Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy 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 radiation therapy. 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. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous 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 patients with rectal cancer to radiation therapy, 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.

The role of autophagy in hypoxia-induced radioresistance.

Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant barrier for curative treatment. Tumour hypoxia is one of the main contributors to radioresistance and is common in most solid tumours. Hypoxia is responsible for many molecular changes within the cell which helps tumours to survive under such challenging conditions. These hypoxia-induced molecular changes are predominantly coordinated by the hypoxia inducible factor (HIF) and have been linked with the ability to confer resistance to radiation-induced cell death. To overcome this obstacle research has been directed towards autophagy, a cellular process involved in self degradation and recycling of macromolecules, as HIF plays a large role in its coordination under hypoxic conditions. The role that autophagy has following radiotherapy treatment is conflicted with evidence of both cytoprotective and cytotoxic effects. This literature review aims to explore the intricate relationship between radiotherapy, hypoxia, and autophagy in the context of cancer treatment. It provides valuable insights into the potential of targeting autophagy as a therapeutic strategy to improve the response of hypoxic tumours to radiotherapy.

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.

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.

Which is the Optimal Frozen Elephant Trunk? A Systematic Review and Meta-Analysis of Outcomes in 2161 Patients Undergoing Thoracic Aortic Aneurysm Surgery Using E-vita OPEN PLUS Hybrid Stent Graft versus Thoraflex™ Hybrid Prosthesis.

OBJECTIVE: To systematically review the rate of morbidity and mortality associated with the use of E-vita hybrid stent graft and ThoraflexTM in patients undergoing complex aortic surgery. METHODS: A comprehensive search was undertaken among the four major databases to identify published data about E-vita or Thoraflex™ in patients undergoing repair of thoracic aortic aneurysms. RESULTS: In total, 28 papers were included in the study, encompassing a total of 2,161 patients (1,919 E-vita and 242 Thoraflex™). Patients undergoing surgery with E-vita or Thoraflex™ were of similar age and sex. The number of patients undergoing non-elective repair with Thoraflex™ was higher than with E-vita (35.2% vs. 28.7%, respectively). Cardiopulmonary bypass time was associated with increasing mortality in E-vita patients, however a meta-analysis of proportions showed higher 30-day mortality, permanent neurological deficit, and one-year mortality for Thoraflex™ patients. Direct statistical comparisons between E-vita and Thoraflex™ was not possible due to heterogeneity of studies. CONCLUSION: Although there are limited studies available, the available data suggests that mortality and morbidity are lower for the E-vita device in thoracic aortic aneurysm surgery than for Thoraflex™. Long-term data of comparative studies do not yet exist to assess viability of these procedures.

Shortening Postoperative Stay after Parathyroidectomy - A District General Hospital Experience

Abstract Introduction Historically, concerns about complications following parathyroid surgery, such as airway compromise, bleeding and hypocalcemia, have precluded its consideration as a short-stay surgical procedure. Recent advancements in perioperative care have resulted in several publications demonstrating that parathyroidectomy can be safely performed as a short-stay procedure. Objectives The aim of the present study was to describe the process of implementing a short-stay protocol focusing on preoperative patient education and postoperative calcium management for those undergoing surgery for primary hyperparathyroidism (PHP). Method A retrospective audit of consecutive parathyroidectomies performed for PHP over the period between 2010 and 2013 was performed. A short-stay protocol (SSP) was introduced focusing on postoperative calcium management. Results were reaudited over the period between 2013 and 2015. Results Consecutive parathyroidectomies in 76 patients were included in the study. A total of 42 patients underwent parathyroidectomy prior to the introduction of the protocol. A total of 26.2% of these patients were symptomatic from hypercalcemia. A total of 40 out of 42 (95.2%) patients had a biochemical cure. A total of 36 out of 42 (85.7%) cases were due to parathyroid adenomas. A total of 34 patients underwent surgery following the introduction of the protocol. A total of 13 out of 34 (38.2%) of the patients had symptomatic hypercalcemia. A total of 33 out of 34 (97.1%) had a biochemical cure. A total of 32 out of 34 (94.1%) cases were due to parathyroid adenomas. The length of stay decreased from a median of 3 days (range 2-9 days; mean 3.32) preprotocol to a median of 2 days (range 2-3 days; mean 2.16) postprotocol (p< 0.0001) with no difference in the 30-day unplanned readmission rate (4.8 versus 2.9%; p= 0.999). Conclusions The postoperative length of stay after parathyroidectomy for PHP can be safely reduced through patient education and by rationalizing postoperative calcium management without adversely affecting outcomes.

