Whole body physiology model to simulate respiratory depression of fentanyl and associated naloxone reversal.

BACKGROUND: Opioid use in the United States and abroad is an endemic part of society with yearly increases in overdose rates and deaths. In response, the use of the safe and effective reversal agent, naloxone, is being fielded and used by emergency medical technicians at a greater rate. There is evidence that repeated dosing of a naloxone nasal spray is becoming more common. Despite this we lack repeated dosing guidelines as a function of the amount of opiate the patient has taken. METHODS: To measure repeat dosing guidelines, we construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdose scenarios. We run a single patient through multiple goal directed resuscitation protocols and measure total naloxone administered. RESULTS: Here we show that naloxone is highly effective at reversing the respiratory symptoms of the patient and recommend dosing requirements as a function of the fentanyl amount administered. We show that for increasing doses of fentanyl, naloxone requirements also increase. The rescue dose displays a nonlinear response to the initial opioid dose. This nonlinear response is largely logistic with three distinct phases: onset, rapid acceleration, and a plateau period for doses above 1.2 mg. CONCLUSIONS: This paper investigates the total naloxone dose needed to properly reverse respiratory depression associated with fentanyl overdose. We show that the current guidelines for a rescue dose may be much lower than required.

Opioids such as fentanyl are a type of drug that reduce pain. However, the overdose of opioids causes severe breathing issues that can lead to death. Overdose of opioids is an increasing problem across the globe, particularly among people with opioid use disorder. To prevent death, first responders can administer a drug called naloxone that rapidly reverses the effects of opioids. However, the optimum amount of naloxone to administer is unclear. We use a mathematical model to investigate the effect of administering different amounts of naloxone during fentanyl overdose. Our findings suggest that the amount of naloxone to administer that is currently usually administered may be insufficient. Further research should enable naloxone usage guidelines to be optimized, which could improve survival following opioid overdose.

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy.

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

Does Time to Asystole in Donors After Circulatory Death Impact Recipient Outcome in Liver Transplantation?

BACKGROUND: The agonal phase can vary following treatment withdrawal in donor after circulatory death (DCD). There is little evidence to support when procurement teams should stand down in relation to donor time to death (TTD). We assessed what impact TTD had on outcomes following DCD liver transplantation. METHODS: Data were extracted from the UK Transplant Registry on DCD liver transplant recipients from 2006 to 2021. TTD was the time from withdrawal of life-sustaining treatment to asystole, and functional warm ischemia time was the time from donor systolic blood pressure and/or oxygen saturation falling below 50 mm Hg and 70%, respectively, to aortic perfusion. The primary endpoint was 1-y graft survival. Potential predictors were fitted into Cox proportional hazards models. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. RESULTS: One thousand five hundred fifty-eight recipients of a DCD liver graft were included. Median TTD in the entire cohort was 13 min (interquartile range, 9-17 min). Restricted cubic splines revealed that the risk of graft loss was significantly greater when TTD ≤14 min. After 14 min, there was no impact on graft loss. Prolonged hepatectomy time was significantly associated with graft loss (hazard ratio, 1.87; 95% confidence interval, 1.23-2.83; P = 0.003); however, functional warm ischemia time had no impact (hazard ratio, 1.00; 95% confidence interval, 0.44-2.27; P > 0.9). CONCLUSIONS: A very short TTD was associated with increased risk of graft loss, possibly because of such donors being more unstable and/or experiencing brain stem death as well as circulatory death. Expanding the stand down times may increase the utilization of donor livers without significantly impairing graft outcome.

Liver Transplantation for Nonresectable Colorectal Liver Metastases (CRLM).

Transplantation represents the most radical locoregional therapy through removal of the liver, associated vasculature and locoregional lymph nodes, and replacing it with an allograft. Recent evidence has demonstrated that transplantation for unresectable CRLM is feasible with acceptable post-transplant outcomes in a highly selected cohort of patients. Controversy exists regarding whether transplantation is an appropriate treatment for such patients, due to concerns regarding disease recurrence in the transplanted graft in an immunosuppressed recipient along with utilising a donor liver which are in short supply. Expanding the indications for liver transplantation may also limit access for other patients with end-stage liver disease having ethical implications due to the effect of increasing the waiting list. In this review, we summarise the current evidence for liver transplantation in patients with nonresectable CRLM and highlight unresolved controversies and future directions for this type of treatment.

