Malignant Solid Pseudopapillary Neoplasm of the Pancreas: An Orthogonal Analysis.

BACKGROUND: Pancreatic solid pseudopapillary neoplasms (SPN) are generally indolent; however, some patients present with "malignant" SPN. An orthogonal analysis of multiple datasets was performed to investigate the utility of complete surgical resection (CSR) for malignant SPN. METHODS: A systematic review was performed for cases of malignant SPN, defined as T4, N1, and/or M1. Malignant SPN was analyzed within the National Cancer Database (NCDB) and compared with T1-3N0M0 SPN. Predictors of malignant SPN were assessed, and treatments were analyzed by using survival analysis. RESULTS: The systematic review yielded 164 cases of malignant SPN. Of 31 children, only one died due to malignant SPN. Among adults, CSR was associated with improved disease-specific survival (DSS) (P = 0.0002). Chemotherapy did not improve malignant SPN DSS, whether resected (P = 0.8485) or not (P = 0.2219). Of 692 adults with SPN within the NCDB, 93 (13.4%) had malignant SPN. Pancreatic head location (odds ratio [OR] 2.174; 95% confidence interval [CI] 1.136-4.166; P = 0.0186) and tumor size (OR 1.154; 95% CI 1.079-1.235; P < 0.0001) associated with the malignant phenotype. Malignant SPN predicted decreased overall survival (OS) compared with T1-3N0M0 disease (P < 0.0001). Resected malignant SPN demonstrated improved OS (P < 0.0001), including resected stage IV malignant SPN (P = 0.0003). Chemotherapy did not improve OS for malignant SPN, whether resected (P = 0.8633) or not (P = 0.5734). Within a multivariable model, resection was associated with decreased hazard of death (hazard ratio 0.090; 95% CI 0.030-0.261; P < 0.0001). CONCLUSIONS: Approximately 13% of patients with SPN present with a malignant phenotype. Pediatric cases may be less aggressive. Resection may improve survival for malignant SPN, which does not appear chemosensitive.

The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals.

BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer.

BACKGROUND & AIMS: We have shown that reciprocally activated rat sarcoma (RAS)/mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathways mediate therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC), while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes such resistance and alters stromal architecture. We now determine whether MEKi+STAT3i reprograms the cancer-associated fibroblast (CAF) and immune microenvironment to overcome resistance to immune checkpoint inhibition in PDAC. METHODS: CAF and immune cell transcriptomes in MEKi (trametinib)+STAT3i (ruxolitinib)-treated vs vehicle-treated Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) tumors were examined via single-cell RNA sequencing (scRNAseq). Clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats associated protein 9 silencing of CAF-restricted Map2k1/Mek1 or Stat3, or both, enabled interrogation of CAF-dependent effects on immunologic remodeling in orthotopic models. Tumor growth, survival, and immune profiling via mass cytometry by time-of-flight were examined in PKT mice treated with vehicle, anti-programmed cell death protein 1 (PD-1) monotherapy, and MEKi+STAT3i combined with anti-PD1. RESULTS: MEKi+STAT3i attenuates Il6/Cxcl1-expressing proinflammatory and Lrrc15-expressing myofibroblastic CAF phenotypes while enriching for Ly6a/Cd34-expressing CAFs exhibiting mesenchymal stem cell-like features via scRNAseq in PKT mice. This CAF plasticity is associated with M2-to-M1 reprogramming of tumor-associated macrophages, and enhanced trafficking of cluster of differentiation 8+ T cells, which exhibit distinct effector transcriptional programs. These MEKi+STAT3i-induced effects appear CAF-dependent, because CAF-restricted Mek1/Stat3 silencing mitigates inflammatory-CAF polarization and myeloid infiltration in vivo. Addition of MEKi+STAT3i to PD-1 blockade not only dramatically improves antitumor responses and survival in PKT mice but also augments recruitment of activated/memory T cells while improving their degranulating and cytotoxic capacity compared with anti-PD-1 monotherapy. Importantly, treatment of a patient who has chemotherapy-refractory metastatic PDAC with MEKi (trametinib), STAT3i (ruxolitinib), and PD-1 inhibitor (nivolumab) yielded clinical benefit. CONCLUSIONS: Combined MEKi+STAT3i mitigates stromal inflammation and enriches for CAF phenotypes with mesenchymal stem cell-like properties to overcome immunotherapy resistance in PDAC.

