Improving the reporting of non-inferiority trials by incorporating non-efficacy benefits: not all non-inferiority trials are created equal.

Non-inferiority trials are used to test if a novel intervention is not worse than a standard treatment by more than a prespecified amount, the non-inferiority margin (ΔNI). The ΔNI indicates the amount of efficacy loss in the primary outcome that is acceptable in exchange for non-efficacy benefits in other outcomes. However, non-inferiority designs are sometimes used when non-efficacy benefits are absent. Without non-efficacy benefits, loss in efficacy cannot be easily justified. Further, non-efficacy benefits are scarcely defined or considered by trialists when determining the magnitude of and providing justification for the non-inferiority margin. This is problematic as the importance of a treatment's non-efficacy benefits are critical to understanding the results of a non-inferiority study. Here we propose the routine reporting in non-inferiority trial protocols and publications of non-efficacy benefits of the novel intervention along with the reporting of non-inferiority margins and their justification. The justification should include the specific trade-off between the accepted loss in efficacy (ΔNI) and the non-efficacy benefits of the novel treatment and should describe whether patients and other relevant stakeholders were involved in the definition of the ΔNI.

Optimizing opioid prescriptions after laparoscopic appendectomy and cholecystectomy

Background: There has been an increase in opioid usage and opioid-related deaths. Opioids prescribed to surgical patients have similarly increased. The aim of this study was to assess opioid consumption in patients undergoing laparoscopic appendectomy (LA) and laparoscopic cholecystectomy (LC) and to determine whether a standardized prescription could affect opioid consumption without affecting patient satisfaction. Methods: Patients undergoing LA or LC were recruited prospectively during 2 time periods (April to June 2017 and November 2017 to January 2018). In the first phase, surgeons continued their usual postoperative analgesia prescribing patterns. In the second phase, a standardized prescription was implemented. Patients were contacted by telephone and a questionnaire was completed for both phases of the study. The primary outcome was the quantity of opioids prescribed and consumed. Results: In the first phase, 166 patients who underwent LC or LA were recruited. The median number of prescribed opioid tablets was 20 and the median number consumed was 2. Ninety-five percent of patients reported satisfaction with their analgesia. Based on these results, a standardized prescription for multimodal analgesia was implemented for the second phase, consisting of 10 opioid tablets. In the second phase, 129 patients who underwent LA or LC were recruited. There was a significant decrease in the median number of opioid pills filled (10) and consumed (0), with no difference in reported satisfaction with analgesia. Conclusion: Patients are prescribed an excess of opioids after LA or LC. Implementation of a standardized prescription based on a quality improvement intervention was effective at decreasing the number of opioids prescribed and consumed.

Contexte: On a observé une augmentation de la consommation d'opioïdes, ainsi qu'une hausse des décès associés à ces substances. On a aussi constaté une augmentation semblable dans la prescription d'opioïdes aux patients ayant subi une chirurgie. La présente étude visait à évaluer la consommation d'opioïdes chez les personnes ayant subi une appendicectomie par laparoscopie (AL) ou une cholécystectomie par laparoscopie (CL), de même qu'à déterminer si une ordonnance normalisée pouvait modifier la consommation d'opioïdes sans nuire à la satisfaction des patients. Méthodes: Des patients devant subir une AL ou une CL ont été recrutés de façon prospective entre avril et juin 2017 et entre novembre 2017 et janvier 2018. Durant la première phase de l'étude, les chirurgiens ont maintenu leurs habitudes de prescription d'analgésie postopératoire. Durant la deuxième phase, toutefois, ils devaient avoir recours à une ordonnance normalisée. Dans les 2 phases de l'étude, les patients ont été joints par téléphone et un questionnaire a été rempli. Le principal résultat à l'étude était la quantité d'opioïdes prescrits et consommés. Résultats: Pour la première phase de l'étude, 166 patients ont été recrutés. Les nombres médians de comprimés prescrits et consommés étaient de 20 et de 2, respectivement. De tous les patients, 95 % se sont dits satisfaits de leur analgésie. Pour la deuxième phase, une ordonnance normalisée d'analgésie multimodale, qui comptait 10 comprimés, a été mise en place, et 129 patients ont été recrutés. On a alors observé une diminution significative du nombre médian de comprimés remis (10) et consommés (0), et aucune différence quant au degré de satisfaction déclaré. Conclusion: Les patients se voient prescrire trop d'opioïdes après une AL ou une CL. La création d'une ordonnance normalisée dans le cadre d'une intervention d'amélioration de la qualité a réduit efficacement le nombre de comprimés d'opioïdes prescrits et consommés.

Does oncoplastic surgery increase immediate (30-day) postoperative complications? An analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database.