The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation.

The time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

Fibrin-based haemostatic agents for reducing blood loss in adult liver resection.

BACKGROUND: Liver resection is the optimal treatment for selected benign and malignant liver tumours, but it can be associated with significant blood loss. Numerous anaesthetic and surgical techniques have been developed to reduce blood loss and improve perioperative outcomes. One such technique is the application of topical fibrin-based haemostatic agents (FBHAs) to the resection surface. There is no standard practice for FBHA use, and a variety of commercial agents and devices are available, as well as non-FBHAs (e.g. collagen-based agents). The literature is inconclusive on the effectiveness of these methods and on the clinical benefits of their routine use. OBJECTIVES: To evaluate the benefits and harms of fibrin-based haemostatic agents in reducing intraoperative blood loss in adults undergoing liver resection. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group (CHBG) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science up to 20 January 2023. We also searched online trial registries, checked the reference lists of all primary studies, and contacted the authors of included trials for additional published or unpublished trials. SELECTION CRITERIA: We considered for inclusion all randomised clinical trials evaluating FBHAs versus no topical intervention or non-FBHAs, irrespective of publication type, publication status, language of publication, and outcomes reported. Eligible participants could have any liver pathology and be undergoing major or minor liver resections through open or laparoscopic surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the literature search and used data extraction forms to collate the results. We expressed dichotomous outcome results as risk ratios (RRs) and continuous outcome results as mean differences (MDs), each with their corresponding 95% confidence interval (CI). We used a random-effects model for the main analyses. Our primary outcomes were perioperative mortality, serious adverse events, haemostatic efficacy, and health-related quality of life. Our secondary outcomes were efficacy as sealant, adverse events considered non-serious, operating time, and length of hospital stay. We assessed the certainty of the evidence with GRADE and presented results in two summary of findings tables. MAIN RESULTS: We included 22 trials (2945 participants) evaluating FBHAs versus no intervention or non-FBHAs; 19 trials with 2642 participants provided data for the meta-analyses. Twelve trials reported commercial funding, one trial reported no financial support, and nine trials provided no information on funding. Below we present the most clinically relevant outcome results, also displayed in our summary of findings table. Fibrin-based haemostatic agents versus no intervention Six trials (1001 participants) compared FBHAs with no intervention. One trial was at low risk of bias in all five domains, and all other trials were at high or unclear risk of bias in at least one domain. Two trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with no intervention have an effect on perioperative mortality (RR 2.58, 95% CI 0.89 to 7.44; 4 trials, 782 participants), serious adverse events (RR 0.96, 95% CI 0.88 to 1.05; 4 trials, 782 participants), postoperative transfusion (RR 1.04, 95% CI 0.77 to 1.40; 5 trials, 864 participants), reoperation (RR 2.92, 95% CI 0.58 to 14.61; 2 trials, 612 participants), or postoperative bile leak (RR 1.00, 95% CI 0.67 to 1.48; 4 trials, 782 participants), as the certainty of evidence was very low for all these outcomes. Fibrin-based haemostatic agents versus non-fibrin-based haemostatic agents Sixteen trials (1944 participants) compared FBHAs with non-FBHAs. All trials had at least one domain at high or unclear risk of bias. Twelve trials were at high risk of bias related to blinding. It is unclear if FBHAs compared with non-FBHAs have an effect on perioperative mortality (RR 1.03, 95% CI 0.62 to 1.72; 11 trials, 1436 participants), postoperative transfusion (RR 0.92, 95% CI 0.68 to 1.25; 7 trials, 599 participants), reoperation (RR 0.48, 95% CI 0.25 to 0.90; 3 trials, 358 participants), or postoperative bile leak (RR 1.15, 95% CI 0.60 to 2.21; 9 trials, 1115 participants), as the certainty of evidence was very low for all these outcomes. FBHAs compared with non-FBHAs may have little or no effect on the risk of serious adverse events (RR 0.99, 95% CI 0.95 to 1.03; 9 trials, 1176 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence for the outcomes in both comparisons (FBHAs versus no intervention and FBHAs versus non-FBHAs) was of very low certainty (or low certainty in one instance) and cannot justify the routine use of FBHAs to reduce blood loss in adult liver resection. While the meta-analysis showed a reduced risk of reoperation with FBHAs compared with non-FBHAs, the analysis was confounded by the small number of trials reporting the event and the risk of bias in all these trials. Future trials should focus on the use of FBHAs in people undergoing liver resection who are at particularly high risk of bleeding. Investigators should evaluate clinically meaningful and patient-important outcomes and follow the SPIRIT and CONSORT statements.