Racial Disparity in Pathologic Response following Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: A Multi-Institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection. METHODS: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS). RESULTS: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts. CONCLUSIONS: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation.

Landmark Series: Importance of Pancreatic Resection Margins.

An important goal of cancer surgery is to achieve negative surgical margins and remove all disease completely. For pancreatic neoplasms, microscopic margins may remain positive despite gross removal of the palpable mass, and surgeons must then consider extending resection, even to the point of completion pancreatectomy, an option that renders the patient with significant adverse effects related to exocrine and endocrine insufficiency. Counterintuitively, extending resection to ensure clear margins may not improve patient outcome. Furthermore, the goal of improving survival by extending the resection may not be achieved, as an initial positive margin may indicate more aggressive underlying tumor biology. There is a growing body of literature on this topic, and this landmark series review will examine the key publications that guide our management for resection of pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasms, and pancreatic neuroendocrine tumors.

Intraoperative Pancreatic Neck Margin Assessment During Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in the Era of Neoadjuvant Therapy: A Multi-institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Data regarding the survival impact of converting frozen-section (FS):R1 pancreatic neck margins to permanent section (PS):R0 by additional resection (i.e., converted-R0) during upfront pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) are conflicting. The impact of neoadjuvant therapy on this practice and its relationship with overall survival (OS) is incompletely understood. METHODS: We reviewed PDAC patients (80% borderline resectable/locally advanced [BR/LA]) undergoing pancreaticoduodenectomy after neoadjuvant therapy at seven, academic, high-volume centers (2010-2018). Multivariable models examined the association of PS:R0, PS:R1, and converted-R0 margins with OS. RESULTS: Of 272 patients receiving at least 2 (median 4) cycles of neoadjuvant chemotherapy (71% mFOLFIRINOX or gemcitabine/nab-paclitaxel) and undergoing pancreaticoduodenectomy with intraoperative frozen-section assessment of the transected pancreatic neck margin, PS:R0 (n = 220, 80.9%) was observed in a majority of patients; 18 patients (6.6%) had converted-R0 margins following additional resection, whereas 34 patients (12.5%) had persistently positive PS:R1 margins. At a median follow-up of 42 months, PS:R0 resection was associated with improved OS compared with either converted-R0 or PS:R1 resection (median 25 vs. 14 vs. 16 months, respectively; p = 0.023), with no survival difference between the converted-R0 and PS:R1 groups (p = 0.9). On Cox regression, SMA margin positivity (hazard ratio 2.2, p = 0.012), but not neck margin positivity (hazard ratio 1.2, p = 0.65), was associated with worse OS. CONCLUSIONS: In this multi-institutional cohort of predominantly BR/LA PDAC patients undergoing pancreaticoduodenectomy following modern neoadjuvant therapy, pursuing a negative neck margin intraoperatively if the initial margin is positive does not appear to be associated with improved survival.

National Institutes of Health Career Development (K) Awards to Young Surgeons: An Academic Milestone or One-hit Wonder?

OBJECTIVE: To assess contemporary trends in the National Institutes of Health (NIH) Career Development (K) Awards within the Departments of Surgery and its impact on the likelihood of achieving independent R01 grants. BACKGROUND: The NIH provides K-type Career Development Awards to nurture young clinicians toward a productive academic career, thereby maintaining a pipeline of physician-scientists. However, the impact of K awards on career trajectory of surgeons remains unclear. METHODS: The NIH grant data was queried for all new K08/K23 grants awarded to Departments of Surgery (1999-2019). Principal Investigators' data and grant-related information was obtained. RESULTS: The NIH awarded 298 K08/23 surgical grants ($41,893,170) over the last 2 decades. Median budget increased from $116,370 to $167,508 (P<0.001). Of grantees, 83.2% were MDs, 15.1% MD/PhD, and 1.7% PhDs, with 25.2% being women. Principal Investigators' were mostly practicing surgeons (91.1%) with fellowship training (82.4%) and young in their careers {4 [interquartile ranges (IQR) 4] years of experience}. Vascular surgery (15.9%), Complex General Surgical Oncology (15.1%), and Trauma/Critical Care (14.6%) were the most frequent specialties. Awards were associated with 3,336 publications [median 8/project (IQR 13)]. The majority of K grantees (77.2%) currently hold an academic faculty position. Only 32.2% of awardees received independent R01 grant funding, at a median of 5.5 years (IQR 5) after their K awards. Sex (P = 0.71), previous fellowship training (P = 0.63), type of surgical specialty (P = 0.72), or MD/PhD degree (P = 0.75) were not associated with increased likelihood of achieving a subsequent R01 award. CONCLUSION: Although the majority of K awardees maintain an academic career, only a limited number of grantees progress to obtain NIH R01 funding. Increased mentorship, financial support, and infrastructure are needed to facilitate career development awardees opportunities to enhance their ability to achieve independent funding.

