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Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1–4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4–6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6–26·3) with CF and 26·1 months (22·5–29·7) with ECX (hazard ratio 0·90 (95% CI 0·77–1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Background Oesophageal cancer is increasing in incidence worldwide. Minimally invasive techniques have been used to perform oesophagectomy, but concerns regarding these techniques remain. Since its description by Cuschieri in 1992, the use of minimally invasive oesophagectomy (MIO) has increased, but still only used in a minority of resections in the UK in 2009. In particular, there has been reluctance to use minimally invasive (thoracoscopic and laparoscopic) techniques in more advanced cancers for fears regarding the adequacy of the oncological resection. In order to identify any factors that could affect survival, we undertook a retrospective analysis on all patients who underwent surgery in our department over an 8-year period. Methods A retrospective data analysis was undertaken on all patients who underwent oesophagectomy in a tertiary upper gastrointestinal surgery unit, from 2005 to 2012 inclusive. Data were collected from the departmental database and case note review, with follow-up and survival data to time of data collection. The survival data were analysed using univariate and multivariate Cox proportional hazard regression models to determine which variables affected survival. Variables examined included age, tumour position, tumour stage (T0, 1, 2 vs T3, 4), nodal stage (N0 vs N1), tumour histology, completeness of resection (R0 vs R1), use of neoadjuvant chemotherapy and operative technique (thoracoscopic/laparoscopic (MIO) vs laparoscopic abdomen/open chest (Lap assisted) vs Open. Results 334 patients underwent oesophagectomy between 2005 and 2012. Male to female ratio was 3.75:1, with a mean age of 64 years (range 36–87). There were 83 open oesophagectomies, 187 laparoscopically assisted oesophagectomies and 64 minimally invasive oesophagectomies. Following univariate regression analysis the following factors were found to be correlated to survival: use of neoadjuvant chemotherapy (Hazard Ratio 2.889, 95 % CI 1.737–4.806), T stage 3 or 4 (3.749, 2.475–5.72), Node positive (5.225, 3.561–7.665), R1 resection (2.182, 1.425–3.341), type of operation (MIO compared to open oesophagectomy) (0.293, 0.158–0.541). There was no significant relationship between age, tumour position or tumour histology and length of survival. When these factors were entered into a multivariate model, the independently significant factors correlated to survival were found to be T stage 3 or 4 (HR 1.969, 1.248–3.105), Node positive (3.833, 2.548–5.766) and type of operation (MIO compared to open) (0.5186, 0.277–0.972). Conclusion Multiple small studies have found reduced pulmonary complication rates and duration of hospital stay when using a minimally invasive approach compared to open. Concerns in the literature over long-term outcomes, however, have led to limited utilisation of this method, especially in advanced disease. The data from this large study show significantly better survival following operations performed using minimally invasive techniques compared to open, however, we have not adjusted for some known or unknown confounding factors. International and national RCTs, however, will provide more information in due course.

IntroductionRandomised controlled trials (RCTs) in surgery are frequently criticised because surgeon expertise and standards of surgery are not considered or accounted for during study design. This is particularly true in pragmatic trials (which typically involve multiple centres and surgeons and are based in ‘real world’ settings), compared with explanatory trials (which are smaller and more tightly controlled).ObjectiveThis protocol describes a process to develop and test quality assurance (QA) measures for use within a predominantly pragmatic surgical RCT comparing minimally invasive and open techniques for oesophageal cancer (the NIHR ROMIO study). It builds on methods initiated in the ROMIO pilot RCT.Methods and analysisWe have identified three distinct types of QA measure: (i) entry criteria for surgeons, through assessment of operative videos, (ii) standardisation of operative techniques (by establishing minimum key procedural phases) and (iii) monitoring of surgeons during the trial, using intraoperative photography to document key procedural phases and standardising the pathological assessment of specimens. The QA measures will be adapted from the pilot study and tested iteratively, and the video and photo assessment tools will be tested for reliability and validity.Ethics and disseminationEthics approval was obtained (NRES Committee South West—Frenchay, 25 April 2016, ref: 16/SW/0098). Results of the QA development study will be submitted for publication in a peer-reviewed journal.Trial registration number ISRCTN59036820, ISRCTN10386621.