Shortening Postoperative Stay after Parathyroidectomy - A District General Hospital Experience.

Introduction Historically, concerns about complications following parathyroid surgery, such as airway compromise, bleeding and hypocalcemia, have precluded its consideration as a short-stay surgical procedure. Recent advancements in perioperative care have resulted in several publications demonstrating that parathyroidectomy can be safely performed as a short-stay procedure. Objectives The aim of the present study was to describe the process of implementing a short-stay protocol focusing on preoperative patient education and postoperative calcium management for those undergoing surgery for primary hyperparathyroidism (PHP). Method A retrospective audit of consecutive parathyroidectomies performed for PHP over the period between 2010 and 2013 was performed. A short-stay protocol (SSP) was introduced focusing on postoperative calcium management. Results were reaudited over the period between 2013 and 2015. Results Consecutive parathyroidectomies in 76 patients were included in the study. A total of 42 patients underwent parathyroidectomy prior to the introduction of the protocol. A total of 26.2% of these patients were symptomatic from hypercalcemia. A total of 40 out of 42 (95.2%) patients had a biochemical cure. A total of 36 out of 42 (85.7%) cases were due to parathyroid adenomas. A total of 34 patients underwent surgery following the introduction of the protocol. A total of 13 out of 34 (38.2%) of the patients had symptomatic hypercalcemia. A total of 33 out of 34 (97.1%) had a biochemical cure. A total of 32 out of 34 (94.1%) cases were due to parathyroid adenomas. The length of stay decreased from a median of 3 days (range 2-9 days; mean 3.32) preprotocol to a median of 2 days (range 2-3 days; mean 2.16) postprotocol ( p < 0.0001) with no difference in the 30-day unplanned readmission rate (4.8 versus 2.9%; p = 0.999). Conclusions The postoperative length of stay after parathyroidectomy for PHP can be safely reduced through patient education and by rationalizing postoperative calcium management without adversely affecting outcomes.

Which is the optimal frozen elephant trunk? a systematic review and meta-analysis of outcomes in 2161 patients undergoing thoracic aortic aneurysm surgery using e-vita open plus hybrid stent graft versus thoraflex hybrid prosthesis

Abstract Objective: To systematically review the rate of morbidity and mortality associated with the use of E-vita hybrid stent graft and ThoraflexTM in patients undergoing complex aortic surgery. Methods: A comprehensive search was undertaken among the four major databases to identify published data about E-vita or Thoraflex™ in patients undergoing repair of thoracic aortic aneurysms. Results: In total, 28 papers were included in the study, encompassing a total of 2,161 patients (1,919 E-vita and 242 Thoraflex™). Patients undergoing surgery with E-vita or Thoraflex™ were of similar age and sex. The number of patients undergoing non-elective repair with Thoraflex™ was higher than with E-vita (35.2% vs. 28.7%, respectively). Cardiopulmonary bypass time was associated with increasing mortality in E-vita patients, however a meta-analysis of proportions showed higher 30-day mortality, permanent neurological deficit, and one-year mortality for Thoraflex™ patients. Direct statistical comparisons between E-vita and Thoraflex™ was not possible due to heterogeneity of studies. Conclusion: Although there are limited studies available, the available data suggests that mortality and morbidity are lower for the E-vita device in thoracic aortic aneurysm surgery than for Thoraflex™. Long-term data of comparative studies do not yet exist to assess viability of these procedures.

Current Controversies in Large-Vessel Inflammatory Vasculitis and Thoracic Aortic Aneurysm Disease.

Large-vessel vasculitis encompasses the spectrum of vasculitides, which pathologically cause chronic granulomatous inflammatory changes, primarily in the aorta and its major branches. These patients are at risk of developing life-threatening aortic lesions that, without recognition and prompt treatment, can cause detrimental effects. Many provocative issues surrounding large-vessel vasculitis and its surgical treatment still remain, spanning from recognition to management. In this review, we discuss the main large-vessel vasculitides, Takayasu's arteritis and giant cell arteritis. We include the key points and current controversies surrounding diagnostic imaging, timing of interventions, and patient outcomes.

Outcomes after Transverse-Incision 'Mini' Carotid Endarterectomy and Patch-Plasty.