National Institutes of Health Research Funding to Academic Surgical Oncologists: Who Are We and Where Do We Stand?

BACKGROUND: The National Institutes of Health (NIH) is the primary public funding source for surgical research in the United States. Surgical oncology is a highly academic career, but NIH funding for surgical oncologists (SOs) is not well characterized. METHODS: The NIH RePORTER (Research Portfolio Online Reporting Tools Expenditures and Results) was queried to identify R01-and-equivalents grants awarded to departments of surgery (DoS) between 2008 and 2018. Surgical oncologists were considered to be those who completed a Society of Surgical Oncology (SSO)-accredited fellowship (breast or complex surgical oncology). RESULTS: Of 1101 projects, 510 (46.3%) were led by practicing surgeons. Among these, general surgeons accounted for most grants (31%), followed by SOs (20.8%). Women represented 211 (24.1%) of the grantees. However, SOs had a higher proportion of female investigators than other surgeons (30.0% vs. 16.1%; P = 0.001). The SO grantees had fewer years of experience (YoE) (12 years; interquartile range [IQR], 8.75 vs. 13 years; IQR, 13 years; P = 0.003), lower senior status (≥ 24 YoE), fewer investigators (4.0% vs. 18.9%; P < 0.001), and fewer PhD holders (30.8% vs. 65.5%; P < 0.001) than the overall cohort. Projects led by SOs accounted for 1121 publications (14.1%), with a higher proportion of high-impact articles (26.3% vs. 9.7%; P < 0.001), and were more likely to hold a registered patent (odds ratio [OR], 3.30; 95% confidence interval [CI], 1.24-8.74; P = 0.016). CONCLUSION: Among surgical subspecialties, SSO-accredited surgeons accounted for the largest share of the NIH grants. The SO grantees were younger in their career and had higher-impact scholarly productivity. A smaller proportion of female SOs received NIH grants than males, but this gender disparity was less significant among SOs than among other surgical specialties. Fellowship programs should continue to stimulate groundbreaking research by integrating grant-writing training and mentorship.

Disparities in Presentation at Time of Hepatocellular Carcinoma Diagnosis: A United States Safety-Net Collaborative Study.

BACKGROUND: While hepatocellular carcinoma (HCC) is ideally diagnosed outpatient by screening at-risk patients, many are diagnosed in Emergency Departments (ED) due to undiagnosed liver disease and/or limited access-to-healthcare. This study aims to identify sociodemographic/clinical factors associated with being diagnosed with HCC in the ED to identify patients who may benefit from improved access-to-care. METHODS: HCC patients diagnosed between 2012 and 2014 in the ED or an outpatient setting [Primary Care Physician (PCP) or hepatologist] were identified from the US Safety-Net Collaborative database and underwent retrospective chart-review. Multivariable regression identified predictors for an ED diagnosis. RESULTS: Among 1620 patients, median age was 60, 68% were diagnosed outpatient, and 32% were diagnosed in the ED. ED patients were more likely male, Black/Hispanic, uninsured, and presented with more decompensated liver disease, aggressive features, and advanced clinical stage. On multivariable regression, controlling for age, gender, race/ethnicity, poverty, insurance, and PCP/navigator access, predictors for ED diagnosis were male (odds ratio [OR] 1.6, 95% confidence interval [CI]: 1.1-2.2, p = 0.010), black (OR 1.7, 95% CI: 1.2-2.3, p = 0.002), Hispanic (OR 1.6, 95% CI: 1.1-2.6, p = 0.029), > 25% below poverty line (OR 1.4, 95% CI: 1.1-1.9, p = 0.019), uninsured (OR 3.9, 95% CI: 2.4-6.1, p < 0.001), and lack of PCP (OR 2.3, 95% CI: 1.5-3.6, p < 0.001) or navigator (OR 1.8, 95% CI: 1.3-2.5, p = 0.001). CONCLUSIONS: The sociodemographic/clinical profile of patients diagnosed with HCC in EDs differs significantly from those diagnosed outpatient. ED patients were more likely racial/ethnic minorities, uninsured, and had limited access to healthcare. This study highlights the importance of improved access-to-care in already vulnerable populations.

