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Introduction Minimally invasive approaches to oncological liver resection is common in many hepatobiliary centres. This study aims to compare the key oncological and survival outcomes of patients with colorectal liver metastases (CRLM) undergoing laparoscopic or open resections using propensity score matching (PSM). Methods A single-centre retrospective study was performed using a prospective database of patients undergoing liver resection for CRLM between January 2016 and December 2019. Different co-variates were selected for matching using PSM. Pre-matching and post-matching analyses were compared. Surgical and survival outcomes were analysed. Results In total, 303 patients who met the inclusion criteria were identified: 214 underwent open liver resection (OLR) and 91 laparoscopic liver resection (LLR). LLR had a significantly reduced length of intensive treatment unit (ITU) and overall in-patient stay but longer pringle and operative times. In the unmatched cohort, the median overall and disease-free survival time was significantly longer in patients undergoing laparoscopic compared with open surgery. A PSM model demonstrated significantly reduced blood loss and length of hospital stay, with a significantly greater Pringle and operative time in the LLR group. Differences seen in overall and disease-free survival were lost with propensity score matching, possibly due to lack of bi-lobar disease within the minimally invasive group. Conclusion In selected patients with CRLM, LLR presents similar survival and oncological outcomes with the advantages of the short-term results associated with the laparoscopic approach.

Background Pancreatic carcinosarcoma is a rare malignant neoplasm and has a very poor prognosis. Diagnosis is mainly by pathological examination including immunohistochemistry (IHC) of the biopsy or resected specimen. Due to the rarity of the cancer, information regarding clinical presentation, pathology and management is limit to a few case reports. Methods We report a 61-year-old fit and healthy male, who presented to the emergency department with melaena and syncope. Initial CT scan showed a pancreatic body/tail tumour, likely pancreatic cancer without nodal or intra-abdominal metastasis. Upper GI endoscopy revealed a lesion in the second part of the duodenum, with a visible vessel, and evidence of recent bleeding . Two clips were applied, and a biopsy of the lesion showed ulcer slough only. Tumour markers and IgG4 levels were normal. An MRI pancreas showed no definite pancreatic mass, features of chronic pancreatitis and irregular bile ducts. HPB MDT consensus was to proceed for EUS, which confirmed a hypoechoic, vascular, 3cm mass lesion in D1-D2. Biopsies again, showed ulcer slough. A PET CT scan showed avidity in the second part of the duodenum and pancreatic head, neck and distal body. The patient presented to the surgical emergency unit twice during this time with symptoms of anaemia requiring IV iron and blood transfusions, and with early signs of obstruction, which settled with conservative management. Interval MRI showed increase in size of the duodenal mass, and stable appearance of the lesion in the head of the pancreas. Eventually, semi-emergency total pancreaticoduodenectomy and splenectomy was undertaken. Results Intraoperatively, a large D2 tumour was found extending into the pancreatic head posteriorly, compressing but not infiltrating the IVC. The rest of the pancreas was hard in consistency and nodular. Soft lymph nodes were found at the aorto-caval, common hepatic and around the SMA. There was no obvious intra-abdominal metastasis. The final histopathology showed a malignant, biphasic tumour favouring pancreatic carcinosarcoma staged pT3 N0 (0/29) L1 V1 R1 (posterior and SMV). On molecular cytogenetic analysis there was no evidence of rearrangement associated with synovial sarcoma in the cells examined. He recovered well post operatively and has commenced adjuvant chemotherapy of modified Folfirinox. Conclusions Pancreatic carcinosarcoma is a rare entity, which due to its unusual presentation, can be challenging to manage. Prompt MDT discussion is instrumental in such cases. The assessment of different radiological modalities, showing progressive increase in the size of the lesion within a short time period, raised the suspicion of an aggressive mitotic lesion, with the repeat biopsies unlikely to yield diagnosis in an otherwise operable lesion. Ultimately, the patient underwent a semi-emergency, total pancreaticoduodenectomy and splenectomy due to ongoing bleeding and the rapidly growing tumour size. In this case, surgery followed by adjuvant chemotherapy has been adopted as the optimum management strategy, for both bleeding control, and oncological benefit.

