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Background Preoperative radio(chemo)therapy (pR(C)T) significantly reduces the local recurrence risk and is therefore recommended in stage II/III rectal cancer. However, this multimodal treatment approach may be associated with late adverse effects. To determine the impact of pR(C)T on long-term anorectal, sexual, and urinary function, we performed a systematic review and meta-analysis. Methods PubMed, Embase, and the Cochrane Library were systematically searched for studies reporting on long-term functional outcome after rectal cancer resection with pR(C)T. Only studies that reported anorectal, sexual, and/or urinary function after rectal cancer resection in TME-technique with pR(C)T were eligible for inclusion. Results Twenty-five studies, including 6,548 patients, were identified. Methodological quality of the eligible studies was low. The majority of studies reported higher rates of anorectal (14/18 studies) and male sexual dysfunction (9/10 studies) after pR(C)T. Few studies examined female sexual dysfunction ( n  = 4). Meta-analysis revealed that stool incontinence occurred more often in irradiated patients (risk ratio (RR) = 1.67; 95 % confidence interval (CI), 1.36, 2.05; p  < 0.0001) and manometric results were significantly worse after pR(C)T (mean resting pressures (weighted mean difference (WMD) = 15.04; 95 % CI, 0.77, 29.31; p  = 0.04) and maximum squeeze pressures (WMD = 30.39; 95 % CI, 21.48, 39.3; p  < 0.0001)). Meta-analysis of erectile dysfunction revealed no statistical significance (RR = 1.41; 95 % CI, 0.74, 2.72; p  = 0.3). Six of eight studies and meta-analysis demonstrated no negative effect of pR(C)T on urinary function (RR = 1.05; 95 % CI, 0.67, 1.65; p  = 0.82). Conclusions Although quality of studies on long-term functional outcome is limited, current evidence demonstrates that pR(C)T negatively affects anorectal function after TME.

PurposeSurgical site infection (SSI) remains to be one of the most frequent infectious complications following abdominal surgery. Prophylactic intra-operative wound irrigation (IOWI) before skin closure has been proposed to reduce bacterial wound contamination and the risk of SSI. However, current recommendations on its use are conflicting especially concerning antibiotic and antiseptic solutions because of their potential tissue toxicity and enhancement of bacterial drug resistances.MethodsTo analyze the existing evidence for the effect of IOWI with topical antibiotics, povidone-iodine (PVP-I) solutions or saline on the incidence of SSI following open abdominal surgery, a systematic review and meta-analysis of randomized controlled trials (RCTs) was carried out according to the recommendations of the Cochrane Collaboration.ResultsForty-one RCTs reporting primary data of over 9000 patients were analyzed. Meta-analysis on the effect of IOWI with any solution compared to no irrigation revealed a significant benefit in the reduction of SSI rates (OR = 0.54, 95 % confidence Interval (CI) [0.42; 0.69], p < 0.0001). Subgroup analyses showed that this effect was strongest in colorectal surgery and that IOWI with antibiotic solutions had a stronger effect than irrigation with PVP-I or saline. However, all of the included trials were at considerable risk of bias according to the quality assessment.ConclusionThese results suggest that IOWI before skin closure represents a pragmatic and economical approach to reduce postoperative SSI after abdominal surgery and that antibiotic solutions seem to be more effective than PVP-I solutions or simple saline, and it might be worth to re-evaluate their use for specific indications.

An accurate blood‐based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti‐EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood‐based RAS mutation testing is a viable alternative to standard‐of‐care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin‐fixed paraffin‐embedded) tumor samples. Discordant tissue RAS results were re‐examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood‐based RAS mutation testing is a viable alternative to tissue‐based RAS testing. Implementation of circulating tumor DNA testing in clinical practice has been hindered by the variable performance of available methods. Here, we demonstrate that plasma mutation testing using BEAMing as a standardized platform is comparable to tumor tissue testing and can be useful in the clinic to select patients with metastatic colorectal cancer for targeted therapy.

