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Patients undergoing major abdominal surgery received restrictive or liberal intravenous fluids during surgery and up to 24 hours thereafter. The restrictive regimen did not improve disability-free survival and resulted in increased acute kidney injury.

SummaryBackgroundSystemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. MethodsIn this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m 2 orally twice daily on days 1–14, oxaliplatin 130 mg/m 2 intravenously on day 1, and a chemotherapy-free interval between days 15–21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m 2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m 2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m 2 intravenously and fluorouracil 600 mg/m 2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3–14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m 2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FindingsBetween June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5–5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8–27·6) in the experimental group versus 30·4% (26·1–34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60–0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). InterpretationThe observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FundingDutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy—irrespective of timing—significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8–13·1), 10-year overall survival was 49·4% (95% CI 44·6–54·1) for the preoperative radiotherapy group and 50·7% (45·9–55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83–1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0–56·4) for the adjuvant chemotherapy group and 48·4% (43·6–53·0) for the surveillance group (HR 0·91, 95% CI 0·77–1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5–48·8) for the preoperative radiotherapy group and 46·4% (41·7–50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79–1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2–51·6) for the adjuvant chemotherapy group and 43·7% (39·1–48·2) for the surveillance group (HR 0·91, 95% CI 0·77–1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1–27·6) with radiotherapy alone, 11·8% (7·8–15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1–18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7–15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p<0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p<0·001). Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication. DFID-MRC-Wellcome Trust Joint Global Health Trial Development Grant, National Institute of Health Research Global Health Research Unit Grant.

Antireflux surgery anatomically restores the antireflux barrier and is a therapeutic option for proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease or PPI intolerance. Laparoscopic fundoplication is the standard antireflux surgery, though its popularity has declined due to concerns regarding wrap durability and adverse events. As the esophagogastric junction is an anatomically complex and dynamic area subject to mechanical stress, wraps are susceptible to disruption, herniation or slippage. Additionally, recreating an antireflux barrier to balance bidirectional bolus flow is challenging, and wraps may be too tight or too loose. Given these complexities it is not surprising that post-fundoplication symptoms and complications are common. Perioperative mortality rates range from 0.1 to 0.2% and prolonged structural complications occur in up to 30% of cases. Upper gastrointestinal endoscopy with a comprehensive retroflexed examination of the fundoplication and barium esophagram are the primary tests to assess for structural complications. Management hinges on differentiating complications that can be managed with medical and lifestyle optimization versus those that require surgical revision. Reoperation is best reserved for severe structural abnormalities and troublesome symptoms despite medical and endoscopic therapy given its increased morbidity and mortality. Though further data are needed, magnetic sphincter augmentation may be a safer alternative to fundoplication.

Background Endoscopic management of leaks/fistulas after laparoscopic sleeve gastrectomy (LSG) is gaining popularity in the bariatric surgery. Objectives This study aimed to review the efficacy and safety of over-the-scope-clip (OTSC) system in endoscopic closure of post-LSG leak/fistula. Methods PubMed/Medline and major journals of the field were systematically reviewed for studies on endoscopic closure of post-LSG leaks/fistula by means of the OTSC system. Results A total of ten eligible studies including 195 patients with post-LSG leaks/fistula were identified. The time between LSG and leak/fistula ranged from 1 day to 803 days. Most of the leaks/fistula were located at the proximal staple line, and they sized from 3 to 20 mm. Time between leak diagnosis and OTSC clipping ranged from 0 to 271 days. Thirty-three out of 53 patients (63.5%) required one clip for closure of the lesion. Regarding the OTSC-related complications, a leak occurred in five patients (9.3%) and OTSC migration, stenosis, and tear each in one patient (1.8%). Of the 73 patients with post-LSG leak treated with OTSC, 63 patients had an overall successful closure (86.3%). Conclusion OTSC system is a promising endoscopic approach for management of post-LSG leaks in appropriately selected patients. Unfortunately, most studies are series with a small sample size, short-term follow-up, and mixed data of concomitant procedures with OTSC. Further studies should distinguish the net efficacy of the OTSC system from other concomitant procedures in treatment of post-LSG leak.