Background Since the first documented use of a robot for surgery in 1985, there has been a rapid global adoption of this technology. Hepatobiliary and pancreatic (HPB) surgery centres worldwide are increasingly sharing their robotic experiences, testing its potential to become a new standard for surgery. We are among the small number of known robotic HPB programs in the UK and here describe our stepwise implementation and share our learning curve. Methods We performed a retrospective review of our prospective database of robotic HPB surgeries carried out by two surgeons from the start of the program in September 2021 up to May 2022. Metrics analysed included surgery console times and 30-day patient perioperative outcomes. Results are shown as mean +/- std unless stated otherwise. Results There were 53 cases performed in 8 months. For all cases mean patient age was 58 years (range 26–82 years), BMI was 27.3 ± 4.3 Kg/m2 and docking time was 3.20 ± 0.97 minutes. There were 2 defined performance phases; early practice which included the following cases - marsupialisation of liver cysts (n = 7), cholecystectomies (n = 22) and radical cholecystectomies (n = 5). Intermediate practice followed when no decrease in console time was observed, and patients’ safety was maintained, and cases included liver wedge resections (n = 9) and distal pancreatectomies (n = 10). Mean console time for marsupialisation of liver cysts was 39 ± 0.01 minutes, cholecystectomies 44 ± 0.01 minutes, radical cholecystectomies 109 ± 0.01 minutes, liver wedge resections 87 ± 0.04 minutes and distal pancreatectomies 153 ± 0.03 minutes. Length of stay for distal pancreatectomies was 6.8 ± 2.2 days and liver wedge resections 2.3 ± 1.1 days. There was 1 conversion to open, 1 reoperation and 3 readmissions. There were 9 postoperative complications Clavien-Dindo grade I (n=1), grade II (n=5), grade IIIa (n= 2) and grade IIIb (n= 1). The rate of pancreatic fistula (International Study Group of Pancreatic Fistula classification grade B) was 3% (n=3), there were no 30-day mortalities. Conclusions Our outcomes show acceptable safety metrics during the implementation our HPB robotic program. Only after evaluating our learning curve and patients’ outcomes in each performance phase do we progress to the next phase, which for our program is the complex phase and includes pancreaticoduodenectomy and more complex liver resections.

Background The telemedicine clinic in general surgery has become widespread since the onset of the COVID-19 pandemic and has remained so following relaxation of restrictions on conventional face-to-face appointments. However, there has been significant scepticism regarding its continued utility. In particular, there is a concern that patients cannot be adequately assessed and counselled for invasive procedures, which may result in high cancellation rates on the day of procedure. The aim of this study was to assess the cancellation rate on the day of surgery for procedures booked in telemedicine clinics. Methods We conducted a retrospective analysis of surgical procedures booked via hepatopancreatobiliary (HPB) and general surgery telemedicine clinics from March 2020 to November 2021. From September 2020 onwards, telemedicine clinics were only run for laparoscopic cholecystectomies for benign gallbladder disease. The primary outcome was the cancellation rate of surgical cases booked from telemedicine clinics. Statistical analysis was done using JASP 0.16.2 software. Results We identified 240 cases booked for surgery from telemedicine clinic. 162 patients (68%) were female; the median age of the study population was 51 (16–81). 186 (78%) patients had gallstones, 19 (8%) gallbladder polyps, 13 (5%) secondary liver tumour, 5 (2%) liver cyst, 5 (2%) pancreatic tumour, 4 (1.7%) primary liver tumour, 2 (0.8%) gallbladder tumour and 6 (2.5%) other pathologies. 225 patients (94%) underwent surgery on their first admission. Procedures included 192 cholecystectomies, 10 open segmental liver resections, 6 laparoscopic segmental liver resections, 4 distal pancreatectomies, 3 open right hepatectomies, 2 Whipple procedures, 2 laparoscopic deroofing of the liver cyst, 2 laparoscopic lymph node biopsy, 1 extended right hepatectomy, 1 left hepatectomy, 1 small bowel resection and 1 exploratory laparotomy. 15 (6%) patients had surgery cancelled on the day of surgery, 14 of those were for laparoscopic cholecystectomy, 1 for laparoscopic liver resection. Only one such cancellation was deemed avoidable as it may have been prevented by a face-to-face assessment. The majority 212 (88%) of patients were ASA class 1–2; only 28 (12%) were ASA class 3. There was no significant association between high ASA (3) and cancellation rate (Chi square test 5% vs 14% p=0.062). Conclusions Telemedicine clinic in general surgery was often the only option to assess and plan operative management for newly referred patients during the COVID-19 pandemic. Our series showed that it was feasible to assess and counsel patients on the phone even for major HPB procedures with a minimal cancellation rate on the day of operation.