The development of new onset post-pancreatitis diabetes mellitus during hospitalisation is not associated with adverse outcomes.

BACKGROUND: Patients with acute pancreatitis (AP) are at increased risk of developing post pancreatitis diabetes mellitus (PPDM). The aim of this study was to explore the incidence, risk factors and sequelae of developing PPDM in a UK tertiary referral centre. METHODS: A prospectively collected single centre database was analysed. Patients were grouped according to whether they had DM or not. Patients with DM were further sub-grouped into pre-existing DM or PPDM. Outcomes measured included incidence of PPDM, mortality, ITU admission, overall length of stay (LOS) and local pancreatitis specific complications. RESULTS: 401 patients with AP between 2018 and 2021 were identified. Sixty-four (16%) of patients had pre-existing DM. Thirty-eight patients (11%) developed PPDM [mild (n = 4, 8.2%), moderate (n = 19, 10.1%), severe (n = 15, 15.2%), p = 0.326]. 71% required insulin therapy for the duration of follow-up or until death. The development of PPDM was strongly associated with the presence (p < 0.001) and extent of necrosis (p < 0.0001). On multi-variate analysis, the development of PPDM was not an independent predictor for increased LOS, ITU admission or overall mortality. CONCLUSIONS: The incidence of PPDM was 11%. There was a strong correlation with extent of necrosis and the development of PPDM. PPDM did not adversely affect morbidity or mortality.

Neoadjuvant Chemotherapy for Intrahepatic, Perihilar, and Distal Cholangiocarcinoma: a National Population-Based Comparative Cohort Study.

INTRODUCTION: Data supporting the utilization of neoadjuvant chemotherapy (NAC) in patients receiving resection for cholangiocarcinoma (CCA) remains uncertain. We aimed to determine whether NAC followed by resection improves long-term survival in intrahepatic (iCCA), perihilar (hCCA), and distal (dCCA) cholangiocarcinoma, analyzed separately. METHODS: Patients undergoing surgery for iCCA, hCCA, and dCCA, receiving either none, NAC, or adjuvant chemotherapy (AC) from 2010 to 2016 were identified from the National Cancer Database (NCDB). Cox regression was performed to account for selection bias and to assess the impact of surgery alone (SA) versus either NAC or AC on overall survival (OS). RESULTS: There were 9411 patients undergoing surgery for iCCA (n = 3772, 39.5%), hCCA (n = 1879, 20%), and dCCA (n = 3760, 40%). Of these, 10.6% (n = 399), 6.5% (n = 123), and 7.2% (n = 271) with iCCA, hCCA, and dCCA received NAC, respectively. On adjusted analyses, patients receiving NAC followed by surgery had significantly improved OS, compared to SA for iCCA (HR 0.75, CI95% 0.64-0.88, p < 0.001), hCCA (HR 0.72, CI95% 0.54-0.97, p = 0.033), and for dCCA (HR 0.65, CI95% 0.53-0.78, p < 0.001). However, sensitivity analyses demonstrated no differences in OS between NACs, followed by surgery or AC after surgery in iCCA (HR 1.19, CI95% 0.99-1.45, p = 0.068), hCCA (HR 0.83 CI95% 0.59-1.19, p = 0.311), and dCCA (HR 1.13 CI95% 0.91-1.41, p = 0.264). CONCLUSIONS: This study associated NAC with increased OS for all CCA subtypes, even in patients with margin-negative and node-negative disease; however, no differences were found between NAC and AC. Our results highlight that a careful and interdisciplinary evaluation should be sought to consider NAC in CCA and warrant the need of larger studies to provide robust recommendation.

Benchmarking of robotic and laparoscopic spleen-preserving distal pancreatectomy by using two different methods.