PURPOSE: Although there has been a significant increase in the use of oncoplastic surgery (OPS), data on the postoperative safety of this approach are limited compared to traditional lumpectomy. This study aimed to compare the immediate (30-day) postoperative complications associated with OPS and traditional lumpectomy. METHODS: An analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was performed on women with breast cancer who underwent OPS or traditional lumpectomy. Logistic regression was used to explore the effect of type of surgery on the outcome of interest. RESULTS: A total of 109,487 women were analyzed of whom 8.3% underwent OPS. OPS had a longer median operative time than traditional lumpectomy. The unadjusted immediate (30-day) overall complication rate was significantly higher with OPS than traditional lumpectomy (3.8% versus 2.6%, p < 0.001). After adjusting for baseline differences, overall 30-day postoperative complications were significantly higher amongst women undergoing OPS compared with traditional lumpectomy (OR 1.41, 95%CI 1.24-1.59). Factors that were independent predictors of overall 30-day complications included higher age, higher BMI, race, smoking status, lymph node surgery, neoadjuvant chemotherapy, ASA class ≥ 3, in situ disease, and year of operation. The interaction term between type of surgery and operative time was not statistically significant, indicating that operative time did not modify the effect of type of surgery on immediate postoperative complications. CONCLUSIONS: Although there were slightly higher overall complication rates with OPS, the absolute rates remained quite low for both groups. Therefore, OPS may be performed in women with breast cancer who are suitable candidates.

Comparing Observation, Axillary Radiotherapy, and Completion Axillary Lymph Node Dissection for Management of Axilla in Breast Cancer in Patients with Positive Sentinel Nodes: A Systematic Review.

PURPOSE: Several randomized controlled trials (RCTs) have investigated observation or axillary radiotherapy (ART) in place of completion axillary lymph node dissection (cALND) for management of positive sentinel nodes (SNs) in clinically node-negative women with breast cancer. The optimal treatment strategy for this population is not known. METHODS: MEDLINE, Embase, and EBM Reviews-NHS Economic Evaluation Database were searched from inception until July 2019. A systematic review and narrative summary was performed of RCTs comparing observation or ART versus cALND in clinically node-negative female breast cancer patients with positive SNs. The Cochrane risk of bias tool for RCTs was used to assess risk of bias. Outcomes of interest included overall survival (OS), disease-free survival (DFS), axillary recurrence, and axillary surgery-related morbidity. RESULTS: Three trials compared observation with cALND, and two trials compared ART with cALND. No studies blinded participants or personnel, and there was heterogeneity in inclusion criteria, study design, and follow-up. Neither observation nor ART resulted in statistically inferior 5- or 8-year OS or DFS compared with cALND. There was also no statistically significant increase in axillary recurrences associated with either approach. Four trials reported morbidity outcomes, and all showed cALND was associated with significantly more lymphedema, paresthesia, and shoulder dysfunction compared with observation or ART. CONCLUSIONS: Women with clinically node-negative breast cancer and positive SNs can safely be managed without cALND.

Propofol versus midazolam with or without short-acting opioids for sedation in colonoscopy: a systematic review and meta-analysis of safety, satisfaction, and efficiency outcomes.

BACKGROUND AND AIMS: Propofol is increasingly being used for sedation in colonoscopy; however, its benefits over midazolam (± short-acting opioids) are not well quantified. The objective of this study was to compare safety, satisfaction, and efficiency outcomes of propofol versus midazolam (± short-acting opioids) in patients undergoing colonoscopy. METHODS: We systematically searched Medline, Embase, and the Cochrane library (to July 30, 2018) for randomized controlled trials of colonoscopies performed with propofol versus midazolam (± short-acting opioids). We pooled odds ratios for cardiorespiratory outcomes using mixed-effects conditional logistic models. We pooled standardized mean differences (SMDs) for patient and endoscopist satisfaction and efficiency outcomes using random-effects models. RESULTS: Nine studies of 1427 patients met the inclusion criteria. There were no significant differences in cardiorespiratory outcomes (hypotension, hypoxia, bradycardia) between sedative groups. Patient satisfaction was high in both groups, with most patients reporting willingness to undergo a future colonoscopy with the same sedative regimen. In the meta-analysis, patients sedated with propofol had greater satisfaction than those sedated with midazolam (± short-acting opioids) (SMD, .54; 95% confidence interval [CI], .30-.79); however, there was considerable heterogeneity. Procedure time was similar between groups (SMD, .15; 95% CI, .04-.27), but recovery time was shorter in the propofol group (SMD, .41; 95% CI, .08-.74). The median difference in recovery time was 3 minutes, 6 seconds shorter in patients sedated with propofol. CONCLUSIONS: Both propofol and midazolam (± short-acting opioids) result in high patient satisfaction and appear to be safe for use in colonoscopy. The marginal benefits to propofol are small improvements in satisfaction and recovery time.