PURPOSE: Traditional exposure for carotid endarterectomy (CEA) involves making a longitudinal incision parallel to the anterior border of the sternocleidomastoid. Such incisions can be painful, aesthetically displeasing, and associated with a high incidence of cranial nerve injury (CNI). This study describes the outcomes of CEA performed through small (<5 cm long), transversely oriented incisions located directly over the carotid bifurcation, as identified by color-enhanced Duplex ultrasound. MATERIALS AND METHODS: Patient demographics and operative data were collected retrospectively from an in-house database of consecutive vascular patients undergoing CEA with a small transversely oriented incision for both symptomatic and asymptomatic carotid artery stenoses. RESULTS: A total of 52 consecutive patients underwent CEA between 2012 and 2016 (median age, 73.5 years; interquartile range, 67-80.3; male/female ratio, 40:12). CEA was performed under regional/local anesthesia (LA) in 48 (92.3%) patients, with 4 (7.7%) being performed under general anesthesia. One patient under LA experienced neurological dysfunction intraoperatively (manifesting as an inability to count out loud) that resolved with insertion of shunt. One patient experienced a transient neurological event (expressive dysphasia) within the immediate postoperative period, which resolved within 6 hours. No in-hospital death or perioperative major adverse cardiovascular events were noted. No persistent CNIs nor bleeding complications necessitating re-exploration were reported. Follow-up data were available for a median period of 3.1 years and for all patients. Three patients experienced strokes following discharge (2 strokes contralateral to and 1 transient ischemic attack ipsilateral to the operated side). CONCLUSION: Small, transversely orientated incisions, hidden within a neck skin crease can be safely performed in the majority of patients undergoing CEA.

Could Cerebrospinal Fluid Biomarkers Offer Better Predictive Value for Spinal Cord Ischaemia Than Current Neuromonitoring Techniques During Thoracoabdominal Aortic Aneurysm Repair - A Systematic Review.

OBJECTIVE: Cerebrospinal fluid (CSF) drainage is a technique that has significantly reduced the incidence of spinal cord ischaemia (SCI). We present results of a systematic review to assess the literature on this topic in relation to thoracoabdominal aortic aneurysm repair (TAAR). METHODS: Major medical databases were searched to identify papers related to CSF biomarkers measured during TAAAR. RESULTS: Fifteen papers reported measurements of CSF biomarkers with 265 patients in total. CSF biomarkers measured included S-100ß, neuron-specific endolase (NSE), lactate, glial fibrillary acidic protein A (GFPa), Tau, heat shock protein 70 and 27 (HSP70, HSP27), and proinflammatory cytokines. Lactate and S-100ß were reported the most, but did not correlate with SCI, which was also the case with NSE and TAU. GFPa showed significant CSF level rises, both intra and postoperative in patients who suffered SCI and warrants further investigation, similar results were seen with HSP70, HSP27 and IL-8. CONCLUSIONS: Although there is significant interest in this topic, there still remains a significant lack of high-quality studies investigating CSF biomarkers during TAAR to detect SCI. A large and multicentre study is required to identify the significant role of each biomarker.

Could cerebrospinal fluid biomarkers offer better predictive value for spinal cord ischaemia than current neuromonitoring techniques during thoracoabdominal aortic aneurysm repair - a systematic review

Abstract Objective: Cerebrospinal fluid (CSF) drainage is a technique that has significantly reduced the incidence of spinal cord ischaemia (SCI). We present results of a systematic review to assess the literature on this topic in relation to thoracoabdominal aortic aneurysm repair (TAAR). Methods: Major medical databases were searched to identify papers related to CSF biomarkers measured during TAAAR. Results: Fifteen papers reported measurements of CSF biomarkers with 265 patients in total. CSF biomarkers measured included S-100ß, neuron-specific endolase (NSE), lactate, glial fibrillary acidic protein A (GFPa), Tau, heat shock protein 70 and 27 (HSP70, HSP27), and proinflammatory cytokines. Lactate and S-100ß were reported the most, but did not correlate with SCI, which was also the case with NSE and TAU. GFPa showed significant CSF level rises, both intra and postoperative in patients who suffered SCI and warrants further investigation, similar results were seen with HSP70, HSP27 and IL-8. Conclusions: Although there is significant interest in this topic, there still remains a significant lack of high-quality studies investigating CSF biomarkers during TAAR to detect SCI. A large and multicentre study is required to identify the significant role of each biomarker.

Brain protection in aortic arch aneurysm: antegrade or retrograde?

During open aortic arch repair, there is an interruption of cerebral perfusion and to prevent neurological sequelae, the hypothermic circulatory arrest has been established to provide sufficient brain protection coupled with adjuncts including retrograde and antegrade cerebral perfusion. To date, brain protection during open aortic arch repair is a contested topic as to which provides superior brain protection with little evidence existing to suggest supremacy of one modality over the other. This article reviews current literature reflecting on key and emerging studies in brain protection and their associated outcomes in patients undergoing open aortic arch surgery.

