. In diesem Kapitel werden die Potenziale einer erneuten Resektion anhand der Analyse der vorliegenden Studien bei gleichzeitiger Berucksichtigung der Limitationen dargestellt.

Combining high-coverage whole-genome sequencing with functional analyses, Giessler et al. demonstrate that tumor initiation and long-term tumor formation in human colorectal cancer are driven by multiple genomic subclones and that the functional heterogeneity of colorectal cancer tumor clone–initiating cells is not based on genomic architecture., A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample. Long-term growth in serial xenografts and spheroids was driven by multiple genomic subclones with profoundly differing growth dynamics and hence different quantitative contributions over time. Strikingly, genetic barcoding demonstrated stable functional heterogeneity of CRC TcICs during serial xenografting despite near-complete changes in genomic subclone contribution. This demonstrates that functional heterogeneity is, at least frequently, present within genomic subclones and independent of mutational subclone differences.

The current gold standard for oncological resection of tumors derived from the middle and lower rectum remains the total mesorectal excision (TME). In contrast, tumors derived from the upper third are often treated with a partial mesorectal excision (PME). In cases where a PME is planned, care must be taken to ensure a minimum distance of 5 cm between tumor and excision margin. In addition, the bordering lamella of the entire resected tissue must be excised without damage, and a coning of the perirectal tissue should be avoided. This is of particular importance because lymph node metastases extending up to 5 cm distal to the lower border of the tumor have been described (Heald). In cases where a deep anterior rectum resection with complete removal of the mesorectal tissue is performed, a tumor-free border at the excision margins is adequate and allows sphincter function to be preserved.

Radical resection with total mesorectal excision (TME) is the accepted standard of care for most rectal cancers. However, T1 rectal cancers may be at low risk for metastases and are therefore treatable with local resection. The aim of our study was to investigate whether the identification of these patients is possible through existing selection criteria. Between 2001 and 2012, radical resection with TME was performed in 68 patients with a histologically confirmed T1 adenocarcinoma of the rectum. Each patient was staged preoperatively as lymph node negative. Patients at low risk to metastasize were defined as proposed by Hermanek and Gall (Int J Colorectal Dis 1(2):79–84, 1986), Kikuchi et al. (Dis Colon Rectum 38(12):1286–1295, 1995) and Hase et al. (Dis Colon Rectum 38(1):19–26, 1995) Postoperative morbidity, mortality, and oncological outcome were analyzed. Despite nodal negative staging, 9 of 68 patients (13 %) were node positive. Following the proposal of Hermanek and Gall, Kikuchi et al., and Hase et al., 14 % (5/37), 12 % (3/26), and 16 % (6/38) of patients, respectively, with low-risk tumors had lymph node metastases. In the univariate analysis, none of the investigated parameters could predict lymph node metastases. Following radical resection, none of the patients, regardless of nodal involvement, developed a recurrence. Preoperative diagnostics regarding lymphatic tumor propagation and histomorphological assessment of tumor samples as predictors of lymph node metastasis are unreliable. Following radical resection with TME, the oncological outcome of node-positive patients with T1 rectal adenocarcinoma is comparable with that of lymph node-negative patients. Considering the lymph node metastases rate, a local excision should always be complemented with additional therapy.

Short-course preoperative radiotherapy (SCPRT) is an alternative method to chemoirradiation for patients with Stage II and III rectal cancer when no downsizing is needed, but there is still widespread reluctance to use this method because of fear of side effects from high-fraction doses. This paper reports on a single institution patient cohort of operated rectal cancer patients after SCPRT, evaluated for chronic adverse effects, local control, progression-free survival and overall survival. Altogether, 257 patients were treated with SCPRT and surgery including total mesorectal excision (92% total mesorectal excision = TME) between 2002 and 2009. Local control and survival were analyzed. Chronic adverse effects for 154 patients without local relapse were evaluated according to the NCI-CTCAE version 4.0 classification, with a median follow-up of 48 months. We found a 5-year disease-free survival (DFS) and overall survival (OS) of 71%. The 5-year estimated local control (LC) rate was 94%. A positive resection margin was found in 4% of the patients and was significantly correlated with decreased DFS, OS and LC. Chronic adverse effects were reported by 58% of the patients, of which 10% were Grade 3 toxicities. The most frequent Grade 2 toxicity was stool incontinence (13%). Sexual dysfunction was found in 36% of the patients (31% Grade 1 or 2, and only 5% Grade 3). SCPRT combined with TME produced excellent LC rates together with a low rate of high-grade chronic adverse effects.