Optimal Operative Strategy for Hinchey III Sigmoid Diverticulitis: A Decision Analysis.

BACKGROUND: Operative approaches for Hinchey III diverticulitis include the Hartmann procedure, primary resection and anastomosis, and laparoscopic lavage. Several randomized controlled trials and meta-analyses have compared these approaches; however, results are conflicting and previous studies have not captured the complexity of balancing surgical risks and quality of life. OBJECTIVE: This study aimed to determine the optimal operative strategy for patients with Hinchey III sigmoid diverticulitis. DESIGN: We developed a Markov cohort model, incorporating perioperative morbidity/mortality, emergency and elective reoperations, and quality-of-life weights. We derived model parameters from systematic reviews and meta-analyses, where possible. We performed a second-order Monte Carlo probabilistic sensitivity analysis to account for joint uncertainty in model parameters. SETTING: This study measured outcomes over patients' lifetime horizon. PATIENTS: The base case was a simulated cohort of 65-year-old patients with Hinchey III diverticulitis. A scenario simulating a cohort of highly comorbid 80-year-old patients was also planned. INTERVENTIONS: Hartmann procedure, primary resection and anastomosis (with or without diverting ileostomy), and laparoscopic lavage were performed. MAIN OUTCOME MEASURES: Quality-adjusted life years were the primary outcome measured. RESULTS: Following surgery for Hinchey III diverticulitis, 39.5% of patients who underwent the Hartmann procedure, 14.3% of patients who underwent laparoscopic lavage, and 16.7% of patients who underwent primary resection and anastomosis had a stoma at 12 months. After applying quality-of-life weights, primary resection and anastomosis was the optimal operative strategy, yielding 18.0 quality-adjusted life years; laparoscopic lavage and the Hartmann procedure yielded 9.6 and 13.7 fewer quality-adjusted life months. A scenario analysis for elderly, highly comorbid patients could not be performed because of a lack of high-quality evidence to inform model parameters. LIMITATIONS: This model required assumptions about the long-term postoperative course of patients who underwent laparoscopic lavage because few long-term data for this group have been published. CONCLUSIONS: Although the Hartmann procedure is widely used for Hinchey III diverticulitis, when considering both surgical risks and quality of life, both laparoscopic lavage and primary resection and anastomosis provide greater quality-adjusted life years for patients with Hinchey III diverticulitis, and primary resection and anastomosis appears to be the optimal approach. See Video Abstract at http://links.lww.com/DCR/B223. ESTRATEGIA OPERATIVA ÓPTIMA EN DIVERTICULITIS HINCHEY III DE SIGMOIDES: UN ANÁLISIS DE DECISION: Los enfoques quirúrgicos para la diverticulitis Hinchey III incluyen el procedimiento de Hartmann, la resección primaria y anastomosis, y el lavado laparoscópico. Varios ensayos controlados aleatorios y metanálisis han comparado estos enfoques; sin embargo, los resultados son contradictorios y los estudios previos no han captado la complejidad de equilibrar los riesgos quirúrgicos y la calidad de vida.Determinar la estrategia operativa óptima para pacientes con diverticulitis Hinchey III de sigmoides.Desarrollamos un modelo de cohorte de Markov, incorporando morbilidad / mortalidad perioperatoria, reoperaciones electivas y de emergencia, y pesos de calidad de vida. Derivamos los parámetros del modelo de revisiones sistemáticas y metaanálisis, cuando fue posible. Realizamos un análisis de sensibilidad probabilístico Monte Carlo de segundo orden para tener en cuenta la incertidumbre conjunta en los parámetros del modelo.Seguimiento de por vida.El caso base fue una cohorte simulada de pacientes de 65 años con diverticulitis de Hinchey III. También se planeó un escenario que simulaba una cohorte de pacientes de 80 años altamente comórbidos.Procedimiento de Hartmann, resección primaria y anastomosis (con o sin desviación de ileostomía) y lavado laparoscópico.Años de vida ajustados por calidad.Después de la cirugía para la diverticulitis de Hinchey III, el 39.5% de los pacientes que se sometieron al procedimiento de Hartmann, el 14.3% de los pacientes que se sometieron a un lavado laparoscópico, y el 16.7% de los pacientes que se sometieron a resección primaria y anastomosis tuvieron un estoma a los 12 meses. Después de aplicar el peso de la calidad de vida, la resección primaria y la anastomosis fueron la estrategia operativa óptima, que dio como resultado 18.0 años de vida ajustados en función de la calidad; el lavado laparoscópico y el procedimiento de Hartmann arrojaron 9.6 y 13.7 meses de vida ajustados en función de la calidad, respectivamente. No se pudo realizar un análisis de escenarios para pacientes de edad avanzada altamente comórbidos debido a la falta de evidencia de alta calidad para informar los parámetros del modelo.Este modelo requirió suposiciones sobre el curso postoperatorio a largo plazo de pacientes que se sometieron a lavado laparoscópico, ya que se han publicado pocos datos a largo plazo para este grupo.Aunque el procedimiento de Hartmann se usa ampliamente para la diverticulitis de Hinchey III, cuando se consideran tanto los riesgos quirúrgicos como la calidad de vida, tanto el lavado laparoscópico como la resección primaria y la anastomosis proporcionan una mayor calidad de años de vida ajustada para los pacientes con diverticulitis de Hinchey III y la resección primaria y anastomosis parece ser el enfoque óptimo. Consulte Video Resumen en http://links.lww.com/DCR/B223.