Background Intraductal papillary neoplasm of the bile duct (IPNB) represents a cohort of uncommon biliary tract tumours. It is commonly unrecognised or misdiagnosed in cross sectional imaging of the liver. This rare tumour is of significant clinical importance as it serves as a pre-cursor lesion for Cholangiocarcinoma. The diagnostic work up of a patient with a suspected IPNB remains predominantly based on imaging and as of yet no consensus has been achieved regarding the optimal diagnostic algorithm. The aim of this study was to compare the radiological and clinico-pathological features of patients with confirmed or suspected IPNB managed in a single tertiary center. Methods Retrospective review of a departmental database of consecutive patients with suspected IPNB was performed. Clinical information regarding patient demographics, disease presentation, radiological imaging characteristics and histo-pathological features was analysed. Results Eighteen patients with suspected IPNB were noted, of which histological confirmation was present in eight cases (62%). The most frequent presentation of IPNB was of an incidental finding (50%). The diagnosis of IPNB was made following MRI in 63% of cases. Invasive adenocarcinoma was present in five patients (63%). In the remaining three patients, low grade dysplasia was noted within their IPNB tumours. Conclusions IPNB is frequently associated with concurrent invasive malignancy. Observation alone is insufficient. Radiological assessment of these tumours remains as the fundamental investigation for diagnosis. However, without confirmatory histology perioperatively, the diagnosis cannot be assured therefore the decision for management must be based upon a patient-centered discussion and a careful evaluation of risk.

Background Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, we tested whether radiotherapy-induced tumour growth delay could be enhanced with anti-PD-L1. Methods Hypofractionated radiotherapy was delivered to TRAMP-C1 and MyC-CaP flank allografts. Tumour growth delay, tumour immune microenvironment flow-cytometry, and immune gene expression were analysed. TRAMP-C1 allografts were then treated with 3 × 5 Gy ± anti-PD-L1. Results 3 × 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post-3 × 5 Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 × 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Conclusion 3 × 5 Gy hypofractionated radiotherapy can result in tumour growth delay and immune cell changes in allograft prostate cancer models. Adjuncts beyond immunomodulation may be necessary to improve the radiotherapy-induced anti-tumour response.

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.

Background Hilar cholangiocarcinoma is an aggressive cancer with poor prognosis. Complex pre-operative workup is required prior to major surgery that frequently involves an extended hepatectomy with biliary reconstruction and is associated with high levels of post-operative morbidity and mortality. Tools to predict overall and disease-specific outcome are required to better tailor pre-habilitation interventions and selection of patients for surgery. Here we investigate whether body morphometrics are associated with disease-free and overall survival. Methods Consecutive patients undergoing resection of hilar cholangiocarcinoma were identified within a prospectively maintained database in a single institution. The CoreSlicer web-based app was used to calculate body morphometrics at the L3 vertebral level (muscle, visceral and subcutaneous fat areas) from portal-phase CT images. Median cut-offs defined patient groups and height-normalised morphometric values were compared at diagnostic and subsequent pre-operative imaging. Multivariate analysis was used to identify relationships between body morphometrics at time of diagnosis, changes in body morphometrics in the pre-operative period and outcome. Results Body morphometrics were assessed in 88 patients at the time of diagnosis. Of these patients, 53 underwent re-staging enabling an assessment of change in body morphometrics during the pre-operative period. Men displayed significantly higher muscle area, visceral fat and lower subcutaneous fat than women. High visceral fat area at diagnosis was an independent predictor of reduced overall survival (HR 1.81, 95% CI 1.1-3.3, P = 0.03), whilst loss of skeletal muscle area during the pre-operative period was an independent predictor of reduced disease-free survival (HR 2.90, 95% CI 1.0-8.8, P = 0.05). Patients with higher visceral fat at diagnosis also appear at increased risk of post-hepatectomy liver failure (PHLF) and experience significantly higher 30-day mortality than those without elevated visceral fat. Conclusions The presented results identify potential value in assessing body morphometrics as a prognostic tool in patients undergoing surgery for hilar cholangiocarcinoma. External validation of these findings in larger patient cohorts will help to determine whether this can be utilised to guide pre-habilitation interventions and appropriately select patients for surgery.

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.

Despite the recent advances in perioperative care and operative technique, pancreatic surgery remains burdened with significant post-operative morbidity. Whilst most post-operative complications are driven by pancreatic fistula formation, there is a spectrum of other less-common complications that can occur. These complications are life threatening and can be associated with a prolonged hospital stay. They can range from vascular complications to bilioenteric anastomotic leak and abdominal wall failure. This chapter serves as a review of the pre-existing literature and includes the authors’ own personal experiences with managing uncommon complications following pancreatic surgery. A low threshold is required for intervention and failure to rescue is detrimental to patient outcome. Successful management is best achieved through a multi-disciplinary team approach.