Colorectal cancer guidelines recommend adjuvant chemotherapy in stage II disease when less than 12 lymph nodes are assessed. The recommendation bases on previous studies showing an association of a low lymph node count and adverse outcome. Compared to current standards, however, the quality of lymph node examination in the studies was low. We, therefore, investigated the prognostic role of

Introduction The glutathione S-transferase (GST) enzymes are involved in the detoxification of a range of carcinogenic compounds as well as chemotherapeutic agents. Therefore, genetic variants in the GST genes could influence survival in patients with colorectal cancer (CRC). Results from previous studies have been inconsistent and therefore we investigated the association between the GSTP1 ile105val polymorphism and the copy number variants of the GSTM1 and GSTT1 genes and survival in CRC patients treated with adjuvant/palliative chemotherapy. Patients and methods We included 755 CRC patients with stage II-IV disease from two population-based studies carried out in Germany. Genotyping of the GSTP1 polymorphism was carried out using fluorescence-based melting curve analysis and copy number variants were determined using a multiplex PCR. Survival analysis was carried out using the Cox regression model, adjusting for age, sex, UICC stage, cancer site, and radiation therapy. Results Compared with noncarriers, CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin [hazard ratio (HR) 2.25, 95% confidence interval (CI) 0.93-5.44] than those not treated with oxaliplatin (HR 0.64, 95% CI 0.30-1.34; P for heterogeneity=0.031). The association was significant in metastatic CRC patients treated with oxaliplatin (HR 3.59, 95% CI 1.29-10.03). Neither the GSTP1 105val allele nor the GSTT1 deletion was significantly associated with CRC survival. Conclusion Our data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy; however, independent large studies are warranted to confirm these results.

Anastomotic leakage is one of the most severe complications following esophageal resection. Among other strategies, gastric ischemic preconditioning has been proposed to improve anastomotic integrity. The aim of this systematic review is to investigate whether gastric preconditioning has influence on peri- or postoperative outcomes after esophageal resection. A systematic literature search was performed to identify studies comparing gastric preconditioning with non-preconditioned patients for any indication of esophageal resection. Random-effects meta-analyses were conducted for main outcomes. Gastric preconditioning did not reduce anastomotic leakages (OR 0.76; 95%-CI 0.51 to 1.13; p = 0.18), anastomotic strictures (OR 1.10; 95%-CI 0.58 to 2.10; p = 0.76;), major complications (OR 1.14; 95%-CI 0.60 to 2.14; p = 0.69), or in-hospital mortality (OR 0.62; 95%-CI 0.28 to 1.40; p = 0.25). However, preconditioning reduced the rate of severe leaks requiring reoperation (OR 0.20; 95%-CI 0.08 to 0.53; p = 0.001). Increasing the period between preconditioning and esophageal resection over 2 weeks did not reduce anastomotic leakage compared to shorter waiting times (OR 0.65; 95%-CI 0.38 to 1.13; p = 0.13). With current evidence, gastric preconditioning does not seem to reduce overall rates of anastomotic leakage after esophageal resection but seems to reduce severity of leakages.

Background The objective of this study was to evaluate the potential benefits of immunonutrition in major abdominal surgery with special regard to subgroups and influence of bias. Methods A systematic literature search from January 1985 to July 2015 was performed in MEDLINE, Embase and CENTRAL. Only RCTs investigating immunonutrition in major abdominal surgery were included. Outcomes evaluated were mortality, overall complications, infectious complications and length of hospital stay. The influence of different domains of bias was evaluated in sensitivity analyses. Evidence was rated according to the GRADE Working Group grading of evidence. Results A total of 83 RCTs with 7116 patients were included. Mortality was not altered by immunonutrition. Taking all trials into account, immunonutrition reduced overall complications (odds ratio (OR) 0·79, 95 per cent c.i. 0·66 to 0·94; P = 0·01), infectious complications (OR 0·58, 0·51 to 0·66; P < 0·001) and shortened hospital stay (mean difference –1·79 (95 per cent c.i. –2·39 to –1·19) days; P < 0·001) compared with control groups. However, these effects vanished after excluding trials at high and unclear risk of bias. Publication bias seemed to be present for infectious complications (P = 0·002). Non-industry-funded trials reported no positive effects for overall complications (OR 1·13, 0·88 to 1·46; P = 0·34), whereas those funded by industry reported large effects (OR 0·66, 0·48 to 0·91; P = 0·01). Conclusion Immunonutrition after major abdominal surgery did not seem to alter mortality (GRADE: high quality of evidence). Immunonutrition reduced overall complications, infectious complications and shortened hospital stay (GRADE: low to moderate). The existence of bias lowers confidence in the evidence (GRADE approach).

