Myoferlin: a potential marker of response to radiotherapy and survival in locally advanced rectal cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neo-adjuvant chemoradiotherapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiotherapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. MATERIALS AND METHODS: Immunohistochemical analysis of a tissue microarray for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using siRNA, a small molecular inhibitor (wj460) and a CRISPR-Cas9 knockout cell line. Radiosensitisation following treatment was assessed using 2D clonogenic assays, 3D spheroid models and patient derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumour resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant LCRT. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (p = 0.01, HR 3.5, 95%CI [1.27, 10.04]). This was externally validated using the S:CORT database. Quantification of myoferlin using immunoblotting in immortalised colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacological manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2D and 3D models. Following irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double strand breaks. This appeared to be mediated via non-homologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of rectal cancer patients to radiotherapy and further work is required.

Enhancing radiotherapy outcomes in rectal cancer: A systematic review of targeting hypoxia-induced radioresistance.

Introduction: Neoadjuvant radiotherapy is successfully used in rectal cancer to improve overall survival. However, treatment response is both unpredictable and variable. There is strong evidence to show that the phenomenon of tumour hypoxia is associated with radioresistance, however the mechanism(s) behind this are poorly understood. Consequently, there have only been a small number of studies evaluating methods targeting hypoxia-induced radioresistance. The purpose of this systematic review is to evaluate the potential effectiveness of targeting hypoxia-induced radioresistance in rectal cancer and provide recommendations for future research in this area. Methods: A comprehensive literature search was performed following the PRISMA guidelines. This study was registered on the Prospero database (CRD42023441983). Results: Eight articles met the inclusion criteria. All studies identified were in vitro or in vivo studies, there were no clinical trials. Of the 8 studies identified, 5 assessed the efficacy of drugs which directly or indirectly targeted hypoxia and three that identified potential targets. There was conflicting in vivo evidence for the use of metformin to overcome hypoxia induced radioresistance. Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance. Discussion: The importance of investigating hypoxia-induced radioresistance in rectal cancer is crucial. However, to date, only a small number of preclinical studies exist evaluating this phenomenon. This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.

Impact on blood loss and transfusion rates following administration of tranexamic acid in major oncological abdominal and pelvic surgery: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Major bleeding and receiving blood products in cancer surgery are associated with increased postoperative complications and worse outcomes. Tranexamic acid (TXA) reduces blood loss and improves outcomes in various surgical specialities. We performed a systematic review and meta-analysis to investigate TXA use on blood loss in elective abdominal and pelvic cancer surgery. METHODS: A literature search was performed for studies comparing intravenous TXA versus placebo/no TXA in patients undergoing major elective abdominal or pelvic cancer surgery. RESULTS: Twelve articles met the inclusion criteria, consisting of 723 patients who received TXA and 659 controls. Patients receiving TXA were less likely to receive a red blood cell (RBC) transfusion (p < 0.001, OR 0.4 95% CI [0.25, 0.63]) and experienced less blood loss (p < 0.001, MD -197.8 ml, 95% CI [-275.69, -119.84]). The TXA group experienced a smaller reduction in haemoglobin (p = 0.001, MD -0.45 mmol/L, 95% CI [-0.73, -0.18]). There was no difference in venous thromboembolism (VTE) rates (p = 0.95, OR 0.98, 95% CI [0.46, 2.08]). CONCLUSIONS: TXA use reduced blood loss and RBC transfusion requirements perioperatively, with no significant increased risk of VTE. However, further studies are required to assess its benefit for cancer surgery in some sub-specialities.

Reducing waiting lists for laparoscopic cholecystectomy: An intensive approach to aid COVID-19 recovery.

