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Small intestinal malignancy is uncommon. The clinical characteristics vary with histologic subtype, and factors predictive of outcome are not well studied. A case series analysis of clinicopathologic data from patients undergoing small intestinal malignancy resection in our institution was used over a 6-year period. Kaplan Meier survival estimates were compared using Log-rank and survival curves constructed. Multivariate analysis enabled determination of factors predictive of outcome. Eighty-seven patients were included; 24 required emergency surgery and neuroendocrine (NET) was the most common histological subtype. NETs were significantly smaller than adenocarcinomas or gastrointestinal stromal tumors (GISTs); however, a greater proportion of NETS had metastatic disease, perineural invasion and underwent R1 resection. Despite their advanced stage at presentation, NETs demonstrated favorable outcome compared with other histologic subtypes. Tumor grade, neuroendocrine histology and nodal metastasis were all independently associated with overall survival. Despite the advanced stage of NETs at presentation, these tumors demonstrated better overall survival than adenocarcinomas or GISTs. De-bulking with R1 resection is an acceptable approach for NET as compared to adenocarcinoma or GIST. Future work needs to focus on the development of targeted therapies for small intestinal adenocarcinoma to improve long-term outcome.

Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery.A retrospective review of a prospective database of patients undergoing surgery for pCCA at a Western centre between January 2009-2020.Eighty-five patients underwent surgical resection for pCCA with a median overall survival of 36.3 months. Post-op (90day) morbidity rates were high with 46% of patients developing a major complication (Clavien-Dindo grade 3-4). Post-op mortality rate was 13%. In total 38% (28/74) of patients experienced at least 1 episode of delayed morbidity (90-days of surgery) resulting in 53 separate admissions with a median LOS of 7 days (IQR 2-15). These episodes were predominately secondary to biliary obstruction with the majority requiring radiological intervention (Clavien-Dindo grade 3). The development of long-term morbidity was associated with increased recurrence rates and correlated with poorer OS (27.6 months vs. 65.7 months HR 2.2 CI 1.63-2.77).Routinely cited 90-day morbidity and mortality does not accurately capture the patient morbidity experienced following surgery for pCCA. Surgery clearly offers a survival benefit and should be pursued in selected patients, but they must be fully counselled on the potential for long-term morbidity before embarking on this strategy.

Microwave ablation (MWA) is a recognised treatment option for liver metastases. The size of the tumour is a well-established factor that influences the success of MWA. However, the effect of "heat sink" on the success of MWA for hepatic metastases is unclear. The aim of this study was to determine whether heat sink effect is a factor that contributes to ablation site recurrence (ASR).A prospectively maintained database of patients who underwent percutaneous MWA for treatment of colorectal liver metastases was analysed. Imaging and demographic characteristics were compared between metastases that recurred following ablation and those that did not. Proximity to a large hepatic vein was defined as10 mm.126 ablations in 87 patients met the inclusion criteria and were studied over a median follow-up period of 28 (12-75) months. ASR was detected in 43 ablations (34%) and was associated with clinical risk score (CRS) ≥2 (OR 2.2 95% CI 1.3-3.3, p = 0.029), metastasis size (OR 0.953 95% CI (0.929-0.978), p 0.001) and proximity to a large hepatic vein (OR 7.5 95%CI 2.4-22.8, p 0.001). Proximity to a large hepatic vein was not associated with reduced overall survival (OS) but was associated with liver-specific recurrence (HR 4.7 95%CI 1.7-12.5, p = 0.004).In addition to tumour size proximity to large hepatic venous structures is an independent predictor of ASR and liver-specific recurrence following MWA. However, this was not associated with overall survival.

Simple Summary The extracellular matrix (ECM) is the acellular part of a tissue, a meshwork of extracellular material produced and secreted by cells into the surrounding medium. The major function of the ECM is to provide structural and support to the surrounding cells. The ECM of malignant tumours is characterised as disorganized with increased production of some components compared to normal tissues. In this review we discuss how cancer ECM affects the tumour immunity and how we could exploit the ECM to boost the anti-tumour immune response. Abstract The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration.