Laparoscopic Versus Open Resection for Rectal Cancer: A Noninferiority Meta-analysis of Quality of Surgical Resection Outcomes.

OBJECTIVE: To determine whether laparoscopic surgery is noninferior to open surgery for rectal cancer in terms of quality of surgical resection outcomes. BACKGROUND: Randomized clinical trials (RCTs) have evaluated the oncologic safety of laparoscopic versus open surgery for rectal cancer with conflicting results. Prior meta-analyses comparing these operative approaches in terms of quality of surgical resection aimed to demonstrate if one approach was superior. However, this method is not appropriate and potentially misleading when noninferiority RCTs are included. METHODS: MEDLINE, EMBASE, and Cochrane were searched to identify RCTs comparing these operative approaches. Risk differences (RDs) were pooled using random-effects meta-analyses. One-sided Z tests were used to determine noninferiority. Noninferiority margins (ΔNI) for circumferential resection margin (CRM), plane of mesorectal excision (PME), distal resection margin (DRM), and a composite outcome ("successful resection") were based on the consensus of 58 worldwide experts. RESULTS: Fourteen RCTs were included. Laparoscopic resection was noninferior compared with open resection for the rate of positive CRM [RD 0.79%, 90% confidence interval (CI) -0.46 to 2.04, ΔNI = 2.33%, PNI = 0.026], incomplete PME (RD 1.16%, 90% CI -0.27 to 2.59, ΔNI = 2.85%, PNI = 0.025), and positive DRM (RD 0.15%, 90% CI -0.58 to 0.87, ΔNI = 1.28%, PNI = 0.005). For the rate of "successful resection" (RD 6.16%, 90% CI 2.30-10.02), the comparison was inconclusive when using the ΔNI generated by experts (ΔNI = 2.71%, PNI = 0.07), although no consensus was achieved for this ΔNI. CONCLUSIONS: Laparoscopy was noninferior to open surgery for rectal cancer in terms of individual quality of surgical resection outcomes. These findings are concordant with RCTs demonstrating noninferiority for long-term oncologic outcomes between the 2 approaches.

Laparoscopic and robotic hysterectomy in endometrial cancer patients with obesity: a systematic review and meta-analysis of conversions and complications.

OBJECTIVE DATA: Robotic assistance may facilitate completion of minimally invasive hysterectomy, which is the standard of care for the treatment of early-stage endometrial cancer, in patients for whom conventional laparoscopy is challenging. The aim of this systematic review was to assess conversion to laparotomy and perioperative complications after laparoscopic and robotic hysterectomy in patients with endometrial cancer and obesity (body mass index, ≥30 kg/m2). STUDY: We systematically searched MEDLINE, EMBASE, and Evidence-Based Medicine Reviews (January 1, 2000, to July 18, 2018) for studies of patients with endometrial cancer and obesity (body mass index, ≥30 kg/m2) who underwent primary hysterectomy. STUDY APPRAISAL AND SYNTHESIS METHODS: We determined the pooled proportions of conversion, organ/vessel injury, venous thromboembolism, and blood transfusion. We assessed risk of bias with the Institute of Health Economics Quality Appraisal Checklist for single-arm studies, and Newcastle-Ottawa Quality Scale for double-arm studies. RESULTS: We identified 51 observational studies that reported on 10,800 patients with endometrial cancer and obesity (study-level body mass index, 31.0-56.3 kg/m2). The pooled proportions of conversion from laparoscopic and robotic hysterectomy were 6.5% (95% confidence interval, 4.3-9.9) and 5.5% (95% confidence interval, 3.3-9.1), respectively, among patients with a body mass index of ≥30 kg/m2, and 7.0% (95% confidence interval, 3.2-14.5) and 3.8% (95% confidence interval, 1.4-9.9) among patients with body mass index of ≥40 kg/m2. Inadequate exposure because of adhesions/visceral adiposity was the most common reason for conversion for both laparoscopic (32%) and robotic hysterectomy (61%); however, intolerance of the Trendelenburg position caused 31% of laparoscopic conversions and 6% of robotic hysterectomy conversions. The pooled proportions of organ/vessel injury (laparoscopic, 3.5% [95% confidence interval, 2.2-5.5]; robotic hysterectomy, 1.2% [95% confidence interval, 0.4-3.4]), venous thromboembolism (laparoscopic, 0.5% [95% confidence interval, 0.2-1.2]; robotic hysterectomy, 0.5% [95% confidence interval, 0.1-2.0]), and blood transfusion (laparoscopic, 2.8% [95% confidence interval, 1.5-5.1]; robotic hysterectomy, 2.1% [95% confidence interval, 1.6-3.8]) were low and not appreciably different between arms. CONCLUSION: Robotic and laparoscopic hysterectomy have similar rates perioperative complications in patients with endometrial cancer and obesity, but robotic hysterectomy may reduce conversions because of positional intolerance in patients with morbid obesity. Existing literature is limited by selection and confounding bias, and randomized trials are needed to inform practice standards in this population.

