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The value of individual variable contributions to post-hepatectomy length of stay (LOS) are difficult to quantify within bundled care pathways.Poisson regression and marginal effects models for prolonged post-hepatectomy LOS (25% median) included Kawaguchi-Gayet (KG) complexity, perioperative variables, and pathways (minimally-invasive = MIS; low-intermediate-risk = KGI/II; high-risk = KGIII; combination).Median LOS was 2, 4, 5, and 5 days for MIS, KGI/II, KGIII and combination pathways (N = 978). Poisson regression identified age, intraoperative fluids, delayed diet tolerance, and combination cases as associated with increased LOS (p 0.01). Marginal effects analysis demonstrated the following added probability of longer LOS: each year of age 0.03x, 250 mL intraoperative fluids 0.06x, each operative hour 0.2x, additional day before diet tolerance 0.4x, combination cases 0.7x. MIS was associated with 1.2x increased probability of shorter LOS.Optimizing intraoperative fluids, operative time, and postoperative diet, while favoring MIS approach when feasible, may maximize effects of post-hepatectomy care pathways to reduce LOS.

Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1,200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGFβ and PD-L1 inhibition. Significance: Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.

OBJECTIVES: The initial settings on an intravenous patient-controlled analgesia (IV-PCA) pump can represent a significant source of postoperative opioid exposure. The primary aim of this study was to evaluate the impact of first day IV-PCA use on total inpatient opioid use after open pancreatectomy, before and after standardization of initial dosing. METHODS: Inpatient oral morphine equivalents (OME) were reviewed for pancreatectomy patients treated with IV-PCA at a single institution before and after (3/2016–8/2017 vs. 3/2019–11/2020) implementation of a standardized initial IV-PCA dosing regimen (initial limit 0.1mg hydromorphone, or 1mg OME, every 10 min as needed). IV-PCA OME in the first 24 hours and total inpatient OME were compared between cohorts. RESULTS: Of 220 total patients, 132 were in the pre-standardization historical cohort. First-24-hour IV-PCA use was different (pre-standardization median 95mg vs. post-standardization 15mg, p

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Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1,200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGFβ and PD-L1 inhibition.Significance:Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.

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Supplementary Figure 3. Overall survival (OS) and recurrence-free survival (RFS) by RAS mutation status.

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Supplementary Figure 1. Patient selection

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival.Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 (“don't eat me signal”) expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival.Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival.Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415–25. ©2017 AACR.

Supplementary Figure 4. Overall survival (OS) by RAS, TP53, and SMAD4 mutation status in 313 patients with unresectable colorectal metastases.

Supplementary Table 1. Genes and codon tested for adequate amplicons Supplementary Table 2. Multivariable hazard ratios (HRs) for OS and RFS by RAS mutation status in 507 patients Supplementary Table 3. Demographic and clinicopathologic characteristics of 313 patients with unresectable colorectal metastases.

As minimally invasive surgery (MIS) approaches to biliary tract cancers become more commonplace, understanding the adequacy of their oncologic performance is key.The National Cancer Database 2010-2016 was queried for patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHC) and T1b or more advanced gallbladder cancer (GBC). Patients were grouped by approach: open (OA), laparoscopic (LA), and robotic (RA). Margin status, rate of lymph node (LN) dissection, and yield of LN dissection were evaluated.This cohort of 8612 patients, including 4034 patients with IHC (OA: 3281, LA: 675, RA: 78) and 4578 patients with GBC (OA: 1893, LA: 2588, RA: 97), MIS was used 40% of the time. R0 resection was achieved in 82% OA, 84% LA, and 91% RA, p = 0.004. Rate of LN dissection was 53% (OA: 60%, LA: 42%, RA: 51%, p 0.001). Among patients who underwent lymphadenectomy, 6 + LN were retrieved less commonly with a LA (OA: 27%, LA: 20%, and RA: 30%, p 0.001). High-volume MIS hepatectomy centers were more likely to perform a lymphadenectomy (odds ratio [OR]: 1.41) and a sampling of 6 + LN (OR: 1.18).Regardless of approach, lymphadenectomy is underperformed nationwide for biliary tract tumors, particularly with LA. As the use of MIS grows for the treatment of biliary tract cancers, scrutiny of oncologic outcomes is required.