Background The use of peritoneal lavage to prevent postoperative intra-abdominal abscess (IAA) after appendicectomy has been debated widely. Methods A systematic review and meta-analysis of suction alone versus lavage for appendicitis was performed to determine the relative benefit of lavage. Primary outcomes were postoperative IAA and wound infection (WI). Inclusion criteria were human studies reporting a comparison of appendicectomy with or without peritoneal lavage. Results Eight studies met the inclusion criteria, the majority of which were retrospective. Only three were RCTs. Four studies included analysis only of the paediatric population. The rate of IAA was 1·0-19·5 per cent in patients receiving suction alone and 1·5-18·6 per cent in those having lavage. WI rates were 1·0-29·2 per cent for suction alone and 0·8-20·5 per cent for lavage. The pooled risk difference for IAA was 0·01 (95 per cent c.i. -0·03 to 0·06; P = 0·50) and that for WI was 0·00 (-0·05 to 0·05; P = 0·98). Analyses of both outcomes indicated a medium degree of heterogeneity between effect estimates with I 2 values of 71 per cent (P = 0·001) and 70 per cent (P = 0·010) for IAA and WI respectively. Conclusion There is no evidence of benefit of lavage over suction for postoperative infective complications, and no individual study demonstrated a significant benefit in patients receiving lavage.

Background: Accumulating evidence implicates the tumour stroma as an important determinant of cancer progression but the protein constituents relevant for this effect are unknown. Here we utilised a bioinformatics approach to identify an extracellular matrix (ECM) gene signature overexpressed in multiple cancer types and strongly predictive of adverse outcome. Methods: Gene expression levels in cancers were determined using Oncomine. Geneset enrichment analysis was performed using the Broad Institute desktop application. Survival analysis was performed using KM plotter. Survival data were generated from publically available genesets. Results: We analysed ECM genes significantly upregulated across a large cohort of patients with ovarian, lung, gastric and colon cancers and defined a signature of nine commonly upregulated genes. Each of these nine genes was considerably overexpressed in all the cancers studied, and cumulatively, their expression was associated with poor prognosis across all data sets. Further, the gene signature expression was associated with enrichment of genes governing processes linked to poor prognosis, such as EMT, angiogenesis, hypoxia, and inflammation. Conclusions: Here we identify a nine-gene ECM signature, which strongly predicts outcome across multiple cancer types and can be used for prognostication after validation in prospective cancer cohorts.

Background: CXCL12 (SDF1) is reported to promote cancer progression in several preclinical models and this is corroborated by the analysis of human tissue specimens. However, the relationship between CXCL12 expression and cancer survival has not been systematically assessed. Methods: We conducted a systematic review and meta-analysis of studies that evaluated the association between CXCL12 expression and cancer survival. Results: Thirty-eight studies inclusive of 5807 patients were included in the analysis of overall, recurrence-free or cancer-specific survival, the majority of which were retrospective. The pooled hazard ratios (HRs) for overall and recurrence-free survival in patients with high CXCL12 expression were 1.39 (95% CI: 1.17–1.65, P=0.0002) and 1.12 (95% CI: 0.82–1.53, P=0.48) respectively, but with significant heterogeneity between studies. On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31–3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21–1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08–1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38–0.66, P

Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis-associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than naive neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching. Conclusion Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920-1935).

Background Individualised risk prediction is crucial if targeted pre-operative risk reduction strategies are to be deployed effectively. Radiologically determined sarcopenia has been shown to predict outcomes across a range of intra-abdominal pathologies. Access to pre-operative cross-sectional imaging has resulted in a number of studies investigating the predictive value of radiologically assessed sarcopenia over recent years. This systematic review and meta-analysis aimed to determine whether radiologically determined sarcopenia predicts post-operative morbidity and mortality following abdominal surgery. Method CENTRAL, EMBASE and MEDLINE databases were searched using terms to capture the concept of radiologically assessed sarcopenia used to predict post-operative complications in abdominal surgery. Outcomes included 30 day post-operative morbidity and mortality, 1-, 3- and 5-year overall and disease-free survival and length of stay. Data were extracted and meta-analysed using either random or fixed effects model (Revman® 5.3). Results A total of 24 studies involving 5267 patients were included in the review. The presence of sarcopenia was associated with a significant increase in major post-operative complications (RR 1.61 95% CI 1.24–4.15 p =