Background and Objectives There is ongoing debate about whether patients planned for liver resection of colorectal liver metastases (CRLM) benefit from neoadjuvant chemotherapy (NC). Therefore, we performed a retrospective survival analysis of patients with and without NC prior to surgery. Methods Data prospectively collected from 468 consecutive patients were analyzed in a retrospective design. We performed a survival analysis and added propensity score matching (PSM). Univariate and multivariate analysis was performed to determine independent prognostic risk factors. Results NC was performed in 145/468 patients. NC did not have a significant influence on overall survival (OS) either before or after PSM. Patients receiving NC showed increased complication rates, especially concerning non-surgical complications after primary resection (P = 0.025) of CRLM. Multivariate analysis before and after PSM revealed that the Memorial Sloan Kettering Cancer Center (MSKCC) score and CEA values are strong predictors for OS in patients with CRLM. Conclusions NC was not associated with increased OS in patients suffering from CRLM. Additionally, potentially harmful chemotherapy prior to surgery increases the risk of postoperative complications in these patients.

BACKGROUND Body weight in colorectal cancer patients may change substantially before and after diagnosis and treatment. The prognostic significance of pre-surgery weight loss is still unclear. We investigated the association of pre-surgery weight loss with clinical outcomes in colorectal cancer patients. METHODS We used prospectively collected data from n=148 newly diagnosed colorectal cancer patients (stage I-IV) from the ColoCare Cohort. Data on body mass index (BMI; (kg)/ m2) 1 year before surgery and at the time of surgery were collected. We calculated BMI differences between these time points. We applied Cox proportional hazard models to investigate associations of BMI change (continuous), biological sex (male, female) and tumor stage (I, II, III, IV) and neoadjuvant chemo- and/or radiotherapy (no/yes). RESULTS After 24 months of follow-up n=22 patients were deceased and n=19 patients had a recurrence. Pre-surgery change in BMI was associated with poorer overall and disease-free survival: for every loss in one unit in BMI patients had a 47% increase in risk of overall death: Hazard Ratio (HR): 1.47; 95% confidence interval (CI) (1.21-1.76), p=0.0001 and a 44% increase in risk for either death or recurrence: HR: 1.44; 95% CI (1.19-1.73), p=0.0002. CONCLUSIONS Pre-surgery weight change is, independently of tumor stage, age, biological sex and neoadjuvant therapy, associated with long-term clinical outcomes in colorectal cancer survivors. Citation Format: Jennifer Ose, Biljana Gigic, Tengda Lin, Juergen Boehm, Petra Schrotz-King, Petra Schrotz-King, Sheetal Hardikar, Caroline Himbert, Martin Schneider, Alexis Ulrich, Cornelia M. Ulrich. Associations of change in BMI before surgery with disease-free and overall survival in colorectal cancer patients: Results from the ColoCare Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3283.