Surgical management of hepatocellular carcinoma patients with portal vein thrombosis: The United States Safety Net and Academic Center Collaborative Analysis.

BACKGROUND: Although consensus guidelines generally discourage any surgical management (ASM; i.e., resection and/or transplantation) in patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT), recent series from Asia have challenged this paradigm. METHODS: Patients from the US Safety Net Collaborative database (2012-2014) with localized HCC and radiographically confirmed PVT were propensity-score matched based on demographic and clinicopathologic factors associated with receipt of ASM and overall survival (OS). OS was compared between patients undergoing ASM and those not selected for surgery. RESULTS: Of 1910 HCC patients, 207 (14.5%) had localized disease and PVT. The majority received either liver-directed therapies (LDTs; 34%) and/or targeted systemic therapies (36%). Twenty-one patients (10.1%) underwent ASM (resection [n = 11], transplantation [n = 10]); a third experienced any complication with no 30-day mortalities. Independent predictors of undergoing ASM were younger age, recent hepatology consultation, and lower model of end-stage liver disease (MELD) score. After matching for age, comorbidities, MELD, tumor size, receipt of LDT, or systemic therapy, OS was significantly longer for patients selected for ASM versus non-ASM patients (median not reached vs. 5.8 months, p < .001). CONCLUSION: In a large North American multi-institutional cohort, a minority of HCC patients with PVT were selected for ASM. Resection or transplantation was associated with improved survival and may have a role in the multimodality management in selected patients.

Attrition during neoadjuvant chemotherapy for gastric adenocarcinoma is associated with decreased survival: A United States Safety-Net Collaborative analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard management for localized gastric cancer (GC). Attrition during NAC due to treatment-related toxicity or functional decline is considered a surrogate for worse biologic outcomes; however, data supporting this paradigm are lacking. We investigated factors predicting attrition and its association with overall survival (OS) in GC. METHODS: Patients with nonmetastatic GC initiating NAC were identified from the US Safety-Net Collaborative (2012-2014). Patient/treatment-related characteristics were compared between attrition/nonattrition cohorts. Cox models determined factors associated with OS. RESULTS: Of 116 patients initiating NAC, attrition during prescribed NAC occurred in 24%. No differences were observed in performance status, comorbidities, treatment at safety-net hospital, or clinicopathologic factors between cohorts. Despite absence of distinguishing factors, attrition was associated with worse OS (median: 11 vs. 37 months; p = 0.01) and was an independent predictor of mortality (hazard ratio [HR]: 4.7, 95% confidence interval [CI]: 1.5-15.2; p = 0.02). Fewer patients with attrition underwent curative-intent surgery (39% vs. 89%; p < 0.001). Even in patients undergoing surgical exploration (n = 89), NAC attrition remained an independent predictor of worse OS (HR: 50.8, 95% CI: 3.6-717.8; p = 0.004) despite similar receipt of adjuvant chemotherapy. CONCLUSION: Attrition during NAC for nonmetastatic GC is independently associated with worse OS, even in patients undergoing surgery. Attrition during NAC may reflect unfavorable tumor biology not captured by conventional staging metrics.

Survival inequity in vulnerable populations with early-stage hepatocellular carcinoma: a United States safety-net collaborative analysis.