To systematically review studies reporting clinicopathological features of intraductal papillary neoplasm of the bile duct (IPNB) to provide evidence-based guidance for management.IPNB is a rare tumor type. Management decisions are currently based upon anecdotal evidence and small case series. To data, there has been no systematic review of IPNB literature.MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched and data were extracted from relevant studies. Meta-analysis was used to pool study estimates. Evidence of association was determined by comparing pooled crude odds ratios (OR) derived from abstracted data.Fifty-seven retrospective case series were included. At least 43% of 476 specimens contained invasive disease. Invasive tumors were found at significantly higher frequency in pancreaticobiliary than intestinal, gastric or oncocytic-type IPNB [pooled OR 2.5, 95% confidence interval (CI) 1.5-4.2, P0.001]. A significantly higher proportion of pancreaticobiliary tumors compared with intestinal tumors expressed MUC-1 [86.4% (95% CI 75.1%-94.7%) vs 13.2% (95% CI 4.6%-25.2%), respectively P0.001]. IPNB identified in centers from Asia were more likely to be intrahepatic and were less frequently invasive compared with those from Western centers. Pooled estimates of absolute survival after IPNB resection were 96% (95% CI 93%-99%) at 1 year, 79% (95% CI 69%-88%) at 3 years, and 65% (95% CI 46%-76%) at 5 years.Early surgery is advisable for radiologically suspected IPNB as it is frequently invasive. The pathobiology of IPNB demonstrates geographic variation. Pancreaticobiliary IPNB expresses MUC1 and is more frequently associated with invasive disease than other IPNB subtypes.

The main cause of cancer-related mortality, metastasis, is a complex, multi-step process. The extracellular matrix (ECM) component of solid tumors has been implicated in metastatic progression; however, the ECM exists as a complex macromolecular substrate and it is unclear how its molecular composition promotes cancer progression. ECM homeostasis is regulated by various secreted proteins including cross-linkers (e.g., lysyl oxidases and transglutaminases), modifying enzymes (e.g., sulfatases and extracellular kinases), proteases (e.g., matrix metalloproteinases, heparanase, and cathepsins) and protease inhibitors (e.g., tissue inhibitors of metalloproteinases, cystatins, and serpins); each of which can alter the structural, mechanical, and biochemical properties of the ECM. Emerging evidence indicates that altered ECM regulator activity in cancer triggers pathological ECM remodeling facilitating metastatic dissemination making ECM regulators potential targets for cancer therapy. In this review, we summarize and critically discuss the existing literature on the role of ECM regulators in cancer metastasis.

Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.

BackgroundTotal pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated.MethodsMEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review.ResultsFive studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow-up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis.ConclusionThis systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation.

OBJECTIVES: Sigmoid volvulus accounts for 5% of cases of large-bowel obstruction. Here, we present the development of a new minimally invasive treatment method that aims to reduce the complication rate of standard percutaneous endoscopic colostomy tube insertion and negate the need for prolonged anesthesia or colectomy. METHODS: Six patients underwent laparoscopic-assisted endoscopic sigmoidopexy for recurrent sigmoid volvulus at a mean age of 80.5 years (range, 76-83). The volvulus was decompressed endoscopically before laparoscopic adhesiolysis and detorsion of the sigmoid. Finally, the sigmoid was approximated with the anterior abdominal wall, and 2 endoscopically placed percutaneous endoscopic colostomy tubes were inserted. Later, the external component of the percutaneous endoscopic colostomy tubes was removed, and the internal parts were passed by way of the rectum. RESULTS: Each operation was completed successfully in a mean time of 69 minutes and with no intraoperative complication. The mean postoperative stay was 20 days (range, 4-54). At median follow-up of 10.8 months, all patients were tube free with no incidence of recurrent volvulus, inadvertent tube traction, or leak. CONCLUSIONS: This preliminary report shows laparoscopic-assisted endoscopic sigmoidopexy to be a safe treatment modality for recurrent sigmoid volvulus. As such, it is particularly useful for elderly patients, for whom colectomy is a high-risk procedure.

Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1mid cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1mid recruitment and decreased tumor burden. Depletion of the CD11b/Gr1mid subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1mid cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. Conclusion: Collectively, our findings highlight the importance of myeloid cells-in this case a selective CD11b/Gr1mid subset-in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy. © 2012 American Association for the Study of Liver Diseases.