3581 Background: Pain is a prevalent, debilitating symptom in more than half of cancer patients. Accumulating evidence suggests a bi-directional relationship between gut microbiota and pain, potentially via inflammation and oxidative stress. Fusobacterium nucleatum (Fn), a pro-inflammatory anaerobic bacterium, is frequently detected in colorectal cancer (CRC) patients. To date, no study has identified a relationship between Fn and cancer pain in CRC patients. We investigated the associations between pre-treatment Fn and cancer pain at 6 months post-surgery in CRC patients. Methods: We utilized pre-surgery stool samples collected from 80 prospectively followed, newly diagnosed CRC patients recruited from the German site of the international ColoCare Study. Eligible patients were neo-adjuvant treatment naïve and did not use antibiotics for at least 1 month before stool collection. Fn DNA was assessed via quantitative real-time polymerase chain reaction. Patients were median split into Fn-high (>17.27; n=40) or Fn-low (≤17.27; n=40). Cancer pain was assessed using the 2 pain symptom items from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core-30 (lower score=lower pain) at pre- and 6 months post-surgery. Results: Before surgery, 48% of all patients reported any pain. At 6 months post-surgery, we observed a decrease in cancer pain by 33% for Fn-low, while there was an increase in cancer pain by 41% for Fn-high. After controlling for pre-surgery cancer pain in ANCOVA model, we observed significantly higher mean cancer pain at 6 months post-surgery in the Fn-high group vs. the Fn-low group (24.07 vs. 13.44; effect size, ES=0.45; p=0.04). These results were maintained even after controlling for age, sex, tumor stage and site, adjuvant chemotherapy, BMI, physical activity, and any pain medications (29.11 vs. 16.55; ES=0.53; p=0.03). Conclusions: These findings suggest that high Fn is an independent predictor of cancer pain at 6 months post-surgery in colorectal cancer patients. Further research is needed to confirm and understand the mechanisms of these results. Funding: NCI U01 CA206110.

T-cell exclusion by tumors is one of the major obstacles for cancer immunotherapies. In colorectal cancer liver metastasis (CRC-LM) patients, effector T-cells are mainly found in the invasive margin and not in the tumor epithelium. Such T-cell exclusion might hinder an effective antitumor immune response and could account for therapy failures with immune checkpoint inhibitors, which is observed in the majority of CRC-LM patients. As T-cell infiltration and distribution are difficult to detect in patients, little is known about detailed immunotherapy effects on tumor-infiltrating lymphocytes (TIL). Therefore, we established a fully human tissue-based ex vivo cell migration analysis model to monitor T-cell infiltration and positioning in the authentic tumor microenvironment of CRC-LM patients. In brief, we isolated T-cells from fresh resected CRC-LM patient tissue samples, labeled the cells with a fluorescent dye and returned the labeled T-cells to the tissues, which were cultured for a certain time period. Besides autologous T-cells, several tissue samples were treated with non-autologous labeled T-cells isolated from a healthy donor. After tissue processing, immunostaining and cell quantification, we observed that remigration of the labeled autologous and donor T-cells into the tissues was significantly associated with numbers of endogenous TIL. The labeled autologous and donor T-cells showed a similar distribution pattern to endogenous TIL with highest densities in the invasive margin of patient tissues. No relevant changes in tumor cell numbers or apoptosis protein concentrations could be observed by both treatments. Furthermore, quantification of the chemokines CXCL9, CXCL10 and CCL5 showed significant associations with labeled autologous and donor T-cell infiltration. Interestingly, treatment with a PD1 inhibitor did not support infiltration of exogenous or endogenous T-cells into the tumor epithelium. Our findings highlight that infiltrating T-cells in CRC-LM are always positioned into the invasive margin independently of the T-cell´s origin. Especially microenvironmental factors such as CXCL9, CXCL10 and CCL5 seem to be involved in this process, preventing T-cell contact with the tumor epithelium, which could also not be abrogated by immune checkpoint inhibition. The similar infiltration and distribution pattern of T-cells in the ex vivo and in vivo settings highlights the functionality and reliability of the human tissue-based cell migration analysis model, emphasizing its use for studying therapy effects on TIL in CRC-LM patient tissues. Citation Format: Anna Berthel, Meggy Suarez-Carmona, Jakob N. Kather, Rodrigo Rojas-Moraleda, Pornpimol Chaorentong, Nektarios A. Valous, Fee Klupp, Martin Schneider, Alexis Ulrich, Markus Buechler, Inka Zoernig, Dirk Jaeger, Niels Halama. A fully human tissue-based ex vivo cell migration analysis model to study T-cell infiltration and distribution in colorectal cancer liver metastases [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A171.