BACKGROUND: Access to health insurance and curative interventions [surgery/liver-directed-therapy (LDT)] affects survival for early-stage hepatocellular carcinoma (HCC). The aim of this multi-institutional study of high-volume safety-net hospitals (SNHs) and their tertiary-academic-centers (AC) was to identify the impact of type/lack of insurance on survival disparities across hospitals, particularly SNHs whose mission is to minimize insurance related access-to-care barriers for vulnerable populations. METHODS: Early-stage HCC patients (2012-2014) from the US Safety-Net Collaborative were propensity-score matched by treatment at SNH/AC. Overall survival (OS) was the primary outcome. Multivariable Cox proportional-hazard analysis was performed accounting for sociodemographic/clinical parameters. RESULTS: Among 925 patients, those with no insurance (NI) had decreased curative surgery, compared to those with government insurance (GI) and private insurance [PI, (PI-SNH:60.5% vs. GI-SNH:33.1% vs. NI-SNH:13.6%, p < 0.001)], and decreased median OS (PI-SNH:32.1 vs. GI-SNH:22.8 vs. NI-SNH:9.4 months, p = 0.002). On multivariable regression controlling for sociodemographic/clinical parameters, NI-SNH (HR:2.5, 95% CI:1.3-4.9, p = 0.007) was the only insurance type/hospital system combination with significantly worse OS. CONCLUSION: NI-SNH patients received less curative treatment than other insurance/hospitals types suggesting that treatment barriers, beyond access-to-care, need to be identified and addressed to achieve survival equity in early-stage HCC for vulnerable populations (NI-SNH).

Patterns of National Institutes of Health Grant Funding to Surgical Research and Scholarly Productivity in the United States.

OBJECTIVE: The aim of this study was to assess the contemporary trends in National Institutes of Health (NIH) grants awarded to surgical investigators, including potential disparities. BACKGROUND: The NIH remains the primary public funding source for surgical research in the United States; however, the patterns for grants and grantees are poorly understood. METHODS: NIH RePORTER was queried for new grants (R01, -03, -21) awarded to Departments of Surgery (DoS). Principal investigators' (PIs) data were extracted from publicly available information from their institutions' websites and/or professional social media accounts. RESULTS: The NIH awarded 1101 new grants (total: $389,006,782; median: $313,030) between 2008 and 2018. Funding to DoS has doubled in the last 10 years ($22,983,500-2008 to $49,446,076-2018). Midwest/Southeast institutions and surgical oncologists accounted for majority of the grants (31.9% and 24.5%, respectively). Only 24.7% of the projects were led by female PIs, who were predominantly nonphysician PhD scientists (52% vs 37.7% PhD-only male PIs; P = 0.002). During this time, there was a significant increase from 12.4% to 31.7% in grants awarded to PIs with >15 years of experience. These grants were associated with 8215 publications; however, only 13.2% were published in high-impact journals (impact factor ≥10). 4.4% of the grants resulted in patents, and these were associated with higher award amounts ($345,801 vs $311,350; P = 0.030). On multivariate analysis, combined MD/PhD degree [odds ratio (OR) 5.98; 95% confidence interval (CI) 2.18-16.39; P < 0.001] was associated with improved odds of patent creation; conversely, practicing surgeon PIs affected patent creation negatively (OR 0.31; 95% CI 0.11-0.85; P = 0.024). CONCLUSION: In the last decade, a greater proportion of NIH grants in DoS were awarded to more experienced investigators. Disparities exist among grantees, and female investigators are underrepresented, especially among practicing surgeons.

A Novel Interdisciplinary Iterative Approach for Optimizing the Electronic Health Record to Improve Perioperative Efficiency.

OBJECTIVE: We present a holistic perioperative optimization approach led by a CI team with the goal to optimize the workflow within our EHR, improve operative room metrics and user satisfaction. SUMMARY OF BACKGROUND DATA: The EHR has become integral to perioperative care. Many approaches are utilized to improve performance including systems-based approaches, process redesign, lean methodology, checklists, root cause analysis, and parallel processing. Although most reports describe strategies improving day or surgery productivity, few include perioperative interventions to improve efficiencies. METHODS: An interdisciplinary CI team consisting of clinicians, informatics specialists, and analysts spent 6 weeks assessing users and optimizing all perioperative areas (scheduling, day of surgery, postop discharge/admission). Elbow-to-elbow retraining and simultaneous content development was performed utilizing an Agile workflow process optimization with the Scrum framework. This iterative approach averaged 1 week from build to change implementation. Pre/post optimization surveys were sent. RESULTS: Two hundred forty-two perioperative enhancements were completed. While most impacted documentation, all areas were enhanced including billing, reporting, registration, device integration, scheduling, central supply, and so on. FCOTS improved from <70% to >85% and total delay was halved. These parameters were consistently sustained for over 1 year after the 6-week optimization. While only 5% of pre-optimization users agreed to proficiency in the EHR system, this improved to 70% post-optimization. Furthermore, EHR confidence and acceptance improved from 40% to 90%. CONCLUSIONS: To improve workflow efficiency, all who contribute to the perioperative process must be assessed. This IT driven initiative resulted in improved FCOTS, perioperative workflows, and user satisfaction.