Cholangiocarcinoma (CCA) are a heterogeneous group of tumors in terms of aetiology, natural history, morphological subtypes, molecular alterations and management, but all sharing complex diagnosis, management, and poor prognosis. Several mutated genes and epigenetic changes have been detected in CCA, with the potential to identify diagnostic and prognostic biomarkers and therapeutic targets. Accessing tumoral components and genetic material is therefore crucial for the diagnosis, management and selection of targeted therapies; but sampling tumor tissue, when possible, is often risky and difficult to be repeated at different time points. Liquid biopsy (LB) represents a way to overcome these issues and comprises a diverse group of methodologies centering around detection of tumor biomarkers from fluid samples. Compared to the traditional tissue sampling methods LB is less invasive and can be serially repeated, allowing a real-time monitoring of the tumor genetic profile or the response to therapy. In this review, we analysis the current evidence on the possible roles of LB (circulating DNA, circulating RNA, exosomes, cytokines) in the diagnosis and management of patients affected by CCA.

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.

This meta-analysis aims to identify the diagnostic accuracy of mutations in the Kirsten Rat Sarcoma (KRAS) oncogene in the diagnosis of pancreatic ductal adenocarcinoma (PDAC). The survival of PDAC remains poor often due to the fact that disease is advanced at diagnosis. We analysed 22 studies, with a total of 2156 patients, to identify if the detection of KRAS mutations from pancreatic exocrine secretions yields sufficient specificity and sensitivity to detect patients with PDAC amongst healthy individuals. The majority of the studies were retrospective, samples were obtained endoscopically or surgically, and included comparator populations of patients with chronic pancreatitis and pre-malignant pancreatic lesions (PanIN) as well as healthy controls. We performed several analyses to identify the diagnostic accuracy for PDAC among these patient populations. Our results highlighted that the diagnostic accuracy of KRAS mutation for PDAC was of variable sensitivity and specificity when compared with PanINs and chronic pancreatitis, but had a higher specificity among healthy individuals. The sensitivity of this test must be improved to prevent missing early PDAC or PanINs. This could be achieved with rigorous prospective cohort studies, in which high-risk patients with normal cross-sectional imaging undergo surveillance following KRAS mutation testing.

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 =

Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell–cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease. NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.

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.

Myeloid cells are known to mediate metastatic progression. Here, we attempted to elucidate the mechanisms underlying these effects by identifying gene expression alterations in cancer cells forming hepatic metastases after myeloid cell depletion. Hepatic metastases are heavily infiltrated by CD11b+ myeloid cells. We established hepatic metastases in transgenic CD11b-diphtheria toxin receptor mice by intrasplenic injection of MC38 colon and Lewis lung carcinoma cells before depleting myeloid cells with diphtheria toxin. Myeloid cell depletion inhibited metastatic growth with a marked diminishment of tumor vasculature. Expression of ANGPTL7 (angiopoietin-like 7), a protein not previously linked to metastasis, was highly up-regulated in cancer cells after myeloid cell depletion. This effect was duplicated in tissue culture, where coculture of cancer cells with tumor-conditioned myeloid cells from liver metastases or myeloid cell conditioned media down-regulated ANGPTL7 expression. Analogous to myeloid cell depletion, overexpression of ANGPTL7 in cancer cells significantly reduced hepatic metastasis formation and angiogenesis. We found that ANGPTL7 itself has strong antiangiogenic effects in vitro. Furthermore, analysis of The Cancer Genome Atlas colorectal and breast cancer data sets revealed striking ANGPTL7 underexpression in cancerous compared to normal tissues. Also, ANGPTL7 was down-regulated in metastatic liver colonies of colorectal cancer patients compared to their adjacent liver tissue. Conclusion: Myeloid cells promote liver metastasis by down-regulating ANGPTL7 expression in cancer cells; our findings implicate ANGPTL7 as a mediator of metastatic progression and a potential target for interference with liver metastases. (Hepatology 2015;62:521–533

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment., Macrophages contribute to tumour progression and response to therapy. Here, the authors show that absence of FGF2 in the tumour microenvironment reduces tumour growth and enhances the anti-tumour immune response by altering macrophage polarization. As a result, disruption of this macrophage programming by anti-FGF2 blocking antibodies enhances the outcome from radiotherapy.

