Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors.

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab

Laparostomy: A review of current practice

Laparostomy is the process by which the abdomen is left open. There are multiple indications which include gross sepsis and abdominal compartment syndrome. In these cases, closure of the abdomen would be detrimental. This is due to the cascade of events secondary to sepsis or critical pressure. The creation of laparostomy has obvious impact on hospital resources secondary to prolonged intensive therapy. At present there are different methods available of abdominal closure in laparostomy. These can be broadly classified into definitive or temporary. Laparostomy is certainly here to stay: this article tries to grapple with the problems of exactly when it is indicated and how to manage the open abdomen

Transversus abdominis plane (TAP) blocks-a review.

INTRODUCTION: Effective post-operative pain management can positively influence patient outcome. Multimodal analgesic regimes are often limited by side-effects. Epidural analgesia may be resource-consuming, restrict mobility and have negative cardiovascular and gastrointestinal consequences. Consequently, there is a need for regional anaesthetic techniques to minimise opioid use, and provide alternatives to epidurals, especially within the context of minimally invasive abdominal surgery and enhanced recovery programmes. This review aims to evaluate the evidence base underlying Transversus abdominis plane (TAP) blockade. METHODS: A literature search was performed using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) using the parameters 'transversus abdominis plane' and 'TAP'. The references within were then searched for applicable studies. Case reports and correspondence were excluded. FINDINGS: Thirteen studies assessed technique and mechanisms of action. Fourteen clinical studies involved a total of 1250 patients. Seven studies (6 Randomised Controlled Trials, RCTs) demonstrated reductions in post-operative morphine requirements (33.3%-73.1%). Five RCTs demonstrated concomitant improvements in pain scores. Five RCTs demonstrated reduced opioid side effects. The one study assessing functional outcome (a Prospective Controlled Trial, PCT) demonstrated earlier return of gastrointestinal function and hospital discharge. CONCLUSION: The limited evidence to date suggests that TAP blockade is an effective adjunct to multimodal post-operative analgesia following a range of abdominal surgical procedures. Whether TAP blocks are a viable alternative to epidural analgesia remains to be determined. However, it is likely that as this technique grows in popularity its role, particularly that in enhanced recovery programmes, will be better delineated and refined

Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel.

A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms

Vascular Surgery within General Surgery: An Analysis of Workload 1989–2005

INTRODUCTION: There is considerable debate as to whether vascular surgery should be a subspecialty separate from general surgery. This study examines the changing relationship between general and vascular surgery in a district general surgical unit over 16 years. PATIENTS AND METHODS: A detailed survey of referrals, admissions and operations to one unit was carried out over 3 months in 2003. This was compared with similar surveys in 1989, 1990 and 1995. In addition a 3-month audit of operations performed was carried out in 2005 following a decision by the Primary Care Trust (PCT) to reduce varicose vein referrals. RESULTS: There was a significant increase in the number of varicose vein and arterial referrals 1989-2003 (P = 0.0001 and P < 0.0001, respectively). This was reflected in increased number of vascular admissions (P < 0.0001). In 1989, 14% of the arterial cases were admitted as emergencies. This figure rose to 52% in 2003 (P < 0.0001). There was a significant increase in the number of arterial operations performed between 1989 and 1995; however, from 1995 to 2003 this number fell P < 0.0001). The number of varicose vein procedures increased significantly 1989-2003 (P < 0.0001), with a significant fall after the PCT decision (P < 0.0001). However, the number of operations carried out in 2005 increased slightly with the proportion of general surgical cases, mostly hernia repairs and laparoscopic cholecystectomies, increasing. CONCLUSIONS: With increasing specialisation comes the risk that reduction in any aspect of a particular specialty may result in that unit becoming unsustainable. In vascular surgery this will inevitably lead to centralisation of services. In a large district general hospital having two general surgeons with a vascular interest, the general surgical component has maintained the workload of the unit following reduction in varicose vein referrals

The economic impact of anastomotic leakage after anterior resections in English NHS hospitals: are we adequately remunerating them?

AIM: Our aim was to determine the frequency and economic impact of anastomotic leakage (AL) at local and national levels in England. METHOD: All patients who underwent AR in Oxford between 2007 and 2009 were evaluated for AL. Hospital Episode Statistics (HES) data were used to determine reoperation rates after elective AR (n = 23 388) in England between 2000 and 2008. Hospital episode remuneration costs were calculated by the local commissioning department and compared with Department of Health (DH) reference index costs. RESULTS: The frequency of AL following anterior resection was 10.9% (31 out of 285) in Oxford. Laparotomy for leakage was performed in 5.6% of cases. The 30-day hospital mortality rate for all ARs was 2.1%, compared with 3.2% after AL. The national relaparotomy rate (within 28 days) and 30-day hospital mortality in English National Health Service (NHS) trusts following AR were 5.9% and 2.9%, respectively. Institutional remunerated tariffs (£6233 (SD ± 965)) were similar to DH reference costs (£6319 (SD ± 1830)) after uncomplicated AR. However, there was a significant (P = 0.008) discrepancy between the remunerated tariff for AL (£9605 (SD ± 6908)) and the actual cost (£17 220 (SD ± 9642)). AL resulted in an additional annual cost of approximately £1.1 million to £3.5 million when extrapolated nationally. CONCLUSION: The estimated economic burden of anastomotic leakage following AR is approximately double that of the remunerated tariff

Detection of circulating tumour cells in peripheral blood with an automated scanning fluorescence microscope.

We have developed an automated, highly sensitive and specific method for identifying and enumerating circulating tumour cells (CTCs) in the blood. Blood samples from 10 prostate, 25 colorectal and 4 ovarian cancer patients were analysed. Eleven healthy donors and seven men with elevated serum prostate-specific antigen (PSA) levels but no evidence of malignancy served as controls. Spiking experiments with cancer cell lines were performed to estimate recovery yield. Isolation was performed either by density gradient centrifugation or by filtration, and the CTCs were labelled with monoclonal antibodies against cytokeratins 7/8 and either AUA1 (against EpCam) or anti-PSA. The slides were analysed with the Ikoniscope robotic fluorescence microscope imaging system. Spiking experiments showed that less than one epithelial cell per millilitre of blood could be detected, and that fluorescence in situ hybridisation (FISH) could identify chromosomal abnormalities in these cells. No positive cells were detected in the 11 healthy control samples. Circulating tumour cells were detected in 23 out of 25 colorectal, 10 out of 10 prostate and 4 out of 4 ovarian cancer patients. Five samples (three colorectal and two ovarian) were analysed by FISH for chromosomes 7 and 8 combined and all had significantly more than four dots per cell. We have demonstrated an Ikoniscope based relatively simple and rapid procedure for the clear-cut identification of CTCs. The method has considerable promise for screening, early detection of recurrence and evaluation of treatment response for a wide variety of carcinomas