Chest Wall Resection for Recurrent Breast Cancer in the Modern Era: A Systematic Review and Meta-analysis.

OBJECTIVE: To review the literature on chest wall resection for recurrent breast cancer and evaluate overall survival (OS) and quality-of-life (QOL) outcomes. BACKGROUND: Full-thickness chest wall resection for recurrent breast cancer is controversial, as historically these recurrences have been thought of as a harbinger of systemic disease. METHODS: A systematic search in MEDLINE, EMBASE, and Cochrane CENTRAL identified 48 eligible studies, all retrospective, accounting for 1305 patients. The review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Primary end points were patient-centered QOL outcomes and OS; secondary outcomes included disease-free survival (DFS) and 30-day morbidity. Risk of bias was assessed using the Methodological Index for Non-Randomized Studies instrument and the Oxford Centre for Evidence-Based Medicine's levels of evidence tool. Random-effects meta-analysis was used to create pooled estimates. Meta-regressions and sensitivity analyses were used to explore study heterogeneity by age, year of publication, risk of bias, and surgical intent (curative vs palliative). RESULTS: Studies consistently reported excellent OS and DFS in properly selected patients. Pooled estimates for 5-year OS in all studies and those from the past 15 years were 40.8% [95% confidence interval (CI) 35.2-46.7) and 43.1% (95% CI 35.8-50.7), whereas pooled 5-year DFS was 27.1% (95% CI 16.6-41.0). Eight studies reported excellent outcomes related to QOL. Mortality was consistently low (<1%) and 30-day pooled morbidity was 20.2% (95% CI 15.3%-26.3%). Study quality varied, and risk of selection bias in included studies was high. CONCLUSIONS: Full-thickness chest wall resection can be performed with excellent survival and low morbidity. Few studies report on QOL; prospective studies should focus on patient-centered outcomes in this population.

Opioid Use After Discharge in Postoperative Patients: A Systematic Review.

BACKGROUND: Over the past 2 decades, there has been an increase in opioid use and subsequently, opioid deaths. The amount of opioid prescribed to surgical patients has also increased. The aim of this systematic review was to determine postdischarge opioid consumption in surgical patients compared with the amount of opioid prescribed. Secondary outcomes included adequacy of pain control and disposal methods for unused opioids. OBJECTIVE: The objective of this study is to characterize postdischarge opioid consumption and prescription patterns in surgical patients. METHODS: A systematic search in MEDLINE and EMBASE identified 11 patient survey studies reporting on postdischarge opioid use in 3525 surgical patients. RESULTS: The studies reported on a variety of surgical operations, including abdominal surgery, orthopedic procedures, tooth extraction, and dermatologic procedures. The majority of patients consumed 15 pills or less postdischarge. The proportion of used opioids ranged from 5.6% to 59.1%, with an outlier of 90.1% in pediatric spinal fusion patients. Measured pain scores of those taking opioids ranged between 2 and 5 out of 10 and the majority of patients were satisfied with their pain control. Seventy percent of patients kept the excess opioids. Where planned disposal methods were reported, between 4% and 59% of patients planned proper disposal. CONCLUSION: This study suggests that surgical patients are using substantially less opioid than prescribed. There is a lack of awareness regarding proper disposal of leftover medication, leaving excess opioid that may be used inappropriately by the patient or others. Education for providers and clinical practice guidelines that provide guidance on prescription of outpatient of opioids are required.

Thirty-day postoperative morbidity and mortality in elderly women with breast cancer: an analysis of the NSQIP database.