Background: Laparoscopic cholecystectomy is one of the most frequently performed operations in the United Kingdom, commonly due to symptomatic gallstones. Delay between diagnosis and definitive surgical intervention often leads to a significant readmission rate, growing financial burden and increased complexity of the ultimate surgical intervention. Resource reallocation and reduced operational capacity during the coronavirus disease 2019 (COVID-19) pandemic has led to an impending waiting list crisis. Methods: In an attempt to address the backlog of cases, five intensive dedicated operating lists were allocated for laparoscopic cholecystectomies across a weekend in October 2020 at a single Trust. Prospective data were collected to include baseline demographics, operative procedure, 30-day post-operative outcomes and financial implications. Results: A total of 21 cholecystectomies were performed in total, with a majority ASA 2 (American Society of Anaesthesiologists) for predominantly biliary colic indication. All were completed laparoscopically, with a 90.5% rate for complete resection. There were no reported on-table complications and 81.0% of patients discharged as a day case. Thirty day follow-up revealed a complication rate of 9.5%, with 2 patients requiring oral antibiotics for a superficial wound infection. The 30 day COVID-19 rate was 14.3%. Compared to completion on an average weekday list, the total weekend was estimated to have saved over £70,000 in overall costs. Conclusion: Our study showed that weekend focused operating, with a caveat of careful patient selection and high-quality multidisciplinary working, can be a feasible solution to long waiting lists due to COVID-19 pandemic. It was safe, with avoidance of increased burden on emergency resources, and significantly increased theatre efficiency.

Proton beam therapy in rectal cancer: A systematic review and meta-analysis.

INTRODUCTION: Locally advanced rectal cancer is often treated with neoadjuvant chemoradiotherapy and surgery. Radiotherapy carries significant risk of toxicity to organs at risk (OAR). Proton beam therapy (PBT) has demonstrated to be effective in other cancers, delivering equivalent dosimetric radiation but with the benefit of improved sparing of OAR. This review compares dosimetric irradiation of OAR and oncological outcomes for PBT versus conventional photon-based radiotherapy in locally advanced rectal cancer. METHODS: An electronic literature search was performed for studies with comparative cohorts receiving proton beam therapy and photon-based radiotherapy for rectal cancer. RESULTS: Eight articles with a total of 127 patients met the inclusion criteria. There was significantly less irradiated small bowel with PBT compared to three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) (MD -17.01, CI [-24.06, -9.96], p < 0.00001 and MD -6.96, CI [-12.99, -0.94], p = 0.02, respectively). Similar dosimetric results were observed for bladder and pelvic bone marrow. Three studies reported clinical and oncological results for PBT in recurrent rectal cancer with overall survival reported as 43 %, 68 % and 77.2 %, and one study in primary rectal cancer with 100 % disease free survival. CONCLUSION: PBT treatment plans revealed significantly less irradiation of OAR for rectal cancer compared to conventional photon-based radiotherapy. Trials for recurrent rectal cancer and PBT have shown promising results. There are currently no ongoing clinical trials for primary rectal cancer and PBT. More research is required to validate its potential role in dose escalation, higher complete response rate and organ preservation without increasing toxicity.

Management of benign anastomotic strictures following rectal resection: a systematic review.

AIM: Benign anastomotic strictures following colorectal surgical resection are a commonly under-reported complication in up to 30% of patients, with a significant impact upon quality of life. In this systematic review, we aim to assess the utility of endoscopic techniques in avoiding the need for surgical reintervention. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases. Additional papers were found by scanning the references of relevant papers. RESULTS: A total of 34 papers were included, focusing upon balloon dilatation, endoscopic stenting, electroincision, stapler stricturoplasty and cortiocosteroids alone and in combination, with success rates varying from 20% to 100%. The most challenging strictures were reported as those with a narrow lumen, frequently observed following neoadjuvant chemoradiotherapy or an anastomotic leak. Endoscopic balloon dilatation was the most commonly used first-line method; however, repeated dilatations were often required and this was associated with an increased risk of perforation. Although initial success rates for stents were good, patients often experienced stent migration and local symptoms. Only a small number of patients experienced endoscopic management failure and progressed to surgical intervention. CONCLUSION: Following identification of an anastomotic stricture and exclusion of underlying malignancy, endoscopic management is both safe and feasible as a first-line option, even if multiple treatment exposures or multimodal management is required. Surgical resection or a defunctioning stoma should be reserved for emergency or failed cases. Further research is required into multimodal and novel therapies to improve quality of life for these patients.

Failure of nonoperative management in patients with acute diverticulitis complicated by abscess: a systematic review.