Background There is a need for evidence of the clinical effectiveness of minimally invasive surgery for the treatment of esophageal cancer, but randomized controlled trials in surgery are often difficult to conduct. The ROMIO (Randomized Open or Minimally Invasive Oesophagectomy) study will establish the feasibility of a main trial which will examine the clinical and cost-effectiveness of minimally invasive and open surgical procedures for the treatment of esophageal cancer. Methods/Design A pilot randomized controlled trial (RCT), in two centers (University Hospitals Bristol NHS Foundation Trust and Plymouth Hospitals NHS Trust) will examine numbers of incident and eligible patients who consent to participate in the ROMIO study. Interventions will include esophagectomy by: (1) open gastric mobilization and right thoracotomy, (2) laparoscopic gastric mobilization and right thoracotomy, and (3) totally minimally invasive surgery (in the Bristol center only). The primary outcomes of the feasibility study will be measures of recruitment, successful development of methods to monitor quality of surgery and fidelity to a surgical protocol, and development of a core outcome set to evaluate esophageal cancer surgery. The study will test patient-reported outcomes measures to assess recovery, methods to blind participants, assessments of surgical morbidity, and methods to capture cost and resource use. ROMIO will integrate methods to monitor and improve recruitment using audio recordings of consultations between recruiting surgeons, nurses, and patients to provide feedback for recruiting staff. Discussion The ROMIO study aims to establish efficient methods to undertake a main trial of minimally invasive surgery versus open surgery for esophageal cancer. Trial registration The pilot trial has Current Controlled Trials registration number ISRCTN59036820 (25/02/2013) at http://www.controlled-trials.com ; the ROMIO trial record at that site gives a link to the original version of the study protocol.

The present report describes a case of an extrahepatic right hepatic artery pseudoaneurysm caused by acalculous cholecystitis. An 85-year-old man was admitted with abdominal pain, cachexia and jaundice. A CT scan showed a saccular false right hepatic artery aneurysm within a soft tissue and fluid mass that was causing biliary obstruction. The soft tissue mass raised the possibility of malignant disease, but this resolved slowly after a period of time and on reviewing the patient's history the only upper gastrointestinal problem noted was an episode of acalculous cholecystitis 3 months previously, which was believed to be the cause of the pseudoaneurysm. The false aneurysm was treated successfully with coil embolisation and the patient recovered fully from this illness.

Sepsis-associated renal failure has a 40-50% mortality. The mechanisms leading to renal failure in sepsis remain poorly understood. The experiments described in this thesis help provide a better understanding of the pathophysiology of renal failure and how it might be treated. Many investigators have reported that early sepsis leads to a hyperdynamic systemic circulation, but visceral (including renal) hypoperfusion. Glomerular hypoperfusion is thought to be a major factor in the genesis of sepsis-associated renal failure. Although major systemic changes occur during early sepsis, it is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. The renal microcirculation is sensitive to a number of arachidonic acid metabolites. These are produced by enzymatic and non-enzymatic conversion of arachidonic acid. Cyclooxygenase and lipoxygenase enzymes produce thromboxane A2 and leukotrienes respectively, both vasoconstrictors. Prostacyclin, a cyclooxygenase product, is a vasodilator. Non-enzymatically produced metabolites such as isoprostanes (free radical-catalysed peroxidation products of arachidonic acid) are powerful vasoconstrictors. I used two models to study the renal microcirculation. The first, a split hydronephrotic kidney, allows direct observation of renal microcirculation. I measured afferent and efferent arteriolar diameters and interlobular arterial diameters and flow. The second, an isolated perfused kidney, allowed measurement of renal vascular resistance and the production of four key metabolites of arachidonic acid, TXB[2], 8-iso-PGF[2α] and peptido-leukotrienes (vasoconstrictors) and 6-keto-PGF[1α] (vasodilator). Using the hydronephrotic kidney model, 1 demonstrated that bacteraemia produces preglomerular vasoconstriction and hypoperfusion despite a hyperdynamic systemic circulation. With the isolated perfused kidney model, I confirmed bacteraemia-induced rise in renal vascular resistance. I measured increased production of all four key metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. 1 studied the effect of two drugs on the renal response to sepsis; pentoxifylline (a phosphodiesterase inhibitor) and U74389G, an antioxidant (thought to prevent free radical induced isoprostane production). Using both models, I have shown pentoxifylline prevents sepsis-induced preglomerular vasoconstriction, as well as preventing the increase in renal vascular resistance seen after bacteraemia. Of the four arachidonic acid metabolites measured, there was a reduction in lipoxygenase-derived peptido- leukotrienes but little change in cyclooxygenase products or isoprostanes. This suggests pentoxifylline's effect on the renal microcirculation is only partly mediated by altered local peptido-leukotriene production and that additional factors are responsible for its protective actions. Again using both models, I have shown that lazaroid reduces the effects of bacteraemia on renal microvascular calibre and flow, as well as a reduction in bacteraemia-induced rises in non-enzyme catalysed isoprostane production as well as cyclooxygenase and lipoxygenase products. These studies demonstrate that sepsis leads to renal microcirculatory hypoperfusion. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.

The present report describes a case of an extrahepatic right hepatic artery pseudoaneurysm caused by acalculous cholecystitis. An 85-year-old man was admitted with abdominal pain, cachexia and jaundice. A CT scan showed a saccular false right hepatic artery aneurysm within a soft tissue and fluid mass that was causing biliary obstruction. The soft tissue mass raised the possibility of malignant disease, but this resolved slowly after a period of time and on reviewing the patient's history the only upper gastrointestinal problem noted was an episode of acalculous cholecystitis 3 months previously, which was believed to be the cause of the pseudoaneurysm. The false aneurysm was treated successfully with coil embolisation and the patient recovered fully from this illness.