Systematic review on surveillance for non-resected branch-duct intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: The management of branch-duct type intraductal papillary mucinous neoplasms (BD-IPMN) varies in existing guidelines. This study investigated the optimal surveillance protocol and safe discontinuation of surveillance considering natural history in non-resected IPMN, by systematically reviewing the published literature. METHODS: This review was guided by PRISMA. Research questions were framed in PICO format "CQ1-1: Is size criteria helpful to determine surveillance period? CQ1-2: How often should surveillance be carried out? CQ1-3: When should surveillance be discontinued? CQ1-4: Is nomogram predicting malignancy useful during surveillance?". PubMed was searched from January-April 2022. RESULTS: The search generated 2373 citations. After screening, 83 articles were included. Among them, 33 studies were identified for CQ1-1, 19 for CQ1-2, 26 for CQ1-3 and 12 for CQ1-4. Cysts <1.5 or 2 cm without worrisome features (WF) were described as more indolent, and most studies advised an initial period of surveillance. The median growth rate of cysts <2 cm ranged from 0.23 to 0.6 mm/year. Patients with cysts <2 cm showing no morphological changes and no WF after 5-years of surveillance have minimal malignancy risk of 0-2%. Two nomograms created with over 1000 patients had AUCs of around 0.8 and appear to be feasible in a real-world practice. CONCLUSIONS: For patients with suspected BD-IPMN <2 cm and no other WF, less frequent surveillance is recommended. Surveillance may be discontinued for cysts that remain stable during 5-year surveillance, with consideration of patient condition and life expectancy. With this updated surveillance strategy, patients with non-worrisome BD-IPMN should expect more streamlined management and decreased healthcare utilization.

Haemosuccus pancreaticus and seven episodes of recurrent unlocalised upper gastrointestinal bleeding.

Upper gastrointestinal (GI) bleeding is a common medical condition that results in extensive morbidity and mortality, as well as substantial healthcare costs. While there is variation among society and consensus guidelines, the approaches to assessment and evaluation are generally consistent. Our case describes a man in his 40s who presented with seven episodes of recurrent upper GI bleeding over 2 years secondary to haemosuccus pancreaticus. While rare, this case study highlights key principles to the initial diagnostic approach that, in appropriate clinical contexts, should be applied to patients with unlocalised upper GI bleeding. We further perform a complete systematic review of similar cases available in PubMed (36 patients in 24 case reports) to further refine these diagnostic principles.

Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study.

BACKGROUND: International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. METHODS: An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005-2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. RESULTS: Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). CONCLUSION: This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.

The impact of surgical-oncologic textbook outcome in patients with stage I to III pancreatic ductal adenocarcinoma: A cross-validation study of two national registries.

BACKGROUND: Using national registries, we aimed to evaluate oncologic textbook outcomes in pancreatic ductal adenocarcinoma patients. METHODS: Patients with stage I to III pancreatic ductal adenocarcinoma and surgical resection from 2010 to 2020 in the US and Germany were identified using the National Cancer Database and National Cancer Registries data. The surgical-oncologic textbook outcome was defined as complete oncologic resection with no residual tumor and ≥12 harvested lymph nodes. The composite endpoint was defined as surgical-oncologic textbook outcome and receipt of perioperative systemic and/or radiation therapy. RESULTS: In total, 33,498 patients from the National Cancer Database and 14,589 patients from the National Cancer Registries were included. In the National Cancer Database, 28,931 (86%) patients had complete oncologic resection with no residual tumor, and 11,595 (79%) in the National Cancer Registries. 8,723 (26%) patients in the National Cancer Database and 556 (4%) in the National Cancer Registries had <12 lymph nodes harvested. The National Cancer Database shows 26,135 (78%) underwent perioperative therapy and 8,333 (57%) in the National Cancer Registries. Surgical-oncologic textbook outcome was achieved in 21,198 (63%) patients in the National Cancer Database and in 11,234 (77%) patients from the National Cancer Registries. 16,967 (50%) patients in the National Cancer Database and 7,878 (54%) patients in the National Cancer Registries had composite textbook outcome. Median overall survival in patients with composite textbook outcomes was 32 months in the National Cancer Database and 27 months in the National Cancer Registries (P < .001). In contrast, those with non-textbook outcomes had a median overall survival of 23 months in the National Cancer Database and 20 months in the National Cancer Registries (P < .001). CONCLUSION: Surgical-oncologic textbook outcomes were achieved in > 50% of stage I to III pancreatic ductal adenocarcinoma for both the National Cancer Database and the National Cancer Registries. Failure to achieve textbook outcomes was associated with impaired survival across both registries.