BACKGROUND We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM). METHODS Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis. RESULTS Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p

BACKGROUND AND OBJECTIVES The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. METHODS Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). RESULTS Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p

Percutaneous thermal ablation is a curative-intent locoregional therapy (LRT) for selected patients with unresectable colorectal liver metastasis (CLM). Several factors have been identified that contribute to local tumour control after ablation. However, factors contributing to disease progression outside the ablation zone after ablation are poorly understood.In this retrospective study, using next-generation sequencing, we identified genetic biomarkers associated with different patterns of progression following thermal ablation of CLM.A total of 191 ablation naïve patients between January 2011 and March 2020 were included in the analysis, and 101 had genomic profiling available. Alterations in the TGFβ pathway were associated with increased risk of development of new intrahepatic tumours (hazard ratio [HR], 2.75, 95% confidence interval [95% CI] 1.39-5.45, P = 0.004); and alterations in the Wnt pathway were associated with increased probability of receiving salvage LRT for any intrahepatic progression (HR, 5.8, 95% CI 1.94-19.5, P = 0.003).Our findings indicate that genomic alterations in cancer-related signalling pathways can predict different progression patterns and the likelihood of receiving salvage LRT following percutaneous thermal ablation of CLM.

Lymphadenectomy (LND) is recommended following surgical resection of ≥ T1b gallbladder cancer (GBC). However, frequency and stage-specific survival benefits of LND remain unclear. The National Cancer Database (NCDB; 2006-15) was queried for resected pathologic stage I–III GBC. LND performance, predictors of receiving LND, and LND association with overall survival (OS) were assessed. Of 2302 total patients, 1343 (58.3%) underwent LND. Patients who underwent LND were younger and more frequently had private health insurance, a negative surgical margin, higher pathologic T stage, and received adjuvant chemotherapy (all p < 0.001). LND rates were highest at academic centers (70.1%) relative to all other facility types (p < 0.001). LND was independently associated with improved OS [hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.44–0.61]. LND was associated with improved OS for pT1b, pT2, and pT3 patients (all p < 0.05) on univariate analysis. LND was independently associated with improved OS in pT2 (HR 0.44, CI 0.35–0.56) and pT3 (HR 0.54, CI 0.43–0.69) patients. LND is associated with a 48% reduction in risk of death in patients with resectable non-metastatic GBC, with greatest impact in pT2–3 patients. Patients without LND have similar OS to patients with node-positive disease, highlighting the importance of LND. Underutilization of LND likely results in undertreatment of patients with undiagnosed nodal disease, which may contribute to unfavorable oncologic outcomes.

Circulating tumor DNA (ctDNA) is a promising biomarker for patients undergoing hepatectomy for colorectal liver metastases (CLM). We hypothesized that post-hepatectomy ctDNA detection would identify patients at highest risk for early recurrence of CLM.Patients with CLM who underwent curative-intent hepatectomy with ctDNA analysis within 180 days postoperatively (1/2013 and 6/2020) were included. Tissue somatic mutations and ctDNA analyses were performed by next-generation sequencing panels. Survival analyses determined factors associated with clinical recurrence 1 year or earlier after hepatectomy. Patients with primary tumors in situ and without 1-year follow-up were excluded. Median follow-up was 28.3 months.Of 105 patients, 32 (30%) were ctDNA positive (ctDNA+) after curative-intent hepatectomy. Compared with ctDNA-negative patients, ctDNA+ patients had multiple CLM (84% vs 55%, p = 0.002) and co-mutated RAS/TP53 (47% vs 23%, p = 0.018). Multiple CLM (odds ration (OR), 5.43; p = 0.005) and co-mutated RAS/TP53 (OR, 3.30; p = 0.019) were independently associated with post-hepatectomy ctDNA. Although perioperative carcinoembryonic antigen levels were not prognostic, postoperative ctDNA+ (hazard ratio (HR), 2.04; p = 0.011) and extrahepatic disease (HR, 2.45, p = 0.004) were independently associated with worse recurrence-free survival. After adjusting for extrahepatic disease, preoperative chemotherapy, multiple CLM, tumor viability of 50% or greater, and co-mutated RAS/TP53, ctDNA+ within 180 days was the only independent risk factor for recurrence 1 year or earlier after hepatectomy (94% vs 49%; HR, 11.8; p = 0.003).Postoperative ctDNA detection is associated with early recurrence 1 year or earlier after curative-intent hepatectomy for CLM, and RAS/TP53 co-mutations result in a more than 3-fold increased risk for postoperative ctDNA positivity. This highlights the complementary effect of tumor tissue and circulating mutational profiling for patients with CLM.