Rates of surgery for nonmalignant colorectal polyps are increasing in the United States despite evidence that most polyps can be managed endoscopically. We aimed to determine nationally representative estimates and to identify predictors of in-hospital mortality and morbidity after surgery for nonmalignant colorectal polyps. Data were analyzed from the National Inpatient Sample for 2005-2014. All discharges for adult patients undergoing surgery for nonmalignant colorectal polyps were identified. Rates of in-hospital mortality and postoperative wound, infectious, urinary, pulmonary, gastrointestinal, or cardiovascular adverse events were calculated. Multivariable logistic regression using survey-weighted data was used to evaluate covariables associated with postoperative mortality and morbidity. An estimated 262,843 surgeries for nonmalignant colorectal polyps were analyzed. In-hospital mortality was 0.8% [95% confidence interval: 0.7%-0.9%] and morbidity was 25.3% [95% confidence interval: 24.2%-26.4%]. Postoperative mortality was associated with open surgical technique (vs laparoscopic), older age, black race (vs non-Hispanic white), Medicaid use, and burden of comorbidities. Female sex and private insurance were associated with lower risk. Patients developing a postoperative adverse event had a 106% increase in mean hospital length of stay (10.3 vs 5.0 days; P < 0.0001) and 91% increase in mean hospitalization cost ($77,015.24 vs $40,258.30; P < 0.0001). Surgery for nonmalignant colorectal polyps is associated with almost 1% mortality and common morbidity. These findings should inform risk vs benefit discussions for clinicians and patients, and although confounding by patient selection cannot be excluded, the risks associated with surgery support consideration of endoscopic resection as a potentially less invasive therapeutic option.

Pancreatic cancer is likely to become the second most frequent cause of cancer-associated mortality within the next decade. Surgical resection with adjuvant systemic chemotherapy currently provides the only chance of long-term survival. However, only 10–20% of patients with pancreatic cancer are diagnosed with localized, surgically resectable disease. The majority of patients present with metastatic disease and are not candidates for surgery, while surgery remains underused even in those with resectable disease owing to historical concerns regarding safety and efficacy. However, advances made over the past decade in the safety and efficacy of surgery have resulted in perioperative mortality of around 3% and 5-year survival approaching 30% after resection and adjuvant chemotherapy. Furthermore, owing to advances in both surgical techniques and systemic chemotherapy, the indications for resection have been extended to include locally advanced tumours. Many aspects of pancreatic cancer surgery, such as the management of postoperative morbidities, sequencing of resection and systemic therapy, and use of neoadjuvant therapy followed by resection for tumours previously considered unresectable, are rapidly evolving. In this Review, we summarize the current status of and new developments in pancreatic cancer surgery, while highlighting the most important research questions for attempts to further optimize outcomes.

Introduction Hepatic, pancreatic, and complex biliary (HPB) surgery can be associated with major morbidity and significant mortality. For the past 5 years, the American College of Surgeons–National Surgical Quality Improvement Program (ACS–NSQIP) has gathered robust data on patients undergoing HPB surgery. We sought to use the ACS–NSQIP data to determine which preoperative variables were predictive of adverse outcomes in patients undergoing HPB surgery. Methods Data collected from ACS–NSQIP on patients undergoing hepatic, pancreatic, or complex biliary surgery between 2005 and 2009 were analyzed ( n  = 13,558). Diagnoses and surgical procedures were categorized into 10 and eight groups, respectively. Seventeen preoperative clinical variables were assessed for prediction of 30-day postoperative morbidity and mortality. Multivariate logistic regression was utilized to develop a risk model. Results Of the 13,558 patients who underwent an HPB procedure, 7,321 (54%) had pancreatic, 4,881 (36%) hepatic, and 1,356 (10%) biliary surgery. Overall, 70.3% of patients had a cancer diagnosis. Post-operative complications occurred in 3,850 patients for an overall morbidity of 28.4%. Serious complications occurred in 2,522 (18.6%) patients; 366 patients died for an overall peri-operative mortality of 2.7%. Peri-operative outcome was associated with diagnosis and type of procedure. Hepatic trisectionectomy (5.8%) and total pancreatectomy (5.4%) had the highest 30-day mortality. Of the preoperative variables examined, age >74, dyspnea with moderate exertion, steroid use, prior cardiac procedure, ascites, and pre-operative sepsis were associated with morbidity and mortality (all P  < 0.05). Conclusions While overall morbidity and mortality for HPB surgery are low, peri-operative outcomes are heterogeneous and depend on diagnosis, procedure type, and key clinical factors. By combining these factors, an ACS–NSQIP “HPB Risk Calculator” may be developed in the future to help better risk-stratify patients being considered for complex HPB surgery.