PURPOSE: Postoperative complication rates for elderly women undergoing breast cancer surgery have not been well studied. We describe the postoperative complication rates of elderly (≥ 70 years) women with breast cancer and compare them with young (40-69 years) women. METHODS: Data were extracted from the National Surgical Quality Improvement Program database (2004-2014). We included women with invasive breast cancer who underwent surgery. Outcomes were 30-day postoperative morbidity and mortality (complications), which were compared between young and elderly women. Morbidity was categorized using the Surgical Risk Preoperative Assessment System (SURPAS) clusters. RESULTS: We identified 100,037 women of which 26.7% were elderly. Compared to young women, elderly women were more likely to have more comorbidities and undergo breast-conserving surgery, but less likely to undergo lymph node surgery, breast reconstruction, and neoadjuvant chemotherapy. While the 30-day overall morbidity rate was not significantly different between young and elderly women (3.9 vs. 3.8%, p = 0.2), elderly women did have significantly higher rates of pulmonary, cardiac (arrest and myocardial infarction), venous thromboembolic, and neurological morbidity. Specific morbidities that showed significantly lower rates among elderly women included wound disruption and deep and organ space surgical site infection. Any cause death was significantly higher in elderly compared to young women (0.2 vs. 0.05%, p < 0.001). CONCLUSIONS: While some specific 30-day postoperative morbidities were more often seen in elderly women, the overall 30-day postoperative complication rate was very low. These data support the safety of breast cancer surgery in well-selected elderly patients.

Defining Non-inferiority Margins for Quality of Surgical Resection for Rectal Cancer: A Delphi Consensus Study.

INTRODUCTION: Quality of surgical resection metrics (QSRMs) have been used as surrogates for long-term oncologic outcomes in non-inferiority randomized clinical trials (RCTs) comparing laparoscopic and open surgery for rectal cancer. However, non-inferiority margins (ΔNI) for QSRMs have not been previously defined. METHODS: A two-round, web-based Delphi was used to define ΔNI for four QSRMs: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes. Overall, 130 international experts in rectal cancer (68 surgeons, 20 medical oncologists, 16 radiation oncologists, and 26 pathologists) were invited to participate. Experts were presented with evidence syntheses summarizing the association between QSRMs and long-term outcomes, and pooled quality of surgical resection outcomes for open surgery, and were asked to provide ΔNI for all outcomes balancing the risks and benefits of minimally invasive surgery. RESULTS: Seventy-two experts participated: 57 completed the initial questionnaire and 58 completed the revised questionnaire, with 43 participating in both rounds. Consensus was reached for all individual QSRM ΔNI but not for the composite. The mean (standard deviation) ΔNI was an absolute difference of 2.33% (1.59%) for the proportion of positive CRMs when comparing surgical interventions for the treatment of rectal cancer: 2.85% (1.83%) for incomplete PME; 1.28% (1.13%) for positive DRMs; and 2.71% (2.28%) for the composite. However, opinions varied widely for the composite outcome. CONCLUSIONS: Web-based Delphi processes are a feasible approach to generate ΔNI to evaluate novel surgical interventions. The generated ΔNI for QSRMs for rectal cancer can be used for future RCTs and non-inferiority meta-analyses.

Operative Strategies for Perforated Diverticulitis: A Systematic Review and Meta-analysis.

BACKGROUND: The traditional approach for perforated diverticulitis, the Hartmann procedure, has considerable morbidity and the challenge of stoma reversal. Alternative procedures, including primary resection and anastomosis and laparoscopic lavage, have been proposed but remain controversial. OBJECTIVE: The purpose of this study was to compare operative strategies for perforated diverticulitis. DATA SOURCES: MEDLINE, Embase, Cochrane Library, and the grey literature were searched from inception to October 2017. STUDY SELECTION: We included randomized clinical trials evaluating operative strategies for perforated diverticulitis. INTERVENTIONS: Hartmann procedure, primary resection and anastomosis, and laparoscopic lavage were included. MAIN OUTCOME MEASURES: Data were independently extracted by 2 investigators. Risk of bias was evaluated using the Cochrane risk-of-bias tool. Pooled risk ratios for major complications, reoperation, and mortality were determined using random-effects models. RESULTS: Six trials including 626 patients with perforated diverticulitis were identified. Laparoscopic lavage and sigmoidectomy had comparable rates of early reoperation and postoperative mortality; major complications (Clavien-Dindo >IIIa) were more frequent after laparoscopic lavage (RR = 1.68 (95% CI, 1.10-2.56); 3 trials, 305 patients). Comparing approaches for sigmoidectomy, primary resection and anastomosis had similar rates of major complications (RR = 0.88 (95% CI, 0.49-1.55); 3 trials, 255 patients) and postoperative mortality (RR = 0.58 (95% CI, 0.20-1.70); 3 trials, 254 patients) compared with the Hartmann procedure. However, patients who underwent primary resection and anastomosis were more likely to be stoma free at 12 months compared with the Hartmann procedure (RR = 1.40 (95% CI, 1.18-1.67); 4 trials, 283 patients) and to experience fewer major complications related to the stoma reversal procedure (RR = 0.26 (95% CI, 0.07-0.89); 4 trials, 186 patients). LIMITATIONS: There were no limitations to this study. CONCLUSIONS: Laparoscopic lavage is associated with increased risk of major complications versus primary resection for Hinchey III diverticulitis. The lower rate of stoma reversal and higher rate of complications after the Hartmann procedure suggest primary resection and anastomosis as the optimal management of perforated diverticulitis.