The main pancreatic duct can become dilated in a number of conditions. We describe a patient with gross dilatation of the main pancreatic duct without evidence of causative underlying pathology suggesting congenital dilatation of the pancreatic duct. A 36-year-old man presented with signs of intestinal obstruction and a history of surgery for congenital pyloric stenosis. Incidental findings on CT showed a massively dilated main pancreatic duct. On MRI there was no duct irregularity or solid mural nodule, making a main duct intraductal papillary mucinous neoplasm unlikely. Endoscopic ultrasound findings were in keeping with those on MRI. Fine needle aspiration revealed a non-viscous fluid with a low carcinoembryonic antigen and high amylase concentration, consistent with normal pancreatic fluid levels rather than a mucinous collection. After 1 year, the cyst remains unchanged. This patient will be kept under surveillance with yearly MRI.

Introduction Litigation for bile duct injury (BDI) following laparoscopic cholecystectomy (LC) places financial strain on the health service, causes significant patient morbidity and adversely affects both the patient and the surgeon. Claimants argue that the injury itself is evidence of negligence. Methods A questionnaire addressing the views on BDI causation was sent to 273 members of the AUGIS working in the National Health Service, UK. A grounded theory was used. Response themes and responses were compared between groups of surgeons. Results Of 117 respondents, 45 % experienced BDI and 22% had medicolegal experience. 47% of respondents identified factors outside the surgeons control as being relevant to BDI. Those that had experienced BDI from their own surgery were less likely to identify surgeon/systems errors as the primary cause for BDI than those that had not (34% vs 74% p Conclusions A significant number of experienced surgeons indicated that BDI following LC should not be assumed to result from surgeon negligence or institutional failure. This suggests that negligence should not be inferred from the act of BDI alone.

(1) Background: Hereditary Pancreatitis is a rare cause of acute pancreatitis. These patients usually present at a young age with recurrent episodes of acute pancreatitis that usually progresses to chronic pancreatitis with associated endocrine and exocrine failure. Hereditary pancreatitis also carries an increased lifetime risk of pancreatic adenocarcinoma. These high risk patients need early intervention where appropriate by specialist multidisciplinary teams and tailored long term management. (2) Methods: A review of the relevant literature regarding the epidemiology , the genetic mechanisms responsible for the disease and current management strategies for Hereditary Pancreatitis was performed. (3) Results: Several underlying genetic driver mutations for Hereditary Pancreatitis have been identified, notably PRSS1, SPINK1, CFTR and CRTC mutations. Recurrent episodes of pancreatitis result in a progressive loss of normal pancreatic parenchyma, which is eventually replaced with non-functioning fibrosis. High rates of diabetes and exocrine insufficiency is observed in this cohort of patients. The cumulative yearly risk of developing pancreatic cancer in patients with hereditary pancreatitis is significantly higher than the general population. Current indications for genetic testing for hereditary pancreatitis is based on low levels of evidence. Total pancreatectomy and auto islet transplantation is a definitive management strategy for hereditary pancreatitis. Early intervention may serve as an opportunity to improve islet cell yield, successful engraftment and long term endocrine function. (4) Conclusions: Hereditary Pancreatitis is associated with a significant morbidity, risk of chronic pancreatitis and pancreatic cancer. Through combining early diagnosis and intervention with a greater understanding of not only of the genetic mutation the individual carries but their own personal risk of disease progression, allows for a personalised treatment strategy for these patients.