The Miami International Evidence-based Guidelines on Minimally Invasive Pancreas Resection.

OBJECTIVE: The aim of this study was to develop and externally validate the first evidence-based guidelines on minimally invasive pancreas resection (MIPR) before and during the International Evidence-based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR) meeting in Miami (March 2019). SUMMARY BACKGROUND DATA: MIPR has seen rapid development in the past decade. Promising outcomes have been reported by early adopters from high-volume centers. Subsequently, multicenter series as well as randomized controlled trials were reported; however, guidelines for clinical practice were lacking. METHODS: The Scottisch Intercollegiate Guidelines Network (SIGN) methodology was used, incorporating these 4 items: systematic reviews using PubMed, Embase, and Cochrane databases to answer clinical questions, whenever possible in PICO style, the GRADE approach for assessment of the quality of evidence, the Delphi method for establishing consensus on the developed recommendations, and the AGREE-II instrument for the assessment of guideline quality and external validation. The current guidelines are cosponsored by the International Hepato-Pancreato-Biliary Association, the Americas Hepato-Pancreato-Biliary Association, the Asian-Pacific Hepato-Pancreato-Biliary Association, the European-African Hepato-Pancreato-Biliary Association, the European Association for Endoscopic Surgery, Pancreas Club, the Society of American Gastrointestinal and Endoscopic Surgery, the Society for Surgery of the Alimentary Tract, and the Society of Surgical Oncology. RESULTS: After screening 16,069 titles, 694 studies were reviewed, and 291 were included. The final 28 recommendations covered 6 topics; laparoscopic and robotic distal pancreatectomy, central pancreatectomy, pancreatoduodenectomy, as well as patient selection, training, learning curve, and minimal annual center volume required to obtain optimal outcomes and patient safety. CONCLUSION: The IG-MIPR using SIGN methodology give guidance to surgeons, hospital administrators, patients, and medical societies on the use and outcome of MIPR as well as the approach to be taken regarding this challenging type of surgery.

Utility of Radiation After Neoadjuvant Chemotherapy for Surgically Resectable Esophageal Cancer.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) ± radiation (NRT) is the "gold standard" approach for locally advanced esophageal cancer (EC). However, the benefits of RT on overall survival (OS) in patients with resectable EC undergoing neoadjuvant therapy followed by esophagectomy remain controversial. METHODS: The National Cancer Data Base was queried for patients with nonmetastatic EC between 2004 and 2014. Kaplan-Meier, log-rank, and Cox multivariable regression analysis were performed to analyze OS. Logistic regression analyzed factors associated with 90-day mortality, lymph node involvement, and complete pathological response (pCR). RESULTS: A total of 12,238 EC patients who underwent neoadjuvant therapy [neoadjuvant chemoradiation (NACR), 92.1% and NAC, 7.9%] followed by esophagectomy were included. OS was similar in patients undergoing NAC ± RT (35.9 vs. 37.6 mo, respectively, p = 0.393). pCR rate was 18.1% (19.2%, NACR vs. 6.3%, NAC, p < 0.001). NRT was an independent predictor for increased pCR (HR 2.593, p < 0.001). Patients with pCR had increased survival compared with those without pCR (62.3 vs. 34.4 mo, p < 0.001); however, no difference was found between NACR and NAC (61.7 mo vs. median not reached, p = 0.745) in pCR patients. In non-pCR patients, NAC had improved OS compared with NACR (37.3 vs. 30.8 mo, p = 0.002). NRT was associated with worse 90-day mortality (8.2% vs. 7.7%, HR1.872, p = 0.036) In Cox regression, NRT was an independent predictor of worse OS (HR 1.561, p < 0.001). CONCLUSIONS: Neoadjuvant RT is associated with improved pCR rates; however, it had deleterious effects in short- and long-term survival. Also, patients who did not achieve pCR had worse OS after neoadjuvant RT.