Background Incisional hernia is the most frequent long-term complication after visceral surgery, with an incidence of between 9 and 20 per cent 1 year after operation. Most controlled studies provide only short-term follow-up, and the actual incidence remains unclear. This study evaluated the incidence of incisional hernia up to 3 years after midline laparotomy in two prospective trials. Methods Three-year follow-up data from the ISSAAC (prospective, multicentre, historically controlled) and INSECT (randomized, controlled, multicentre) trials focused on the rate of incisional hernia 1 and 3 years after surgery. Differences between the two groups were compared using t tests for continuous data and the χ2 test for categorical data. Results Analysis of 775 patients included in the two trials suggested that the incisional hernia rate increased significantly from 12·6 per cent at 1 year to 22·4 per cent 3 years after surgery (P < 0.001), a relative increase of more than 60 per cent. Conclusion This follow-up of two trials demonstrated that 1 year of clinical follow-up for detection of incisional hernia is not sufficient; follow-up for at least 3 years should be mandatory in any study evaluating the rate of postoperative incisional hernia after midline laparotomy.

Selected patients with peritoneal surface malignancies (PSM) have been treated effectively by the combination of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).The purpose of this study is to summarize the treatment outcomes and general considerations regarding definitions and staging systems of current CRS and HIPEC modalities in malignant peritoneal mesothelioma and in secondary peritoneal malignancies such as peritoneal metastasis from appendiceal, colorectal, gastric, and epithelial ovarian cancers.Disease progression within the peritoneal cavity has in the past been regarded as a terminal event. Accumulating evidence underlines the therapeutic potential and the acceptable morbidity and mortality rates of CRS and HIPEC in selected patients.

The treatment of rectal cancer has evolved significantly in recent decades. Both modern radiotherapy treatment concepts and surgical techniques have been able to improve oncological as well as functional outcomes for rectal cancer patients. Large-scale, multicenter, randomized trials have been able to demonstrate the benefits of neoadjuvant treatment over adjuvant radiotherapy. In addition, local tumor control is improved by neoadjuvant irradiation. Conversely, patients receiving a total mesorectal excision showed no survival advantage following irradiation vs. only surgically resected patients. In addition, radiation therapy is associated with a certain morbidity and mortality. This paper summarizes the available evidence regarding postoperative morbidity, mortality, and long-term chronic effects of neoadjuvant radiotherapy.

This study evaluates the anorectal and genitourinary function of patients treated by preoperative short-term radiotherapy (RT) or chemoradiotherapy (CRT) followed by surgery and surgery alone for rectal cancer.For this study, a total of 613 patients, who were identified from a prospective rectal cancer database, underwent anterior resection of the rectum between October 2001 and December 2007. Standardized questionnaires were used to determine fecal incontinence, urinary, and sexual function. Relevant clinical variables were evaluated using univariate and multivariate analyses. Independent predictors of functional outcome were identified by a binary logistic regression analysis.The data of 263 (43 %) patients were available for analysis. On multivariate analysis, neoadjuvant RT (P 0.01) and low anterior resection (LAR) (P = 0.049) were associated with fecal incontinence. In univariate analysis, fecal incontinence was linked to preoperative neoadjuvant treatment (RT and/or CRT vs. LAR) (P 0.01). The hazard ratio for developing fecal incontinence was 3.3 (1.6-6.8) for patients who received RT. One hundred twenty-five patients (51.2 %) experienced urinary incontinence following surgery, the majority of whom were female (P 0.01). On univariate analysis, male sexual function was associated with age (P 0.01), ASA class (P = 0.01) and LAR (P = 0.01).Multimodal therapy of low rectal cancer increases the incidence of fecal incontinence and negatively affects sexual function. The potential benefits of RT or CRT need to be balanced against the risk of increased bowel dysfunction when determining the appropriate treatment for individual patients with rectal cancer.

Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.