Background: Acute acalculous cholecystitis (AAC) accounts for 5-10% of cases of acute cholecystitis. The advantage of interval cholecystectomy for patients with AAC is unclear. Therefore, a retrospective analysis of patients diagnosed with AAC at our institution was performed over a 5-year period. Methods: Patients were identified via hospital coding using the keywords “acalculous cholecystitis, cholecystostomy and gall bladder perforation.” Follow-up data was obtained by performing a retrospective review of the patients' hospital records. Results: A total of 33 patients with AAC were identified and followed for a median period of 18 months. The median age at presentation was 70 (10-96) and American Society of Anesthesiologists (ASA) grade was 3 (1-5). Twenty-three patients (70%) were treated with antibiotics alone, 7 patients (21%) with percutaneous cholecystostomy and 3 patients (9%) with laparoscopic cholecystectomy. The 90-day mortality rate was 30% with significant correlation to comorbid status, as all deaths occurred in ASA grade 3-5 individuals (p = 0.020). Two patients (6%) developed recurrent AAC and were managed non-operatively. Conclusion: Antibiotics and cholecystostomy were the mainstay of AAC management, and comorbid status influenced related mortality. Our results suggest that it appears safe to avoid interval cholecystectomy in patients who recover from AAC, as they are typically high-risk surgical candidates.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Despite improvements in the clinical management, the prognosis of PDAC remains dismal. In the present comprehensive review, we will examine the knowledge of PDAC genetics and the new insights into human genome sequencing and clonal evolution. Additionally, the biology and the role of the stroma in tumour progression and response to treatment will be presented. Furthermore, we will describe the evidence on tumour chemoresistance and radioresistance and will provide an overview on the recent advances in PDAC metabolism and circulating tumour cells. Next, we will explore the characteristics and merits of the different mouse models of PDAC. The inflammatory milieu and the immunosuppressive microenvironment mediate tumour initiation and treatment failure. Hence, we will also review the inflammatory and immune escaping mechanisms and the new immunotherapies tested in PDAC. A better understanding of the different mechanisms of tumour formation and progression will help us to identify the best targets for testing in future clinical studies of PDAC.

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.

Emerging pre-clinical data suggests that radiation both stimulates and suppresses tumor immunity. The role of tumor associated macrophages (TAMs) has been extensively investigated in the non-irradiated tumor microenvironment. We aimed to investigate the role of macrophages in the immune response to radiation. Single dose 10Gy irradiation to tumors generated from colorectal (MC38) and pancreatic (KPC) cell lines induced Colony Stimulating Factor (CSF-1). Coincident with the elevation in CSF1, significant increases of CD11b+ F480+ macrophages within the tumor microenvironment peaked five days following irradiation returning to baseline during tumor regrowth. These TAMs were skewed toward an immunosuppressive phenotpye (CD206hi iNOSlo) compared to those from controls. Furthermore, the TAMs from irradiated tumors were more effective in suppression of CD8 T cell expansion in ex vivo assays. As a result of these data, we investigated the effect of anti-Colony Stimulating Factor (αCSF-1), which reduced macrophages in both control and irradiated tumors. αCSF had no effect on the growth of control tumors, yet led to a significant enhancement of tumor growth delay after radiation. TAMs sorted from irradiated tumors after aCSF treatment had reduced inflammatory gene expression and increased expression of some genes associated with immune suppression (Arg-1, IL-10, CCL2). Following aCSF, there was a significant increase in CD8 T lymphocytes with greater expression of cytotoxic markers. Radiation is also immune-stimulatory to tumors consistent with enhanced recognition of tumor cell antigens by T cells isolated from irradiated tumors. CD8 depletion however abrogated the growth delay from aCSF further documenting the immunosuppressive effect of the macrophages within irradiated tumors. aCSF1 was given to mice bearing two tumors, one of which was irradiated. An increased growth delay was only observed in the irradiated tumours. These data document the immunosuppressive nature of macrophages generated in irradiated tumors. TAMs expressed high levels of PD-L1 and aCSF treatment resulted in a reduction in tumor PD-L1. As a result we determined the effect of checkpoint inhibition using anti-PD-L1 in combination with aCSF following 10Gy irradiation. Whilst combination treatment did not augment outcomes in mice bearing MC38 tumors, there was complete tumor regression in a minority of mice bearing KPC tumors. These results suggest that infiltrating macrophages limit the adaptive immune response initiated following of radiation. Whilst it has been demonstrated that tumor cell PD-L1 expression plays an important role in checkpoint blockade, our data suggests macrophages are an important additional source. This is of particular importance in the context of radiation which can elicit a potent immune response but in which the TAMs from irradiated tumors also suppress this in part via altered PD-L1 expression. Citation Format: Keaton I. Jones, Jiske Tiersma, Jon Buzzelli, Alex Gordon-Weeks, Arseniy Yuzhalin, Jaehong Im, Ruth J. Muschel. Radiation-induced immunosuppressive macrophages limit CD8 T-cell mediated tumor killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 998.

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.

INTRODUCTION Use of the Consolidated Standards of Reporting Trials (CONSORT) statement has been shown to improve the reporting of randomised controlled trials and it is endorsed by leading surgical journals. The CONSORT statement for non-pharmacological treatment (CONSORT-NPT) provides specific items to aid in the reporting of trials of operative intervention. This study compares the reporting practice of trials of operative intervention published in time periods before and after publication of the CONSORT-NPT statement. METHODS A 30-point checklist containing the salient CONSORT-NPT items was designed and the adherence of trials meeting the inclusion criteria determined independently by two authors. RESULTS There was a significant improvement of 3.95 points in the mean CONSORT-NPT score from 2004 to 2010 (95% confidence interval: 3.61–4.29, p

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.