Administration of dexamethasone to mitigate postoperative nausea and vomiting has been suggested to improve short- and long-term outcomes after pancreatic ductal adenocarcinoma (PDAC) resection. This study aimed primarily to evaluate these hypotheses in a contemporary patient cohort treated with multimodality therapy. The clinicopathologic and perioperative characteristics of consecutive resected PDAC patients (July 2011 to October 2018) were analyzed from a prospectively maintained database. Intraoperative administration of dexamethasone (4–10 mg) was retrospectively abstracted from the electronic medical record. The majority of 373 patients (59.8%) received intraoperative dexamethasone. Most of these patients underwent neoadjuvant therapy (75.3%), were potentially resectable at presentation (69.7%), and underwent pancreaticoduodenectomy (79.9%). Women were more likely to receive dexamethasone than men (69.9 vs 30.1%; p

Background The objective of this study was to assess current perceptions surrounding opioid prescribing in surgical oncology to inform perioperative quality improvement initiatives. Methods After the Society of Surgical Oncology (SSO) approval, a survey was distributed to its membership. Five sample procedures were used to assess provider perceptions and prescribing habits. Data were summarized and compared by self-reported demographics. Results One hundred and seventy-five participants completed the survey: 149 (85%) faculty, 24 (14%) trainees, and 2 (1%) advanced practice providers. Most participants (76%) practiced in academic programs and 21% practiced in non-US locations. Few differences were identified based on clinical role, academic rank, or practice years. Compared with non-US providers, US providers expected higher pain scores at discharge, recommended greater opioid prescriptions, and estimated more days of opioid use for almost every procedure. More non-US providers believed discharge opioids should not be distributed to patients who are opioid-free in their last 24 inpatient hours (80% vs 50%, P = .001). All providers ranked education as "very important" for reducing opioid prescriptions. Conclusions Compared with their international counterparts, US surgical oncology providers expected greater opioid needs and recommended higher prescription numbers. Educating providers on multimodal opioid-sparing bundles, accelerated weaning protocols, and standardized discharge prescribing habits could have a positive impact the US opioid epidemic.

Non-anatomic resection (NAR) has emerged as a safe and effective technique for resection of colorectal liver metastases (CRLM). More recently, RAS mutation has been identified as an important indicator of aggressive disease, which may require anatomic resection (AR). In this retrospective study, we compared the long-term outcomes of AR versus NAR in CRLM patients with and without RAS mutations. Patients with known RAS mutation status who underwent AR or NAR for CRLM between 2006 and 2016 were included. Differences in baseline characteristics were adjusted using 1:1 propensity score matching, including the most important factors that contributed to the decision to use the resection technique. Overall survival (OS), recurrence-free survival (RFS), and liver-specific recurrence-free survival (L-RFS) were compared between cohorts. Among 622 total patients, 338 (54%) underwent AR and 284 (46%) NAR. There was no difference in OS or L-RFS between the AR and NAR groups, regardless of mutation status. There was increased RFS in the RAS WT patients with NAR (P = 0.034), but no difference in RFS in the whole cohort or RAS mutant group. After propensity score matching, 360 patients were analyzed, and no differences in OS, RFS, or L-RFS rates were seen between any groups. There was also no difference in margin recurrence. Similar outcomes can be achieved with both AR and NAR, regardless of RAS mutation status. These data do not support a universal requirement for AR in RAS mutant CRLM when not necessary to achieve an R0 resection.