The International Study Group of Rectal Cancer (ISREC) has proposed a generally applicable definition and severity grading of (AL) after sphincter-preserving resection of the rectum. This work has been carried out to test for validity.A total of 746 patients who were identified from a prospective rectal cancer database underwent sphincter-preserving anterior resection of the rectum between October 2001 and January 2011. The incidence and severity of AL was determined using the criteria established by the ISREC. Patients with AL were categorized according to the ISREC scheme. The clinical outcomes were analyzed and compared between the groups.The overall AL rate was 7.5% (56/746). The 56 patients with AL were distributed among the different groups as follows: Grade A, 16%; grade B, 23%; and grade C, 61%. Compared with the grade A patients, grades B and C patients had significantly elevated serum C-reactive protein levels (P.01). None of the grade A patients were transferred to the intensive care unit (ICU). Their further hospital stay was uneventful. The length of stay in the ICU was significantly longer for grade C patients compared with grade B patients (P.001). The median hospital stay of grade C patients was significantly longer than that of grades A and B patients (P.001).The definition and severity grading of AL after anterior resection of the rectum proposed by the ISREC provides a simple, easily applicable, and valid classification. Using this classification system may facilitate comparison of results from different studies on AL after sphincter-preserving rectal surgery.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical procedure for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). While minimal invasive techniques have been applied increasingly, clear evidence of superiority for laparoscopic pouch procedures is not yet available. The aim of the LapConPouch Trial was to compare the effectiveness of laparoscopic (LAP) versus conventional (CON) ileoanal pouch procedure in patients undergoing elective restorative proctocolectomy. The trial was designed as a single-centre, pre-operatively randomized, controlled trial using a two-group parallel superiority design. Eligible for participation were patients scheduled for restorative proctocolectomy either for FAP or for UC. Patients and outcome assessors were blinded to group assignment. The primary endpoint was defined as the amount of blood loss. Statistical analyses were explorative since the trial had to be stopped prematurely. A total of 42 patients (21 LAP (50.0 %); 21 CON (50.0 %)) were randomized. The trial had to be stopped prematurely due to insufficient patient recruitment. There was no difference in the amount of blood loss between both groups: LAP 261.5 ± 195.4 ml, CON 228.1 ± 119.5 ml. Secondary endpoints differ in both groups. Laparoscopic surgery was superior regarding the length of skin incision; in contrast, the conventional approach was superior in duration of operation. There were no discrepancies in length of hospital stay, postoperative pain, bowel function, and quality of life between both approaches. The conversion rate from LAP to CON approach was 23.8 %. There was no difference with respect to blood loss between the LAP and the CON group. The LAP approach is feasible for restorative proctocolectomy, and IPAA seems at least as safe as CON surgery. The most obvious advantage of the minimal invasive technique is the improved cosmesis.

Aims In adult humans, the follicle-stimulating hormone receptor (FSHR) is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. Recently, it has been shown that FSHR is expressed selectively on the surface of blood vessels in a wide range of tumours. So far, the expression of FSHR in mesenchymal tumours has not been studied. Methods and results We performed a semiquantitative evaluation of FSHR protein expression in a large cohort of soft tissue sarcomas (STS; n = 335), including 11 subtypes. FSHR-positive vessels were detected in all sarcoma subtypes analysed. Among liposarcomas, significantly more cases of dedifferentiated liposarcomas (28 of 44) showed FSHR expression compared to well-differentiated liposarcomas (WDLS; four of 21; P

Intersphincteric resection (ISR) is an alternative to abdominoperineal resection (APR) for a selected subset of patients with low rectal cancer, combining equivalent oncological outcome and sphincter preservation. However, functional results are heterogeneous and often imperfect. The aim of the present investigation was to determine the long-term functional results and quality of life after ISR. One hundred forty-three consecutive patients who underwent surgery for low rectal cancer were analysed. Sixty patients received ISR and 83 patients APR, respectively. Kaplan-Meier estimate was used to analyse patients’ survival. The EORTC QLQ-C30, -C29 and the Wexner score were used to determine functional outcome and quality of life. ISR and APR were both associated with comparable morbidity and no mortality. Patients’ disease- and recurrence-free survival after ISR and APR were similar (p = 0.2872 and p = 0.4635). Closure of ileostomy was performed in 73% of all patients after ISR. Long-term outcome showed a rate of incontinence (Wexner score ≥10) in 66% of the patients. Despite this, patients’ quality of life was significantly better after ISR compared to APR in terms of abdominal complaints and psycho-emotional functioning. ISR is technically feasible with acceptable postoperative morbidity rates. Functional results following ISR are compromised by incontinence as the most important complication. However, long-term quality of life is superior to APR, which should be considered when selecting patients for ISR.

On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10 µm distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30 µm to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8+ T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30 µm region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.