Harmful or Physiologic: Diagnosing Fibrinolysis Shutdown in a Trauma Cohort With Rotational Thromboelastometry.

BACKGROUND: Despite its central role in early trauma coagulopathy, abnormal fibrinolysis continues to be poorly understood. Excessive fibrinolysis is a known contributor to mortality. Recent studies with thromboelastography (TEG) suggest decreased fibrinolysis (or shutdown) may be just as harmful. Considering the broad use of 2 different viscoelastic assays, which are not interchangeable, we proposed for the first time to define and characterize fibrinolysis shutdown using rotational thromboelastometry (ROTEM). METHODS: Retrospective cohort study of severely injured patients with admission ROTEM. Shutdown was defined by the best Youden index value of the maximum lysis. Fibrinolysis phenotypes were physiologic, hyperfibrinolysis, and shutdown. Multivariable logistic regression evaluated association between Injury Severity Score and the fibrinolysis phenotypes, and the association among shutdown phenotype with mortality, blood transfusion, and thrombotic events. RESULTS: Five hundred fifty patients were included. Maximum lysis <3.5% was selected to define shutdown. Predominant phenotype was physiologic (70.7%), followed by shutdown (25.6%) and hyperfibrinolysis (3.6%). Shutdown patients had higher Injury Severity Score, lower base excess, and required more transfusions than physiologic group. Shutdown was associated with acidosis (base excess: odds ratio [OR] for a 1 mEq/L increase, 0.93; 95% confidence interval [CI], 0.88-0.98; P = .0094) and the combination of clotting derangements, higher clot firmness (maximum clot formation: OR for a 2 mm increase, 1.8; 95% CI, 1.5-2.27; P < .0001), lower fibrinogen (OR for a 0.5 g/dL decrease, 1.47; 95% CI, 1.18-1.84; P = .0006), and poor clot formation dynamics (clot formation time: OR for a 5 seconds increase, 1.25; 95% CI, 1.15-1.36; P < .0001). Fibrinolysis shutdown was not independently associated with mortality (OR, 0.61; 95% CI, 0.28-1.33; P = .21), massive transfusion (OR, 2.14; 95% CI, 0.79-5.74; P = .1308), or thrombotic events (OR, 1.08; 95% CI, 0.37-3.15; P = .874). Shutdown was associated with increased 24-hour transfusion (OR, 2.24; 95% CI, 1.24-4.04; P = .007). CONCLUSIONS: Despite higher injury burden, evidence of shock, and greater need for blood transfusions, early fibrinolysis shutdown was not associated with mortality, suggesting that it could represent an adaptive physiologic response to life-threatening trauma.

Intra-arterial therapies for unresectable and chemorefractory colorectal cancer liver metastases: a systematic review and meta-analysis.

BACKGROUND: A large proportion of patients with colorectal cancer liver metastases (CRCLM) not amenable to curative liver resection will progress on systemic therapy. Intra-arterial therapies (IAT) including conventional transarterial chemoembolization (cTACE), drug eluting beads (DEB-TACE) and yttrium-90 radioembolization (Y-90) are indicated to prolong survival and palliate symptoms. The purpose of this systematic review and meta-analysis is to compare the survival benefit and radiologic response of three intra-arterial therapies in patients with chemorefractory and unresectable CRCLM. METHODS: A systematic search for eligible references in the Cochrane Library and the EMBASE, MEDLINE and TRIP databases from January 2000 to November 2016 was performed in accordance with PRISMA guidelines. Methodological quality of included studies was assessed using the MINORS scale. One-year overall survival rates and RECIST responder rates were pooled using inverse-variance weighted random-effects models. Overall survival outcomes were collected according to transformed pooled median survivals from first IAT with a subgroup analysis of patients with extrahepatic disease. RESULTS: Twenty-three prospective studies were included and analyzed: 5 cTACE (n = 746), 5 DEB-TACE (n = 222) and 13 Y-90 (n = 615). All but five were clinical trials. Eleven of 13 Y-90 studies were industry funded. Pooled RECIST response rates with 95% confidence intervals (CI) were: cTACE 23% (9.7, 36), DEB-TACE 36% (0, 73) and Y-90 23% (11, 34). The pooled 1-year survival rates with CI were: cTACE, 70% (49, 87), DEB-TACE, 80% (74, 86) and Y-90, 41% (28, 54). Transformed pooled median survivals from first IAT and ranges for cTACE, DEB-TACE and Y-90 were 16 months (9.0-23), 16 months (7.3-25) and 12 months (7.0-15), respectively. Significant heterogeneity in inclusion criteria and reporting of confounders, including previous therapy, tumor burden and post-IAT therapy, precluded statistical comparisons between the three therapies. CONCLUSION: Methodological and statistical heterogeneity precluded consensus on the optimal treatment strategy. Given the common use and significant cost of radioembolization in this setting, a more robust prospective comparative trial is warranted.