BACKGROUND: The aim of this study was to assess failure rates following nonoperative management of acute diverticulitis complicated by abscess and trends thereof. METHOD: Pubmed, MEDLINE, EMBASE, CINAHL, Cochrane Library, and Web of Science were systematically searched. Nonoperative management was defined as a combination of nil per os, IV fluids, IV antibiotics, CT scan-guided percutaneous drainage, and total parenteral nutrition. The primary endpoint was failure of nonoperative management defined as persistent or worsening abscess and/or sepsis, development of new complications, such as peritonitis, ileus, or colocutaneous fistula, and urgent surgery within 30-90 days of index admission. Data were stratified by three arbitrary time intervals: 1986-2000, 2000-2010, and after 2010. The primary outcome was calculated for those groups and compared. RESULTS: Thirty-eight of forty-four eligible studies published between 1986 and 2019 were included in the quantitative synthesis of data (n = 2598). The pooled rate of failed nonoperative management was 16.4% (12.6%, 20.2%) at 90 days. In studies published in 2000-2010 (n = 405), the pooled failure rate was 18.6% (10.5%, 26.7%). After 2000 (n = 2140), the pooled failure rate was 15.3% (10.7%, 20%). The difference was not statistically significant (p = 0.725). After controlling for heterogeneity in the definition of failure of nonoperative management, subgroup analysis yielded the pooled rate of failure of 21.8% (16.1%, 27.4%). CONCLUSION: This meta-analysis found that failure rates following nonoperative management of acute diverticulitis complicated by abscess did not significantly decrease over the past three decades. The general quality of published data and the level and certainty of evidence produced were low.

Intra-operative assessment of left-sided colorectal anastomotic integrity: a systematic review of available techniques.

AIM: Anastomotic leak (AL) after colorectal resection is associated with increased rates of morbidity and mortality: potential permanent stoma formation, increased local recurrence, reduced cancer-related survival, poor functional outcomes and associated quality of life. Techniques to reduce leak rates are therefore highly sought. METHOD: A literature search was performed for published full text articles using PubMed, Cochrane and Scopus databases with a focus on colorectal surgery 1990-2020. Additional papers were detected by scanning references of relevant papers. RESULTS: A total of 53 papers were included after a thorough literature search. Techniques assessed included leak tests, endoscopy, perfusion assessment and fluorescence studies. Air-leak testing remains the most commonly used method across Europe, due to ease of reproducibility and low cost. There is no evidence that this reduces the leak rate; however, identification of a leak intra-operatively provides the opportunity for either suture reinforcement or formal takedown with or without re-do of the anastomosis and consideration of diversion. Suture repair alone of a positive air-leak test is associated with an increased AL rate. The use of fluorescence studies to guide the site of anastomosis has demonstrated reduced leak rates in distal anastomoses, is safe, feasible and has a promising future. CONCLUSION: Although over reliance on any assessment tool should be avoided, intra-operative techniques with the aim of reducing AL rates are increasingly being employed. Standardization of these methods is imperative for routine use. However, in the interim it is recommended that all anastomoses should be assessed intra-operatively for mechanical failure, particularly distal anastomoses.

Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.

The incidence and causative organisms of infection in elective shoulder surgery.

BACKGROUND: Deep infection remains a serious complication of orthopaedic surgery. Knowledge of infection rates and causative organisms is important to guide infection control measures. The aim of the present study was to determine infection rates and causative organisms in elective shoulder surgery. METHODS: Cases complicated by infection were identified and prospectively recorded over a 2-year period. All patients undergoing elective shoulder surgery in the concurrent period at a single Specialist Upper Limb Unit in the UK were identified from the hospital electronic database. RESULTS: In total, 1574 elective shoulder cases were performed: 1359 arthroscopic (540 with implant insertion) and 215 open (197 with implant insertion). The overall infection rate in open surgery of 2.5% was significantly higher than arthroscopic implant cases at 0.7% (p < 0.005). The overall infection rate in implant arthroscopic surgery was significantly higher at 0.7% compared to 0% in non-implant related surgery. (p < 0.05). CONCLUSIONS: Patients undergoing open shoulder surgery have a significantly higher risk of infection compared to arthroscopic shoulder surgery. Arthroscopic surgery with implant insertion has a statistically significantly higher risk of developing deep infection compared to procedures with no implant insertion. We recommend prophylactic antibiotics in open shoulder surgery and arthroscopic shoulder surgery with implant insertion.