First postoperative day drain fluid amylase (DFA1)5000 U/L is commonly used for early drain removal. We manage patients with risk-stratified pancreatectomy care pathways determined preoperatively by risk for postoperative pancreatic fistula. We hypothesized that preoperative risk stratification would yield unique DFA1/DFA3 cutoffs for safe early drain removal.Patients with DFA1/DFA3 values after pancreaticoduodenectomy or distal pancreatectomy were identified. Patients were risk stratified as "low-risk pancreaticoduodenectomy," "high-risk pancreaticoduodenectomy," or "distal pancreatectomy." Receiver operator characteristic analyses yielded clinically relevant sensitivity thresholds for International Study Group on Pancreatic Surgery grade B/C postoperative pancreatic fistulas.From October 2016 to April 2018, 174 patients were preoperatively stratified as low-risk pancreaticoduodenectomy (n = 78, 45%), high-risk pancreaticoduodenectomy (n = 51, 29%), and distal pancreatectomy (n = 45, 26%). B/C postoperative pancreatic fistulas developed in 3% (n = 2) of low-risk pancreaticoduodenectomies, 37% (n = 19) of high-risk pancreaticoduodenectomies, and 24% (n = 11) of distal pancreatectomies (low- vs high-risk pancreaticoduodenectomy P.001, low-risk pancreaticoduodenectomy versus distal pancreatectomy P = .004, high-risk pancreaticoduodenectomy versus distal pancreatectomy P = .25). B/C postoperative pancreatic fistulas occurred in 16% (n = 21) pancreaticoduodenectomy patients (high- + low-risk pancreaticoduodenectomy), and B/C postoperative pancreatic fistulas were excluded in pancreaticoduodenectomy with 100% sensitivity if DFA1 ≤ 136 or DFA3 ≤ 93. DFA15000 excluded B/C postoperative pancreatic fistulas with only 57% sensitivity after pancreaticoduodenectomy. Exclusion of B/C postoperative pancreatic fistulas occurred with 100% sensitivity if DFA1 ≤ 661 or DFA3 ≤ 141 in low-risk pancreaticoduodenectomy patients, DFA1 ≤ 136 or DFA3 ≤ 93 in high-risk pancreaticoduodenectomy patients, and DFA149 or DFA326 in distal pancreatectomy patients.Preoperative risk stratification results in unique DFA1/DFA3 thresholds to exclude B/C postoperative pancreatic fistulas, thus allowing for safe drain removal and potential for accelerated discharge. Rather than applying generic DFA cutoffs based on national databases, we propose institution-specific DFA1 and DFA3 values tailored to 3 replicable postoperative pancreatic fistula-risk pathways.

The liver is the most common site of metastasis for patients with colorectal cancer, and resection is associated with significantly improved survival for selected patients. Advancements in perioperative care, operative technique, and multidisciplinary management have led to improved outcomes for patients with colorectal liver metastases (CLM).This review discusses recent advances in perioperative management, patient selection and prognostication, and surgical technique that make up the state-of-the-art management for patients with CLM.Novel approaches to prognostication and measurement of treatment response, such as tumor somatic mutational profiling and circulating tumor DNA (ctDNA), are revolutionary instruments for patient selection and treatment sequence. Further, refinements to surgical approaches for patients with bilateral CLM, including two-stage hepatectomy (TSH), are available for these patients and may lead to improved surgical outcomes. The advances discussed in this review will result in more patients being considered for resection and refined selection for perioperative care strategies that will lead to improved survival for patients with CLM.