Background FOLFIRINOX is an active but relatively toxic chemotherapeutic regimen for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The increased frequency of responding tumors shift interest to neoadjuvant approaches. We report our institutional experience with FOLFIRINOX for therapy-naïve patients with locally advanced and initially unresectable PDAC. Methods All patients with unresectable locally advanced PDAC who underwent treatment with FOLFIRINOX at a single center between 2011 and 2014 were identified and evaluated retrospectively regarding chemotherapy response, toxicity, conversion to resectability, and survival. Resectability, response to chemotherapy, and postoperative complications were reported according to NCCN-guidelines, RECIST-criteria, and Clavien–Dindo-classification, respectively. Results Overall, 14 patients received FOLFIRINOX as first-line therapy for locally advanced and unresectable PDAC. Fifty-seven percent of the patients had severe tumor-related comorbidities at the time of diagnosis, and in 86 %, dose reduction due to toxicity was necessary during a median of seven cycles. Nevertheless, only one patient had progressive disease during FOLFIRINOX, whereas the others experienced stable disease ( n  = 6) or partial remission ( n  = 6; no restaging in one patient). Oncological tumor resection was possible in 4 patients (29 % of all patients) with no postoperative mortality and only one grade 2 surgical complication. After a median follow-up of 10 months, 4 of the 14 patients were still in remission, 5 were alive with stable disease under ongoing systemic chemotherapy, and 5 died tumor-related. Conclusions FOLFIRINOX is a powerful first-line regimen that leads to resectability in a substantial portion of patients with initially unresectable pancreatic cancer.

Background A widespread shift to non-operative management (NOM) for blunt hepatic and splenic injuries has been observed in most centers worldwide. Furthermore, many countries introduced safety measures to systematically reduce severe traffic and leisure sports injuries. This study aims to evaluate the effect of these nationwide implementations on individual patient characteristics and outcomes through a time-trend analysis over 17 years in an Austrian high-volume trauma center. Methods A retrospective review of all emergency trauma patients admitted to the Medical University of Innsbruck from 2000 to 2016. Injury severity, clinical data on admission, operative and non-operative treatment parameters, complications, and in-hospital mortality were evaluated. Results In total, 731 patients were treated with blunt hepatic and/or splenic injuries. Among these, 368 had a liver injury, 280 splenic injury, and 83 combined hepatic/splenic injury. Initial NOM was performed in 82.6% of all patients (93.5% in hepatic and 71.8% in splenic injuries) with a success rate of 96.7%. The secondary failure rate of NOM was 3.3% and remained consistent over 17 years ( p  = 0.515). In terms of injury severity, we observed a reduction over time, resulting in an overall mortality rate of 4.8% and 3.5% in the NOM group (decreasing from 7.5 to 1.9% and from 5.6 to 1.3%, respectively). These outcomes confirmed an improved utilization of the NOM approach. Conclusion Our cohort represents one of the largest Central European single-center experiences available in the literature. NOM is the standard of care for blunt hepatic and splenic injuries and successful in > 96% of all patients. This rate was quite constant over 17 years ( p  = 0.515). Overall, national and regional safety measures resulted in a significantly decreased severity of observed injury patterns and deaths due to blunt hepatic or splenic trauma. Although surgery is nowadays only applied in about one third of splenic injury patients in our center, these numbers might further decrease by intensified application of interventional radiology and modern coagulation management.

Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis. Our cells need to be able to communicate with each other to coordinate many processes in the body, including the formation and maintenance of our organs. A system called Wnt signaling allows cells in different tissues to communicate. During Wnt signaling, one cell releases a protein called Wnt that then binds to a receptor protein known as Frizzled on the surface of another cell. This triggers a cascade of signaling events in the second cell, which leads to changes in the activity of particular genes. Wnt signaling is vital to many processes in cells, and any defects can cause cancer and other severe diseases. Frizzled is a member of a large family of receptor proteins known as the G protein-coupled receptors (or GPCRs for short). These proteins can bind to other proteins called G proteins. When a GPCR is active, it can activate the G protein, which can then interact with several other signal proteins to amplify the signal from the GPCR. However, there is currently no firm evidence that Frizzled can directly bind to G proteins. Some researchers have suggested that it may interact with G proteins via another ‘linker’ protein, but no such protein has yet been identified. Here, Aznar et al. investigated how Frizzled can activate G proteins in human cells. The experiments revealed that a protein called Daple can bind to both Frizzled and the G proteins when the cells are exposed to Wnt to activate the G proteins. Aznar et al. show that Daple can act as a ‘tumor suppressor’ that reduces the risk of healthy cells becoming cancerous and can inhibit the growth of tumors. However, the amount of Daple increases in some tumor cells in the later stages of cancer, which makes it easier for these cells to spread around the body. Aznar et al. also observed that Daple was present at different levels in the late-stage tumor cells taken from a variety of cancer patients. Patients with higher levels of Daple were less likely to have a positive outcome from their cancer treatment, and their illness progressed more rapidly than patients with lower levels of Daple. The next challenge is to understand what causes Daple to switch from its tumor suppressor role to one that promotes the spread of tumors in the later stages of disease.