Tumor-infiltrating immune cells play important roles in metastasis. We have recently revealed the recruitment of a specific myeloid cell subset (CD11b/Gr1(mid)) to hepatic metastases. Such a recruitment relies on CCL2/CCR2 signaling and acts to sustain metastatic growth. A similar cell subset was identified in patients bearing hepatic metastases of colorectal cancer, highlighting the potential therapeutic relevance of our findings.

INTRODUCTION: Use of the Consolidated Standards of Reporting Trials (CONSORT) statement has been shown to improve the reporting of randomised controlled trials and it is endorsed by leading surgical journals. The CONSORT statement for non-pharmacological treatment (CONSORT-NPT) provides specific items to aid in the reporting of trials of operative intervention. This study compares the reporting practice of trials of operative intervention published in time periods before and after publication of the CONSORT-NPT statement. METHODS: A 30-point checklist containing the salient CONSORT-NPT items was designed and the adherence of trials meeting the inclusion criteria determined independently by two authors. RESULTS: There was a significant improvement of 3.95 points in the mean CONSORT-NPT score from 2004 to 2010 (95% confidence interval: 3.61-4.29, p

Background The aim of this systematic review was to assess the evidence on tumour downstaging before liver transplantation in patients with hepatocellular carcinoma (HCC) initially staged beyond the Milan criteria. Methods MEDLINE (from 1952), Embase (from 1980) and the Cochrane Library were searched. The review included cohort studies that reported the outcomes of patients with HCC outside the Milan criteria who underwent downstaging before transplantation. Results Eight studies met the inclusion criteria and included a total of 720 patients who underwent transplantation following downstaging after initial presentation with disease outside the Milan criteria. The rate of successful downstaging varied from 24 to 69 per cent of patients. Reported survival rates ranged from 82 to 100 per cent, 79 to 100 per cent and 54·6 to 94 per cent at 1, 3 and 5 years respectively. These were comparable with results for patients presenting within the Milan criteria. Conclusion Successful downstaging of HCC to within the Milan criteria is feasible in a proportion of patients. Absolute and disease-free survival rates in patients transplanted following downstaging are comparable to those in patients within the Milan criteria.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine whether pentoxifylline provides any benefit to patients with CLI in terms of disease progression or symptom improvement.

In a previous investigation reduced apoptosis was identified in normal breast tissue from cancer-containing breasts away from the cancer in comparison to age-matched normal breast from women without cancer. The hypothesis for this study was that defects in expression of apoptotic regulatory and DNA repair proteins would facilitate persistence of genetic alterations and predispose to breast cancer development. Using immunohistochemistry normal breast from 120 age-matched women (58 with breast cancer, 62 without) was analysed for proliferation, apoptosis, bcl2, BAX, caspase 3, Hsp27, Hsp70, BRCA1, ATM and BARD1. All assessments were performed without knowledge as to whether it was a cancer case or control. A significant difference was found for apoptotic index which was higher in controls (P < 0.02). There was no change in apoptotic and proliferation index with age for cancer cases unlike controls. Higher expression of bcl2 (P = 0.001) and Hsp27 (P = 0.001) was found in normal breast from cancer-containing breast in comparison to controls. There were no differences in the other proteins. Apoptosis has been found to be reduced in normal breast in a separate cohort of women with breast cancer, along with increased expression of the anti-apoptotic proteins bcl2 and Hsp27. These alterations in apoptotic regulation would enhance tumour development. Further studies are needed to examine the value of these proteins as risk markers.