BACKGROUND: Benchmarking is an important tool for quality comparison and improvement. However, no benchmark values are available for minimally invasive spleen-preserving distal pancreatectomy, either laparoscopically or robotically assisted. The aim of this study was to establish benchmarks for these techniques using two different methods. METHODS: Data from patients undergoing laparoscopically or robotically assisted spleen-preserving distal pancreatectomy were extracted from a multicentre database (2006-2019). Benchmarks for 10 outcomes were calculated using the Achievable Benchmark of Care (ABC) and best-patient-in-best-centre methods. RESULTS: Overall, 951 laparoscopically assisted (77.3 per cent) and 279 robotically assisted (22.7 per cent) procedures were included. Using the ABC method, the benchmarks for laparoscopically assisted and robotically assisted spleen-preserving distal pancreatectomy respectively were: 150 and 207 min for duration of operation, 55 and 100 ml for blood loss, 3.5 and 1.7 per cent for conversion, 0 and 1.7 per cent for failure to preserve the spleen, 27.3 and 34.0 per cent for overall morbidity, 5.1 and 3.3 per cent for major morbidity, 3.6 and 7.1 per cent for pancreatic fistula grade B/C, 5 and 6 days for duration of hospital stay, 2.9 and 5.4 per cent for readmissions, and 0 and 0 per cent for 90-day mortality. Best-patient-in-best-centre methodology revealed milder benchmark cut-offs for laparoscopically and robotically assisted procedures, with operating times of 254 and 262.5 min, blood loss of 150 and 195 ml, conversion rates of 5.8 and 8.2 per cent, rates of failure to salvage spleen of 29.9 and 27.3 per cent, overall morbidity rates of 62.7 and 55.7 per cent, major morbidity rates of 20.4 and 14 per cent, POPF B/C rates of 23.8 and 24.2 per cent, duration of hospital stay of 8 and 8 days, readmission rates of 20 and 15.1 per cent, and 90-day mortality rates of 0 and 0 per cent respectively. CONCLUSION: Two benchmark methods for minimally invasive distal pancreatectomy produced different values, and should be interpreted and applied differently.

Benchmarking of minimally invasive distal pancreatectomy with splenectomy: European multicentre study.

BACKGROUND: Benchmarking is the process to used assess the best achievable results and compare outcomes with that standard. This study aimed to assess best achievable outcomes in minimally invasive distal pancreatectomy with splenectomy (MIDPS). METHODS: This retrospective study included consecutive patients undergoing MIDPS for any indication, between 2003 and 2019, in 31 European centres. Benchmarks of the main clinical outcomes were calculated according to the Achievable Benchmark of Care (ABC™) method. After identifying independent risk factors for severe morbidity and conversion, risk-adjusted ABCs were calculated for each subgroup of patients at risk. RESULTS: A total of 1595 patients were included. The ABC was 2.5 per cent for conversion and 8.4 per cent for severe morbidity. ABC values were 160 min for duration of operation time, 8.3 per cent for POPF, 1.8 per cent for reoperation, and 0 per cent for mortality. Multivariable analysis showed that conversion was associated with male sex (OR 1.48), BMI exceeding 30 kg/m2 (OR 2.42), multivisceral resection (OR 3.04), and laparoscopy (OR 2.24). Increased risk of severe morbidity was associated with ASA fitness grade above II (OR 1.60), multivisceral resection (OR 1.88), and robotic approach (OR 1.87). CONCLUSION: The benchmark values obtained using the ABC method represent optimal outcomes from best achievable care, including low complication rates and zero mortality. These benchmarks should be used to set standards to improve patient outcomes.

Laparoscopic versus open resections in the posterosuperior liver segments within an enhanced recovery programme (ORANGE Segments): study protocol for a multicentre randomised controlled trial.