226 Background: Appendiceal adenocarcinoma (AA) is a rare and heterogenous cancer with marked differences in clinical course between high- and low-grade tumors. Unlike colorectal cancer (CRC) and other gastrointestinal malignancies, AA virtually never has hematogenous metastases, rather, metastasis is limited to the peritoneum. Here we present a retrospective, single institution study of AA to identify the prevalence of detectable ctDNA, evaluate the clinical predictive value of positive ctDNA, and assess what clinical, pathologic, or molecular features predict positive ctDNA. Methods: 160 blood samples from 147 patients with AA metastatic to the peritoneum were profiled with a CLIA approved 73 gene mutational panel as part of routine clinical practice. Paired tumor sequencing was available for 73 patients. Survival was measured starting from day ctDNA was drawn. Mutations that most likely represented clonal hematopoiesis were removed from analysis. Results: Out of 160 ctDNA samples, 120 were taken in the setting of radiographically apparent metastatic disease. Of these, 46 (38.3%) had any detectable mutation. 40 ctDNA tests were performed when patients had no radiographic evidence of disease (NED); 15 (37.5%) of which had any detectable mutation. High-grade tumors were more likely to have detectable ctDNA with detection rates of 10/46 (21.7%), 18/46 (39.1%), and 33/68 (48.5%) for well, moderately, and poorly-differentiated tumors, respectively. Restricting analysis to the 73 patients with paired tissue and blood samples and 73 genes sequenced in both, of 81 mutations detected in tumor only, 21 were detected in blood (sensitivity of 26%). Sensitivity was highest for mutation in TP53 (53.8%) suggesting these tumors may have a greater propensity to shed DNA into circulation. Overall, the sensitivity of ctDNA detection in metastatic AA was markedly less than what was observed in a cohort of 274 metastatic CRC patients from the same institution (288/581 = 49.6%). For AA patients with detectable ctDNA, variant allele frequency (VAF) in AA was significantly lower compared to CRC (median VAF 0.04% vs. 6%, p =

196 Background: The association between tumor mutations beyond KRAS and BRAF for patients with peritoneal metastases (PM) from colorectal cancer (CRC) are poorly understood. Here we describe these associations with survival after diagnosis of PM. Methods: CRC patients with PM with or without synchronous liver or lung metastases treated at a single institution from 2016 to 2020 were retrospectively studied. Standard of care next-generation sequencing was performed on tissue specimens with a targeted panel of genes frequently mutated in cancer. Clinical data, including survival and last contact, were obtained from medical records. Multivariate Cox regression was used to identify associations between overall survival after diagnosis of PM (OS) with clinical, histopathologic and somatic mutation data. Results: Of 526 PM patients, 179 (34.2%) also had synchronous liver metastases, and these patients had worse OS compared to PM alone (HR 1.67, [1.26-2.22], p=0.0003). Lung metastases were identified in 57 (10.8%) and were not associated with worse OS (HR 1.34, [0.90-1.97], p=0.15). Poorly differentiated grade (HR 2.08, [1.42-3.04], p=0.0002), mucinous histology (HR 1.44, [1.07-1.94], p=0.016), male gender (HR 1.37, [1.05-1.78), p=0.019), and age (HR 1.02, [1.01-1.04], p=0.004) were independently associated with OS. Tumor sequencing data was available for 442 (87%) patients. TP53 was the most common mutation (61.5% of patients) and was associated with decreased OS (HR=1.51 [1.12-2.02], p=0.005). BRAF mutation (85% of which were V600E) was identified in 9.7% of patients and was also associated with decreased OS (HR=1.88 [1.23-2.86], p=0.003). In contrast, PTEN mutation (4.3%) was associated with improved OS (0.41 (0.17-0.99), p=0.049), while both KRAS (51.4%) and SMAD4 mutations (16%) were not (KRAS: HR 0.94, [0.72-1.24], p=0.68; SMAD4: HR 0.78, [0.53-1.16], p=0.21). Conclusions: Mutational data for PM patients has a distinct profile and unique associations with OS when compared to other sites of metastatic disease. TP53 and BRAF mutations were associated with worse survival, while PTEN mutation was associated with improved OS. KRAS mutation was more prevalent than expected in an unselected cohort, and not associated with OS. A better understanding of PM-specific associations with survival may influence treatment strategies for this difficult disease site.