Purpose Besides classical colorectal adenocarcinomas (AC), mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC) occur. Controversy remains regarding their prognostic role. Aim of this study was to define prognostic and histopathological specifications of mucinous and signet-ring cell colorectal cancer. Methods A total of 28,056 patients with AC, MAC, and SC between 1998 and 2012 in the catchment area of the Munich Cancer Registry were analyzed. Time to locoregional recurrence and distant recurrence was calculated by cumulative incidence. Survival was analyzed by the Kaplan–Meier method, calculation of relative survival, and Cox proportional hazards regression. Results AC occurred in 25,172 patients (90 %), MAC in 2724 (9.7 %), and SC in 160 (0.6 %). AC were less frequently localized in the proximal colon (34 %) compared to MAC (57 %, p  < 0.001) and SC (76 %, p  < 0.001). Both, MAC and SC had higher T, N, and M categories, lymphatic invasion, and worse grading ( p  < 0.001 for each). There were significant differences regarding the 10-year cumulative incidence of locoregional recurrence ( p  < 0.001), and distant recurrence ( p  < 0.001). For AC, the 5-year overall survival was 59 % (95 % confidence interval 58.0; 59.3), for MAC 52 % (50.2; 54.2), and for SC 40 % (32.1; 48.5; p  < 0.001). However, MAC or SC did not remain independent prognostic factors for overall survival compared to AC upon multivariable analysis ( p  = 0.981). Conclusion This large cohort reveals specific histopathological and recurrence patterns for patients with colorectal AC, MAC, and SC. MAC and SC are diagnosed at more advanced tumor stages and therefore entail reduced survival rates.

Background Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. Methods Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC ( n  = 36) and chronic pancreatitis (CP) ( n  = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls ( n  = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. Results TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. Conclusion This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

Background In colorectal cancer, CDX2 expression is lost in approximately 20% of cases and associated with poor outcome. Here, we aim to validate the clinical impact of CDX2 and investigate the role of promoter methylation and histone deacetylation in CDX2 repression and restoration. Methods CDX2 immunohistochemistry was performed on multi-punch tissue microarrays ( n  = 637 patients). Promoter methylation and protein expression investigated on 11 colorectal cancer cell lines identified two CDX2 low expressors (SW620, COLO205) for treatment with decitabine (DNA methyltransferase inhibitor), trichostatin A (TSA) (general HDAC inhibitor), and LMK-235 (specific HDAC4 and HDAC5 inhibitor). RNA and protein levels were assessed. HDAC5 recruitment to the CDX2 gene promoter region was tested by chromatin immunoprecipitation. Results Sixty percent of tumors showed focal CDX2 loss; 5% were negative. Reduced CDX2 was associated with lymph node metastasis ( p  = 0.0167), distant metastasis ( p  = 0.0123), and unfavorable survival (multivariate analysis: p  = 0.0008; HR (95%CI) 0.922 (0.988–0.997)) as well as BRAF V600E , mismatch repair deficiency, and CpG island methylator phenotype. Decitabine treatment alone induced CDX2 RNA and protein with values from 2- to 25-fold. TSA treatment ± decitabine also led to successful restoration of RNA and/or protein. Treatment with LMK-235 alone had marked effects on RNA and protein levels, mainly in COLO205 cells that responded less to decitabine. Lastly, decitabine co-treatment was more effective than LMK-235 alone at restoring CDX2. Conclusion CDX2 loss is an adverse prognostic factor and linked to molecular features of the serrated pathway. RNA/protein expression is restored in CDX2 low-expressing CRC cell lines by demethylation and HDAC inhibition. Importantly, our data underline HDAC4 and HDAC5 as new epigenetic CDX2 regulators that warrant further investigation.

Background Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. Methods Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox’s proportional hazard models and integrative two-step cluster analysis. Results Distant metastasis risk was significantly correlated with oncogenic KRAS mutations ( p  = 0.015), expression of SASH1 ( p  = 0.016), and the density of CD8-positive T-cells ( p  = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation ( p  = 0.008) and density of CD8-positive TILs ( p  = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) ( p  = 0.032). Increased expression of osteopontin ( p  = 0.019) and low density of CD8-positive T-cells ( p  = 0.043) were significantly associated with unfavourable response to 5-FU. Conclusions Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.