Minimally Invasive Surgery is Associated with an Increased Risk of Postoperative Venous Thromboembolism After Distal Pancreatectomy.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality following distal pancreatectomy (DP). However, the influence of operative technique on VTE risk after DP is unknown. OBJECTIVE: The purpose of this study was to examine the association between the MIS technique versus the open technique and the development of postoperative VTE after DP. METHODS: Patients who underwent DP from 2014 to 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program pancreas-specific database. Multivariable logistic regression was then used to identify independent associations with the development of postoperative VTE after DP. RESULTS: A total of 3558 patients underwent DP during this time period. Of these cases, 47.8% (n = 1702) were performed via the MIS approach. After adjusting for significant covariates, the MIS approach was independently associated with the development of any VTE (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.06-2.40; p = 0.025), as well as increasing the risk of developing a postdischarge VTE (OR 1.80, 95% CI 1.05-3.08; p = 0.033) when compared with the open approach. There was an association between VTE and the development of numerous postoperative complications, including pneumonia, unplanned intubation, need for prolonged mechanical ventilation, and cardiac arrest. CONCLUSION: Compared with the open approach, the MIS approach is associated with higher rates of postoperative VTE in patients undergoing DP. The majority of these events are diagnosed after hospital discharge.

Survival Outcomes Associated With Clinical and Pathological Response Following Neoadjuvant FOLFIRINOX or Gemcitabine/Nab-Paclitaxel Chemotherapy in Resected Pancreatic Cancer.

OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC. RESULTS: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP. CONCLUSION: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.

NFκB in Pancreatic Stellate Cells Reduces Infiltration of Tumors by Cytotoxic T Cells and Killing of Cancer Cells, via Up-regulation of CXCL12.

BACKGROUND & AIMS: Immunotherapies are ineffective against pancreatic cancer. We investigated whether the activity of nuclear factor (NF)κB in pancreatic stromal cells contributes to an environment that suppresses antitumor immune response. METHODS: Pancreata of C57BL/6 or Rag1-/- mice were given pancreatic injections of a combination of KrasG12D/+; Trp53 R172H/+; Pdx-1cre (KPC) pancreatic cancer cells and pancreatic stellate cells (PSCs) extracted from C57BL/6 (control) or mice with disruption of the gene encoding the NFκB p50 subunit (Nfkb1 or p50-/- mice). Tumor growth was measured as an endpoint. Other mice were given injections of Lewis lung carcinoma (LLC) lung cancer cells or B16-F10 melanoma cells with control or p50-/- fibroblasts. Cytotoxic T cells were depleted from C57BL/6 mice by administration of antibodies against CD8 (anti-CD8), and growth of tumors from KPC cells, with or without control or p50-/- PSCs, was measured. Some mice were given an inhibitor of CXCL12 (AMD3100) and tumor growth was measured. T-cell migration toward cancer cells was measured using the Boyden chamber assay. RESULTS: C57BL/6 mice coinjected with KPC cells (or LLC or B16-F10 cells) and p50-/- PSCs developed smaller tumors than mice given injections of the cancer cells along with control PSCs. Tumors that formed when KPC cells were injected along with p50-/- PSCs had increased infiltration by activated cytotoxic T cells along with decreased levels of CXCL12, compared with tumors grown from KPC cells injected along with control PSCs. KPC cells, when coinjected with control or p50-/- PSCs, developed the same-size tumors when CD8+ T cells were depleted from C57BL/6 mice or in Rag1-/- mice. The CXCL12 inhibitor slowed tumor growth and increased tumor infiltration by cytotoxic T cells. In vitro expression of p50 by PSCs reduced T-cell migration toward and killing of cancer cells. When cultured with cancer cells, control PSCs expressed 10-fold higher levels of CXCL12 than p50-/- PSCs. The CXCL12 inhibitor increased migration of T cells toward KPC cells in culture. CONCLUSIONS: In studies of mice and cell lines, we found that NFκB activity in PSCs promotes tumor growth by increasing expression of CXCL12, which prevents cytotoxic T cells from infiltrating the tumor and killing cancer cells. Strategies to block CXCL12 in pancreatic tumor cells might increase antitumor immunity.