Pathogenesis of large vessel vasculitis: Implications for disease classification and future therapies.

Despite being recognised over a century ago, the aetiology and pathogenesis of large vessel vasculitis (LVV) still remains elusive. Takayasu's arteritis (TA) and giant cell arteritis (GCA) represent the two major categories of LVV, each with distinctive clinical features. Over the last 10 years an increased understanding of the immunopathogenesis of the inflammatory cascade within the aortic wall has revived the view that LVVs may represent subtypes of the same pathological process, with implications in the treatment of this disease. In this review, the histological, genetic and immunopathological features of TA and GCA will be discussed and the evidence for a common underlying disease mechanism examined. Novel markers of disease activity and therapies based on advances in our understanding of the immunopathogenesis of these conditions will also be discussed.

Incidental Mesenteric Paraganglioma: A Case Report and Literature Review.

Mesenteric paragangliomas are a rare entity; consequently, only 12 cases have been reported to date. Although considered benign and often found incidentally, they have the potential to metastasize and are an important diagnosis to consider for patients with a mesenteric tumor. We report the case of a 71-year-old woman who was found on magnetic resonance imaging to have an incidental, large, complex, intra-abdominal mass that had initially been misdiagnosed as ovarian in origin. She underwent an open resection of the tumor and adjacent small bowel with no perioperative complications; histology confirmed the mass to be a mesenteric paraganglioma. This case report highlights several important key issues regarding paraganglioma, including diagnosis, imaging, genetic testing, and surgical resection. The results of a literature review are also discussed.

Video-Assisted Thoracoscopic Versus Robotic-Assisted Thoracoscopic Thymectomy: Systematic Review and Meta-analysis.

OBJECTIVE: Minimally invasive thoracic surgical procedures, performed with or without the assistance of a robot, have gained popularity over the last decade. They have increasingly become the choice of intervention for a number of thoracic surgical operations. Minimally invasive surgery decreases postoperative pain, hospital stay and leads to a faster recovery in comparison with conventional open methods. Minimally invasive techniques to perform a thymectomy include video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS). In this study, we aim to systematically review and interrogate the literature on minimally invasive thymectomy and draw a meta-analysis on the outcomes between the two approaches. METHODS: An extensive electronic health database search was performed on all articles published from inception to May 2015 for studies describing outcomes in VATS and RATS thymectomy. RESULTS: A total of 350 patients were included in this study, for which 182 and 168 patients underwent RATS and VATS thymectomy, respectively. There were no recorded in-hospital deaths for either procedure. There was no statistical difference in conversion to open, length of hospital stay, or postoperative pneumonia. Operational times for RATS thymectomy were longer. CONCLUSIONS: The VATS and RATS thymectomy offer good and safe operative and perioperative outcomes. There is little difference between the two groups. However, there is poor evidence basis for the long-term outcomes in minimally invasive procedures for thymectomy. It is imperative that future studies evaluate oncological outcomes both short and long term as well as those related to safety.

Acute type A aortic dissection in the United Kingdom: Surgeon volume-outcome relation.

OBJECTIVES: Surgery for acute type A aortic dissection (ATAD) carries a high risk of operative mortality. We examined the surgeon volume-outcome relation with respect to in-hospital mortality for patients presenting with this pathology in the United Kingdom. METHOD: Between April 2007 and March 2013, 1550 ATAD procedures were identified from the National Institute for Cardiovascular Outcomes Research database. A total of 249 responsible consultant cardiac surgeons from the United Kingdom recorded 1 or more of these procedures in their surgical activity over this period. We describe the patient population and mortality rates, focusing on the relationship between surgeon volume and in-hospital mortality. RESULTS: The mean annual volume of procedures per surgeon during the 6-year period ranged from 1 to 6.6. The overall in-hospital mortality rate was 18.3% (283/1550). A mortality improvement at the 95% level was observed with a risk-adjusted mean annual volume >4.5. Surgeons with a mean annual volume <4 over the study period had significantly higher in-hospital mortality rates in comparison with surgeons with a mean annual volume ≥4 (19.3% vs 12.6%; P = .015). CONCLUSIONS: Patients with ATAD who are operated on by lower-volume surgeons experience higher levels of in-hospital mortality. Directing these patients to higher-volume surgeons may be a strategy to reduce in-hospital mortality.