Paul Sutton

Laparoscopic preperitoneal mesh repair using a novel self-adhesive mesh

Prosthetic mesh is now used routinely in inguinal hernia repairs, although its fixation is thought to be a potential cause of chronic groin pain. The Parietene ProGrip™ (TYCO Healthcare) mesh, which is semi-resorbable and incorporates self-fixing properties, has been shown to provide satisfactory repair in open surgery. We describe the use of this mesh in TAPP hernia repair, which has not previously been reported in the literature. A prospective study of 29 patients showed a mean operative time to be 47.6 min, with 96% of patients discharged home on the day of surgery or the day after. Visual analog pain scales (out of 10) reduced from 4 preoperatively to 0 at 6 months, and only 1 patient suffered a minor wound complication. The use of this mesh in transabdominal preperitoneal hernia repair is therefore feasible, safe, and may reduce postoperative pain.

Infected total knee arthroplasty due to postoperative wound contamination with Pasteurella multocida.

Pasteurella multocida is a small Gram-negative bacterium comprising part of the normal gastrointestinal and nasopharyngeal flora of domestic pets, such as dogs and cats. It rarely causes infection in humans. Previous reports of P multocida causing prosthetic joint infection have described either haematogenous spread of infection from a distant site through a scratch or bite, or reactivation of infection from a previous injury. We report a case of acute total knee arthroplasty joint infection becoming acutely infected by P multocida. We postulate that the mechanism of infection was direct contamination of the wound as a consequence of the patient being licked by his pet dog. We discuss the potential role played by thromboprophylaxis as a factor contributing to prolonged wound leak.

From mice to men: Murine models of colorectal cancer for use in translational research.

Colorectal cancer (CRC) is the third most common carcinoma worldwide and despite advances in treatment, survival for patients with metastatic disease remains poor. With nearly 50% of patients developing metastases, in vivo investigation is essential to improve outcomes for these patients and numerous murine models of CRC have been developed to allow the study of chemoprevention and chemotherapy, in addition to improving our understanding of the pathogenesis of CRC. Selecting the most appropriate murine model for a specific application will maximize the conversion of potential therapies from the laboratory to clinical practice and requires an understanding of the various models available. This review will provide an overview of the murine models currently used in CRC research, discussing the limitations and merits of each and their most relevant application. It is aimed at the developing researcher, acting as a guide to prompt further reading in planning a specific study.

The use of Gore Bio-A in the management of the open abdomen.

Non-permanent, non-woven options for the closure of an open abdomen have previously been limited to biologics such as Permacol or Strattice. Gore Bio-A is constructed from biocompatible synthetic fibres, the use of which has only been described in the repair of inguinal hernia, hiatal hernia and fistula-in-ano. A 60-year-old male underwent emergency laparotomy, partial gastrectomy and formation of a feeding jejunostomy for a strangulated and perforated intrathoracic hiatus hernia. His abdominal wall subsequently dehisced for which he underwent laparostomy and subsequent early closure with a Gore Bio-A mesh, secured in an onlay manner with 2/0 vicryl. Functional and cosmetic outcomes were satisfactory and the patient was discharged home. The use of Gore Bio-A is a safe, feasible and cost effective alternative to traditional biologics for the closure of a laparostomy, deployment of which is safe within a contaminated field. Further prospective data is needed to clarify its role.

Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer

Background:Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer.Methods:Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network.Results:We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54–4.98), P=0.001), N stage (HR 1.51 (1.01–2.26), P=0.04), curative intent surgery (HR 0.51 (0.34–0.76), P=0.001), tumour grade (HR 0.44 (0.30–0.65), P=0.001) and KRAS mutation (1.54 (1.23–2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27–2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15–4.25), P=0.01) and p.G12V (HR 1.69 (1.08–2.62), P=0.02) were predictive of overall survival.Conclusions:For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.

Proteomic profiling of rectal cancer reveals acid ceramidase is implicated in radiation response

BACKGROUND Neoadjuvant chemoradiotherapy (CRT) is used in locally advanced rectal cancer when tumours threaten the circumferential resection margin, with varying response to treatment. This experimental study aimed to identify significantly differentially expressed proteins between patients responding and not responding to CRT, and to validate any proteins of interest. METHODS Mass spectrometry (with isobaric tagging for relative quantification) analysis of rectal cancers pre- and post-CRT, and at resection. Validation of proteins of interest was performed by assessing tissue microarray (TMA) immunohistochemistry expression in a further 111 patients with rectal cancer. RESULTS Proteomic data are available via ProteomeXchange with identifier PXD008436. Reduced abundance of contributing peptide ions for acid ceramidase (AC) (log fold change -1.526, p = 1.17E-02) was observed in CRT responders. Differential expression of AC was confirmed upon analysis of the TMAs. Cancer site expression of AC in stromal cells from post-CRT resection specimens was observed to be relatively low in pathological complete response (p = 0.003), and relatively high with no response to CRT (p = 0.017). CONCLUSION AC may be implicated in the response of rectal cancer to CRT. We propose its further assessment as a novel potential biomarker and therapeutic target. SIGNIFICANCE There is a need for biomarkers to guide the use of chemoradiotherapy in rectal cancer, as none are in routine clinical use. We have determined acid ceramidase may have a role in radiation response, based on novel proteomic profiling and validation in a wider dataset using tissue microarrays. The ability to predict or improve response would positively select those patients who will derive benefit, prevent delays in the local and systemic management of disease in non-responders, and reduce morbidity associated with chemoradiotherapy.

Proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases

BACKGROUND Colorectal cancer is the fourth commonest cancer in the UK, and the second commonest cause of cancer-related death. A knowledge of the biological phenotype of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases. METHODS Fresh tissue from both primary colorectal tumour and liver metastases from 17 patients was subjected to proteomic analysis using isobaric tagging for relative quantification. Data were analysed with Protein Pilot (Ab Sciex, Framingham, MA, USA), with stratification of patients into those showing low or high response to chemotherapy permitting the identification of potential predictive biomarkers. These markers were subsequently validated by immunohistochemistry on a tissue microarray of 63 patients. FINDINGS We identified 5768 discrete proteins. Five of them predicted histopathological response to fluorouracil-based chemotherapy regimens, of which the FAD binding protein NQO1 was subsequently validated by immunohistochemistry. When compared with the chemotherapeutic agent alone, knockdown of the corresponding gene with small interfering RNA decreased cell viability when co-incubated with fluorouracil (77·1% vs 46·6%, p=0·037) and irinotecan (41·7% vs 24·4%, p=0·006). Similar results were also seen after inhibition of protein activity by pretreating cells with dicoumarol. INTERPRETATION These results show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible, with high protein coverage. The high degree of similarity between the primary and secondary proteomes suggests that primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in the liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity. FUNDING Cancer Research UK.

Targeting Heat Shock Proteins in Colorectal Cancer

Colorectal cancer (CRC) causes over half a million deaths worldwide and has a particularly poor prognosis when diagnosed at an advanced stage. Heat shock proteins (HSP) have been found to be elevated in CRC patients and HSPB1, HSPA1A and HSPC1 has been shown to have some prognostic value. CRC, in common with all cancers, has important associated oncogene and tumor suppressor gene associations and we show how many of these interact directly with one or more of the HSP. We discuss the current chemotherapeutic options available to the clinician when presented with CRC and how these may be improved with a consideration of the role of HSP in the development of the tumor as well as the response to therapy. Direct manipulation of HSP has the potential to decrease the therapeutic dose of anti-tumor drugs and we propose novel strategies that have the potential to be adapted to the clinic.

Refeeding syndrome: The danger of feeding a starving man

Refeeding syndrome is a potentially fatal clinical condition characterized by severe electrolyte and fluid shifts associated with metabolic abnormalities in severely malnourished or starved patients undergoing oral, enteral or parenteral refeeding. We here present a case of a 50-year-old Indian male with a background of depression and alcoholic liver disease presented with alleged ingestion of a detergent. He subsequently developed an oesophageal stricture resulting in severe malnutrition. He developed refeeding syndrome following commencement of TPN associated with clear biochemical alteration. This was immediately identified and rectified. This case report highlights the prevalence of refeeding syndrome in a typical hospital setting that can easily be overlooked and stresses the importance of early recognition as this is a preventable disorder.

Transarterial angioembolization versus surgery after failed endoscopic therapy for non-variceal upper gastrointestinal bleeding.

BACKGROUND AND OBJECTIVE To compare the outcome of transarterial angioembolization (TAE) and surgery with endoscopically unmanageable non-variceal hemorrhage of the upper gastrointestinal tract. MATERIALS AND METHODS A case note review of all patients treated for non-variceal upper gastrointestinal bleeding from January 2006 till January 2012 was performed. RESULTS Fifty-four of 667 patients with non-variceal bleeding did not respond to endoscopic treatment. Nine of the 54 patients had incomplete data, leaving 45 patients in the study; 24 had angiography and another 21 had surgery. The two groups were broadly similar in terms of relevant clinical variables. Nineteen of 24 having angiography had embolisation. Re-bleeding recurred in 8 patients (33%) in the TAE group and 6 patients (28.6%) in the surgery group (p = 0.28). There was no statistically significant difference in post procedural complications (81% vs 62.5%, p = 0.17), 30-day mortality (33% vs 29.1%, p = 0.17 ) units of blood transfused (12.24 vs 8.92, p = 0.177) and mean hospital stay (30.7 vs 22.9 days, p = 0.281) observed in patients undergoing surgery as compared to TAE. CONCLUSIONS TAE and surgery have similar outcomes in patients with endoscopically unmanageable non-variceal upper gastrointestinal haemorrhage.