Background The safety and oncological efficacy of laparoscopic re-resection of incidental gallbladder cancer have not been studied. This study aimed to compare laparoscopic with open re-resection of incidentally discovered gallbladder cancer while minimizing selection bias. Methods This was a multicentre retrospective observational cohort study of patients with incidental gallbladder cancer who underwent re-resection with curative intent at four centres between 2000 and 2017. Overall survival (OS) and recurrence-free survival (RFS) were analysed by intention to treat. Inverse probability of surgery treatment weighting using propensity scoring was undertaken. Results A total of 255 patients underwent re-resection (190 open, 65 laparoscopic). Nineteen laparoscopic procedures were converted to open operation. Surgery before 2011 was the only factor associated with conversion. Duration of hospital stay was shorter after laparoscopic re-resection (median 4 versus 6 days; P < 0·001). Three-year OS rates for laparoscopic and open re-resection were 87 and 62 per cent respectively (P = 0·502). Independent predictors of worse OS were residual cancer found at re-resection (hazard ratio (HR) 1·91, 95 per cent c.i. 1·17 to 3·11), blood loss of at least 500 ml (HR 1·83, 1·23 to 2·74) and at least four positive nodes (HR 3·11, 1·46 to 6·65). In competing-risks analysis, the RFS incidence was higher for laparoscopic re-resection (P = 0·038), but OS did not differ between groups. Independent predictors of worse RFS were one to three positive nodes (HR 2·16, 1·29 to 3·60), at least four positive nodes (HR 4·39, 1·96 to 9·82) and residual cancer (HR 2·42, 1·46 to 4·00). Conclusion Laparoscopic re-resection for selected patients with incidental gallbladder cancer is oncologically non-inferior to an open approach. Dissemination of advanced laparoscopic skills and timely referral of patients with incidental gallbladder cancer to specialized centres may allow more patients to benefit from this operation.

As inpatient stays become shorter, one concern with standardizing discharge opioid prescriptions is the potential risk of "rebound refills." We sought to compare opioid prescription refill rates and volumes for surgical patients discharged on postoperative day (POD) 2-3, 4-7, and 8+.In a prospective quality improvement protocol, faculty volunteered to use either a 5x-multiplier (5x) or usual care (UC) for discharge prescriptions after inpatient (≥48 h stay) surgery from Sep-Dec 2019. The 5x-multiplier is 5-times the patient's last 24-h opioid use (by oral morphine equivalents, OME). Cohorts were compared by POD of discharge: POD 2-3 ("SHORT"), POD 4-7 ("INTERMEDIATE"), and POD 8+ ("LONG"). The primary endpoint was 30-d refill rates. Secondary endpoints included 30-d refill OME and inpatient opioid weaning/discharge metrics.From 22 faculty, 409 patients were included. When stratified by POD, 154 (37.7%) were discharged SHORT, 176 (43.0%) INTERMEDIATE, and 79 (19.3%) LONG. SHORT stay patients had a median last 24-h OME of 10 mg (versus 5 mg INTERMEDIATE, 5 mg LONG; P = 0.268), and a median discharge OME of 55 mg (versus 75 mg INTERMEDIATE, 100 mg LONG; P = 0.221). Patients with SHORT stays did not have higher refill rates (11.7% versus 18.2% INTERMEDIATE, 19.0% LONG; P = 0.193) or higher median refill OME (150 mg versus 300 mg INTERMEDAITE, 339 mg LONG; P = 0.154).Despite concerns of increased refills, patients discharged by POD 2-3 were not associated with "rebound refills." A patient-centered 5x-multiplier standardization of discharge opioid prescriptions is feasible in all inpatient surgery patients, even those discharged following a short inpatient stay.