BACKGROUND: A shift towards parenchymal-sparing liver resections in open and laparoscopic surgery emerged in the last few years. Laparoscopic liver resection is technically feasible and safe, and consensus guidelines acknowledge the laparoscopic approach in the posterosuperior segments. Lesions situated in these segments are considered the most challenging for the laparoscopic approach. The aim of this trial is to compare the postoperative time to functional recovery, complications, oncological safety, quality of life, survival and costs after laparoscopic versus open parenchymal-sparing liver resections in the posterosuperior liver segments within an enhanced recovery setting. METHODS: The ORANGE Segments trial is an international multicentre randomised controlled superiority trial conducted in centres experienced in laparoscopic liver resection. Eligible patients for minor resections in the posterosuperior segments will be randomised in a 1:1 ratio to undergo laparoscopic or open resections in an enhanced recovery setting. Patients and ward personnel are blinded to the treatment allocation until postoperative day 4 using a large abdominal dressing. The primary endpoint is time to functional recovery. Secondary endpoints include intraoperative outcomes, length of stay, resection margin, postoperative complications, 90-day mortality, time to adjuvant chemotherapy initiation, quality of life and overall survival. Laparoscopic liver surgery of the posterosuperior segments is hypothesised to reduce time to functional recovery by 2 days in comparison with open surgery. With a power of 80% and alpha of 0.04 to adjust for interim analysis halfway the trial, a total of 250 patients are required to be randomised. DISCUSSION: The ORANGE Segments trial is the first multicentre international randomised controlled study to compare short- and long-term surgical and oncological outcomes of laparoscopic and open resections in the posterosuperior segments within an enhanced recovery programme. TRIAL REGISTRATION: ClinicalTrials.gov NCT03270917 . Registered on September 1, 2017. Before start of inclusion. PROTOCOL VERSION: version 12, May 9, 2017.

Comparative analysis of open, laparoscopic and robotic distal pancreatic resection: The United Kingdom's first single-centre experience.

INTRODUCTION: Laparoscopic distal pancreatectomy (LDP) has potential advantages over its open equivalent open distal pancreatectomy (ODP) for pancreatic disease in the neck, body and tail. Within the United Kingdom (UK), there has been no previous experience describing the role of robotic distal pancreatectomy (RDP). This study evaluated differences between ODP, LDP and RDP. METHODS: Patients undergoing distal pancreatectomy performed in the Department of Hepatobiliary and Pancreatic Surgery at the Freeman Hospital between September 2007 and December 2018 were included from a prospectively maintained database. The primary outcome measure was length of hospital stay, and the secondary outcome measures were complication rates graded according to the Clavien-Dindo classification. RESULTS: Of the 125 patients, the median age was 61 years and 46% were male. Patients undergoing RDP (n = 40) had higher American Society of Anesthesiologists grading III compared to ODP (n = 38) and LDP (n = 47) (57% vs. 37% vs. 38%, P = 0.02). RDP had a slightly lower but not significant conversion rate (10% vs. 13%, P = 0.084), less blood loss (median: 0 vs. 250 ml, P < 0.001) and a higher rate of splenic preservation (30% vs. 2%, P < 0.001) and shorter operative time, once docking time excluded (284 vs. 300 min, P < 0.001) compared to LDP. RDP had a higher R0 resection rate than ODP and LDP (79% vs. 47% vs. 71%, P = 0.078) for neoplasms. RDP was associated with significantly shorter hospital stay than LDP and ODP (8 vs. 9 vs. 10 days, P = 0.001). While there was no significant different in overall complications across the groups, RDP was associated with lower rates of Grade C pancreatic fistula than ODP and LDP (2% vs. 5% vs. 6%, P = 0.194). CONCLUSION: Minimally invasive pancreatic resection offers potential advantages over ODP, with a trend showing RDP to be marginally superior when compared to conventional LDP, but it is accepted that that this is likely to be at greater expense compared to the other current techniques.

Adjuvant radiotherapy improves long-term survival after resection for gallbladder cancer A population-based cohort study.

BACKGROUND: Data supporting routine use of adjuvant radiotherapy (RT) compared to without RT (noRT) for gallbladder cancer (GBC) is unclear. This study aimed to determine whether RT improves long-term survival following resection for GBC. METHODS: Patients receiving resection for GBC followed by RT from 2004 to 2016 were identified from the National Cancer Database (NCDB). Patients with survival <6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of RT on overall survival. RESULTS: Of 7514 (77%) noRT and 2261 (23%) RT, 2067 noRT and 2067 RT patients remained after PSM. After matching, RT was associated with improved survival (median: 26.2 vs 21.5 months, p < 0.001), which remained after multivariable adjustment (HR: 0.82, CI95%: 0.76-0.89, p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (HR: 0.84, CI95%: 0.77-0.93), N1 (HR: 0.77, CI95%: 0.68-0.88), N2/N3 (HR: 0.56, CI95%: 0.35-0.91), margin status: R0 (HR: 0.85, CI95%: 0.78-0.93), R1 (HR: 0.78, CI95%: 0.68-0.88) and use of adjuvant chemotherapy (AC) (HR: 0.67, CI95%: 0.57-0.79). Benefit with RT were also seen in patients with T2 - T4 disease and in patients undergoing simple and extended cholecystectomy. CONCLUSION: RT following resection was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings may suggest addition of RT into multimodality therapy for GBC.