Oncologic Outcomes Following Laparoscopic versus Open Resection of pT4 Colon Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Locally advanced colon cancer is considered a relative contraindication for laparoscopic resection, and clinical trials addressing the oncologic safety are lacking. OBJECTIVE: The aim of this study was to synthesize the oncologic outcomes associated with laparoscopic versus conventional open surgery for locally advanced colon cancers. DATA SOURCES: We systematically searched Medline, Embase, Central, and ClinicalTrials.gov. STUDY SELECTION: Two reviewers independently screened the literature for controlled trials or observational studies comparing curative-intent laparoscopic and open surgery for colon cancer. Studies were included if it was possible to determine outcomes for the T4 colon cancers separately, either reported in the article or calculated with individual patient data. INTERVENTIONS: Included studies were systematically reviewed and assessed for risk of bias. Meta-analyses were done by using random-effects models. MAIN OUTCOME MEASURES: Outcomes of interest were disease-free survival, overall survival, resection margins, and lymph node harvest. RESULTS: Of 2878 identified studies, 5 observational studies met eligibility criteria with a total of 1268 patients (675 laparoscopic, 593 open). There was no significant difference in overall survival (HR, 1.28; 95% CI, 0.94-1.72), disease-free survival (HR, 1.20; 95% CI, 0.90-1.61), or positive surgical margins (OR, 1.16; 95% CI, 0.58-2.32) between the groups. The open group had a larger lymph node retrieval (pooled mean difference, 2.26 nodes; 95% CI, 0.58-3.93). The pooled rate of conversion from laparoscopy to an open procedure was 18.6% (95% CI, 9.3%-27.9%). LIMITATIONS: These results are limited by the inherent selection bias in the included nonrandomized studies. CONCLUSIONS: Based on the available literature, minimally invasive resection of selected locally advanced colon cancer is oncologically safe. There is a small increase in lymph node harvest with open resections, but it is unclear whether this is clinically significant. Surgeons should be prepared for a significant rate of conversion to laparotomy as required to perform en bloc resection.

Preoperative localization of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Preoperative colorectal tumor localization is crucial for appropriate resection and treatment planning. As the localization accuracy of conventional colonoscopy is considered to be low, several localization techniques have been developed. We systematically reviewed the tumor localization error rates of several preoperative endoscopic techniques and synthesized information on risk factors for localization errors and procedure-related adverse events. METHODS: MEDLINE, EMBASE, the Cochrane Library, and the grey literature were searched. Studies were included if they reported tumor localization errors in patients with colorectal cancer undergoing resection with curative intent. Using random-effects models, pooled incidence of tumor localization errors were derived for conventional colonoscopy and colonoscopic tattooing. Due to the lack of comparative studies, a direct comparison of the pooled estimates was performed. Procedure-related adverse events, risk factors for localization errors, and the localization outcomes of other techniques such as colonoscopic clip placement, radioguided occult colonic lesion identification, and the use of magnetic endoscope imaging were also synthesized. RESULTS: A total of 38 non-randomized controlled and observational studies were included in this review (2578 patients underwent conventional colonoscopy and 643 colonoscopic tattooing). The pooled incidence of localization errors with conventional colonoscopy was 15.4 % (95 % CI 12.0-18.7), whereas that of colonoscopic tattooing was 9.5 % (95 % CI 5.7-13.3), mean difference 5.9 % (95 % CI 0.65-11.14, p = 0.03). Adverse events secondary to tattooing were infrequent, and most were cases of ink spillage. Limited information was available for other localization techniques. CONCLUSION: Conventional colonoscopy has a higher incidence of localization error compared to colonoscopic tattooing for localization of colorectal cancer. Colonoscopic tattooing is safe and leads to fewer tumor localization errors. Given the widespread adoption of laparoscopic resections for colorectal cancer, routine colonoscopic tattooing should be adopted. However, studies directly comparing different localization techniques are needed.

Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques.

Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.