Pathologic response to preoperative chemotherapy predicts survival in patients with colorectal liver metastases (CLMs) who undergo hepatectomy. In multiple CLMs, mixed pathologic response, wherein tumors exhibit different degrees of treatment response, is possible. We sought to evaluate survival outcomes of mixed response in patients with multiple CLMs.We conducted a retrospective cohort study using a single-institution database of patients with two or more CLMs who underwent preoperative chemotherapy and hepatectomy (2010-2018). Pathologic response of each tumor was measured on pathology. Patients were stratified by pathologic response as complete (pCR) = 0-1% viability; major (pMajR) = 2-49% viability; minor (pMinR) = 50-99% viability; or mixed (pMixR) = at least one pCR/MajR tumor and one pMinR. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adjusted risk of death was evaluated using Cox regression.Among 444 patients, 6% had pCR, 34% had pMajR, 36% had pMinR, and 24% had pMixR. Median and 5-year RFS for patients with pMixR was 10.4 months and 16%, respectively, compared with pMajR (11.3 months and 18%, respectively), pMinR (7.7 months and 13%, respectively), and pCR (23.1 months and 38%, respectively) [log-rank p 0.001]. Median and 5-year OS for patients with pMixR was 77.4 months and 60%, respectively, compared with pMajR (80.5 months and 63%, respectively), pMinR (49.9 months and 39%, respectively), and pCR (median OS not reached; median follow-up of 37.1 months and 5-year OS of 65%) [log-rank p = 0.002]. pMixR was associated with a 52% risk of death reduction (hazard ratio 0.48, 95% confidence interval 0.30-0.78 vs. pMinR).One-quarter of patients with multiple CLMs have pMixR following preoperative chemotherapy and hepatectomy. OS and RFS for patients with pMixR mirror those of pMajR rather than pMinR, suggesting the greatest response achieved in any metastasis best predicts survival.

Podcasts are increasingly being utilized in the surgical field as an asynchronous educational resource. This article discusses podcasts devoted to the field of surgery and their growing contribution to surgical education.We provide examples of current podcasts and their varied structures, including those that distribute clinical and educational content, discuss recent literature and advancements, interview leaders in the field, and/or showcase unique perspectives on topics such as career development, diversity, and wellness.Podcasts generated from surgical societies stand on unique ground to educate and engage the surgical community.

Previous implementation of risk-stratified pancreatectomy clinical pathways (RSPCPs) decreased length of stay (LOS) following pancreaticoduodenectomy (PD). This study's primary aim was to measure the association of iterative RSPCP revisions with accelerated discharge and early postoperative outcomes.This is a retrospective cohort study of a prospectively maintained surgical database (10/2016-9/2020). In February 2019, revised RSPCPs were implemented with earlier nasogastric tube (NGT) removal (postoperative day [POD] 1 for low risk; POD 2 for high risk) and updated drain fluid amylase cutoffs for POD 1/POD 3 removal. Perioperative outcomes between original and revised pathways were compared. Predictors of accelerated discharge (defined as ≤ POD 5 for low risk; ≤ POD 6 for high risk) were identified.There were 233 (36% high risk) patients in original and 131 (32% high risk) in revised RSPCPs. After revision, the rate of POD 1 NGT removal was higher while POD ≤ 3 drain removal was similar. Median LOS decreased for low risk (5 vs. 6 days, p = 0.011) and high risk (6 vs. 9 days, p = 0.005) with no increase in delayed gastric emptying, postoperative pancreatic fistula, or readmissions. With POD 1 NGT removal, diet tolerance was earlier without increased NGT reinsertions. In low-risk patients, younger age, POD 1 NGT removal, and POD ≤ 3 drain removal were independent predictors of accelerated discharge. In high-risk patients, POD 1 NGT removal and POD ≤ 3 drain removal were independent predictors of accelerated discharge.Following iterative revisions in RSPCPs, LOS after PD decreased further without increasing readmissions, and NGTs were removed earlier without increased reinsertions. Early NGT and drain removal are modifiable practices within RSPCPs that are associated with accelerated discharge.

We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM).Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis.Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p 0.001) and overall recurrence (p 0.001). However, incidence of LR did not differ significantly by RAS/TP53, BRAF, SMAD4, or FBXW7 mutation. Extrahepatic disease (hazard ratio [HR], 1.47; p = 0.034), 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p 0.001) were independently associated with poor overall survival, but surgical margin status was not.Although somatic mutations were associated with overall recurrence, neither surgical margin width nor somatic mutations affected LR risk after R0-intent hepatectomy for CLM. LR and prognosis were likely driven by individual tumor biology rather than surgical margins.