Does minimally invasive liver resection improve long-term survival compared to open resection for hepatocellular carcinoma? A systematic review and meta-analysis.

INTRODUCTION: Minimally invasive liver surgery for hepatocellular carcinoma has gained widespread interest as an alternative to conventional open liver surgery. However, long-term survival benefits of this approach seem unclear. This meta-analysis was conducted to investigate long-term survival following minimally invasive liver surgery. METHOD: A systematic review was performed to identify studies comparing long-term survival after minimally invasive liver surgery and open liver surgery until January 2020. The I2 test was used to test for statistical heterogeneity and publication bias was assessed using Egger test. Random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year mortality, and disease-specific 5-year and 3-year mortality. Meta-regression was performed for the 5-year and 3-year survival outcomes with adjustment for study factors (region, design), annual center volume, patient factors (American Society of Anesthesiologists (ASA) grade, gender, age, body mass index, cirrhosis, tumor size, and number), and resection extent. Sensitivity analyses were performed on studies by study year, region, annual center volume, and resection type. RESULT: The review identified 50 relevant studies including 13,731 patients undergoing liver resection for hepatocellular carcinoma of which 4071 (25.8%) underwent minimally invasive liver surgery. Pooled analysis revealed similar all-cause (odds ratio: 0.83, 95% confidence interval: 0.70-1.11, p = 0.3) and disease-specific (odds ratio: 0.93, 95% confidence interval: 0.80-1.09, p = 0.4) 5-year mortality after minimally invasive liver surgery compared with open liver surgery. Sensitivity analysis of published studies from 2010 to 2019 demonstrated a significantly lower disease-specific 3-year mortality (odds ratio: 0.75, 95% confidence interval: 0.59-0.96, p = 0.022) and all-cause 5-year mortality (odds ratio: 0.63, 95% confidence interval: 0.50-0.81, p = 0.002). Meta-regression identified no confounding factors in all analyses. CONCLUSIONS: Improvement in minimally invasive liver surgery techniques over the past decade appears to demonstrate superior disease-specific mortality with minimally invasive liver surgery compared to open liver surgery. Therefore, minimally invasive liver surgery can be recommended as an alternative surgical approach for hepatocellular carcinoma.

Adjuvant chemotherapy for perihilar cholangiocarcinoma: A population-based comparative cohort study.

BACKGROUND: Data supporting routine use of adjuvant chemotherapy (AC) compared to no AC (noAC) for perihilar cholangiocarcinoma (hCCA) is unclear. This study aimed to determine whether AC improves long-term survival following resection for hCCA. METHODS: Patients receiving resection for hCCA followed by AC or no AC from 2010 to 2016 were identified from the National Cancer Database (NCDB). Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival. RESULTS: Of 924 (56%) noAC and 719 (44%) AC, 320 noAC and 320 AC patients remained after PSM. After matching, AC was associated with improved survival (median: 28.2 vs 19.9 months, p < 0.001), which remained after multivariable adjustment (HR: 0.61, CI95%: 0.50-0.75, p < 0.001). On multivariable interaction analyses, the benefit of AC over no AC persisted irrespective of nodal status: N0 (HR: 0.62, CI95%: 0.41-0.92, p = 0.019), N1 (HR: 0.52, CI95%: 0.36-0.75, p = 0.001), N2 (HR: 0.31, CI95%: 0.11-0.90, p = 0.032), Nx (HR: 0.22, CI95%: 0.09-0.55, p = 0.001) and margin status: R0 (HR: 0.74, CI95%: 0.57-0.97, p = 0.026), R1 (HR: 0.31, CI95%: 0.21-0.47, p < 0.001). Stratified analysis by nodal, margin and AC status demonstrated consistent results. CONCLUSION: AC following resection for hCCA was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings suggest incorporation of AC into multimodality therapy for hCCA in all cases, where appropriate.