Host immune cells in the tumor microenvironment play a vital role in tumor development and metastasis. We previously reported that accumulation of CD11b+ Gr1mid- and Gr1low-expressing myeloid cells is important for metastatic progression and growth in a mouse model of liver metastasis. However, little is known about the mechanisms whereby these cells support metastatic development. To characterize the molecular mechanisms by which CD11b+ Gr1mid and Gr1low cells contribute to liver metastasis, MC38 tumor cells were isolated after CD11b+ cell depletion and analyzed using whole-genome expression profiling. CD11b+ Gr1mid- and Gr1low cells accumulate in liver metastases generated by splenic injection of MC38 colon carcinoma and Lewis lung carcinoma cells. The Gr1mid population is recruited to liver metastases where they differentiated into Gr1low cells. This differentiation is stimulated by tumor cells in tissue culture. CD11b+ cells were depleted by DT administration in CD11b-DTR mice, resulting in markedly smaller metastases, decreased proliferation of the tumor cells and greatly reduced metastasis-associated blood vessels. However, depletion had only a negligible effect on tumor cell apoptosis and necrosis. CD11b+ Gr1mid and Gr1low cells enhanced MC38 and LLC tumor cell proliferation, migration and invasion in in vitro co-culture systems. These responses were dependent on ERK1/2 activation and its inhibition in tumor cells minimized the pro-tumorigenic effects of Gr1mid and Gr1low cells. Stimulation of ERK1/2 by Gr1mid and Gr1low cells may explain why depletion of CD11b+ cells diminished proliferation of liver metastases in the murine model. Gene expression analysis of MC38 cells in liver metastases after CD11b+ cell depletion revealed upregulation of ANGPTL7, an angiopoietin-like protein. To test the functional significance of this upregulation, we overexpressed ANGPTL7 in MC38 tumor cells. Overexpression of ANGPTL7 resulted in a striking reduction in tumor burden and tumor-associated vessels. Our findings show that CD11b+ Gr1mid and Gr1low myeloid cells augment proliferation and the migratory and invasive potential of tumor cells in liver metastases by stimulating ERK1/2 signaling. They further suggest that these myeloid cells mediate angiogenesis through upregulation of ANGPTL7 in tumor cells. These studies reinforce the importance of host myeloid cells in sustaining liver metastasis and identify potential targets for therapeutic manipulation. Citation Format: Su Yin Lim, Alex Gordon-Weeks, Lei Zhao, Veerle Kersemans, Danny Allen, Sean Smart, Ruth J. Muschel. Accumulation of CD11b+ Gr1 myeloid cells in liver metastases stimulates tumor growth and angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1087. doi:10.1158/1538-7445.AM2014-1087

Metastatic colorectal cancer (CRC) is one of the most prominent causes of cancer-related mortality. However, therapeutic options for patients with metastatic CRC are limited and development of new and more effective therapeutics aimed at downstaging the disease and prolonging survival is urgently required. Primary tumor dissemination to secondary sites, predominantly the liver, is a dynamic process dependent on the interactions between tumor cells and the host tissue microenvironment. Immune cells in the tumor microenvironment have been shown to play pivotal roles in the metastatic process but their pro-metastatic functions in CRC liver metastasis remains incompletely understood. To simulate liver metastasis, MC38 colon carcinoma cells were injected into the spleen of C57BL/6 mice. A population of CD11b/Gr1mid cells, distinct from other metastasis-associated myeloid cells previously described, increased dramatically during establishment of liver metastases. Adoptive transfer of bone marrow cells confirmed that these CD11b/Gr1mid cells were derived from bone marrow progenitor cells. MC38 tumor cells expressed high levels of CCL2 and serum levels were elevated in tumor-bearing mice compared to controls. Inhibition of tumor-derived CCL2 using shRNA, and absence of its cognate receptor in CCR2 KO mice significantly diminished CD11b/Gr1mid cell infiltration into tumor-bearing livers. Importantly, inhibition of CD11b/Gr1mid cell recruitment led to a marked reduction in tumor burden. Moreover, when CD11b/Gr1mid cells were depleted in a transgenic CD11b-DTR mouse model, a striking decrease in tumor vessel density was observed, with a concomitant reduction in tumor cell proliferation. Serum CCL2 concentrations were similarly elevated in CRC patients, including those who present metastasis, compared to normal controls. Furthermore, CD11b/CCR2 myeloid cells, analogous to the CD11b/Gr1mid population described in our mouse model, were identified in liver metastases of several CRC patients. Together, our studies demonstrate the importance of a distinct CD11b/Gr1mid myeloid subset in sustaining CRC liver metastasis and implicate a CCL2/CCR2-dependent pathway in their recruitment to metastatic sites. Our findings reinforce how tumor cells utilize host systems for successful propagation and identify a potential target for therapeutic manipulation. Citation Format: Su Yin Lim, Lei Zhao, Alex Gordon-Weeks, Thomas Tapmeier, Ruth Muschel. Tumor-derived CCL2 promotes recruitment of CD11b/Gr1mid myeloid cells to sustain colorectal cancer liver metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2871. doi:10.1158/1538-7445.AM2013-2871