A Network Meta-Analysis of Induction Immunosuppression for Simultaneous Pancreas-Kidney Transplant From Randomized Clinical Trials.

OBJECTIVES: Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab.Thisnetwork meta-analysis aimedto compare differentinductionregimens for simultaneouspancreaskidney transplantin terms ofbothpancreas and patient graft survival, as well to assess acute rejection. MATERIALS AND METHODS: A systematic review was conducted to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for simultaneous pancreas-kidney transplant. Study characteristics, postoperative data (patient, pancreas, and kidney graft survival), complications (eg, bleeding), infection rates, and malignancy rates were extracted. We compared all regimens using randomeffects network meta-analyses to maintain randomization within trials. RESULTS: This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included antithymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked first for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for acute rejection (both pancreas and kidney). Rates of majorinfection (ie, cytomegalovirus) and malignancy were reported in 3 studies, precluding a reliable analysis. CONCLUSIONS: Daclizumab with 2 doses, given before simultaneous pancreas-kidney transplant, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-interleukin 2 induction regimen (basiliximab) has demonstrated promising results in nonrandomized series, warranting that further highquality large-scale randomized clinical trials are still needed.

Adjuvant Chemotherapy Associated with Survival Benefit Following Neoadjuvant Chemotherapy and Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Population-Based Cohort Study.

BACKGROUND: Data supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection. METHODS: Patients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of < 6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression analysis were performed to account for selection bias and analyze the impact of AC on overall survival. RESULTS: Of 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p < 0.001), which remained after multivariable adjustment (HR 0.81, 95% confidence interval [CI] 0.75-0.88; p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (hazard ratio [HR] 0.80, 95% CI 0.72-0.90; p < 0.001), N1 (HR 0.76, 95% CI 0.67-0.86; p < 0.001), R0 margin status (HR 0.82, 95% CI 0.75-0.89; p < 0.001), R1 margin status (HR 0.77, 95% CI 0.64-0.93; p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74-0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73-0.88; p < 0.001). Stratified analysis by nodal, margin, and NART status demonstrated consistent results. CONCLUSION: AC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC.

Long-term survival after minimally invasive resection versus open pancreaticoduodenectomy for periampullary cancers: a systematic review, meta-analysis and meta-regression.

BACKGROUND: It remains unclear whether minimally invasive pancreaticoduodenectomy (MIPD) and open pancreaticoduodenectomy (OPD) influences long-term survival in periampullary cancers. This review aims evaluate long-term survival between MIPD and OPD for periampullary cancers. METHODS: A systematic review was performed to identify studies comparing long-term survival after MIPD and OPD. The I2 test was used to test for statistical heterogeneity and publication bias using Egger test. Random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year survival, and disease-specific 5-year and 3-year survival. Meta-regression was performed for the 5-year and 3-year survival outcomes with adjustment for study (region, design, case matching), hospital (centre volume), patient (ASA grade, gender, age), and tumor (stage, neoadjuvant therapy, subtype (i.e. ampullary, distal bile duct, duodenal, pancreatic)). Sensitivity analyses performed on studies including pancreatic ductal adenocarcinoma (PDAC) only. RESULTS: The review identified 31 relevant studies. Among all 58,622 patients, 8716 (14.9%) underwent MIPD and 49,875 (85.1%) underwent OPD. Pooled analysis revealed similar 5-year overall survival after MIPD compared with OPD (HR: 0.78, 95% CI 0.50-1.22, p = 0.2). Meta-regression indicated case matching, and ASA Grade II and III as confounding covariates. The statistical heterogeneity was limited (I2 = 12, χ2 = 0.26) and the funnel plot was symmetrical both according to visual and statistical testing (Egger test = 0.32). Sensitivity subset analyses for PDAC demonstrated similar 5-year overall survival after MIPD compared with OPD (HR 0.69, 95% CI: 0.32-1.50, p = 0.3). CONCLUSION: Long-term survival after MIPD is non-inferior to OPD. Thus, MIPD can be recommended as a standard surgical approach for periampullary cancers.