Caregiver-reported quality of communication in pancreatic and periampullary cancer.

BACKGROUND: Communication between caregivers and clinical team members is critical for transitional care, but its quality and potential impact on outcomes are not well understood. This study reports on caregiver-reported quality of communication with clinical team members in the postpancreatectomy period and examines associations of these reports with patient and caregiver outcomes. METHODS: Caregivers of patients with pancreatic and periampullary malignancies who had undergone pancreatectomy were surveyed. Instrument measures assessed care experiences using the Caregiver Perceptions About Communication with Clinical Team Members (CAPACITY) instrument. The instrument has two main subscales: communication, assessing the extent to which providers helped caregivers comprehend details of clinical visits, and capacity, defined as the extent to which providers assessed whether caregivers were able to care for patients. RESULTS: Of 265 caregivers who were approached, 240 (90.6%) enrolled in the study. The mean communication and capacity subscale scores were 2.7 ± 0.6 and 1.5 ± 0.6, respectively (range, 0-4 [higher = better]). Communication subscale scores were lower among caregivers of patients who experienced (vs. those who did not experience) a 30-day readmission (2.6 ± 0.5 vs. 2.8 ± 0.6, respectively; p = .047). Capacity subscale scores were inversely associated with restriction in patient daily activities (a 0.04 decrement in the capacity score for every 1 point in daily activity restriction; p = .008). CONCLUSIONS: After pancreatectomy, patients with pancreatic and periampullary cancer whose caregivers reported worse communication with care providers were more likely to experience readmission. Caregivers of patients with greater daily activity restrictions were less likely to report being asked about the caregiver's skill and capacity by clinicians. PLAIN LANGUAGE SUMMARY: This prospective study used a validated survey instrument and reports on the quality of communication between health care providers and caregivers as reported by caregivers of patients with pancreatic and periampullary cancer after pancreatectomy. In an analysis of 240 caregivers enrolled in the study, lower communication scores (the extent to which providers helped caregivers understand clinical details) were associated with higher odds of 30-day patient readmission to the hospital. In addition, lower capacity scores (the extent to which providers assessed caregivers' ability to care for patients) were associated with greater impairment in caregivers. The strikingly low communication quality and capacity assessment scores suggest substantial room for improvement, with the potential to improve both caregiver and patient outcomes.

Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.

INTRODUCTION: Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. METHODS: All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. RESULTS: Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. CONCLUSION: The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.

Portal Vein or Superior Mesenteric Vein Thrombosis with Dose-Escalated Radiation for Borderline or Locally Advanced Pancreatic Cancer.

PURPOSE: Portal vein and superior mesenteric vein thrombosis (PVT/SMVT) are potentially morbid complications of radiation dose-escalated local therapy for pancreatic cancer. We retrospectively reviewed records for patients treated with and without intraoperative radiation (IORT) to identify risk factors for PVT/SMVT. METHODS: Ninety-six patients with locally advanced or borderline resectable pancreatic adenocarcinoma received neoadjuvant therapy followed by surgical exploration from 2009 to 2014. Patients at risk for close or positive surgical margins received IORT boost to a biologically effective dose (BED10) > 100. Prognostic factors for PVT/SMVT were evaluated using competing risks regression. RESULTS: Median follow-up was 79 months for surviving patients. Fifty-six patients (58%) received IORT. Twenty-nine patients (30%) developed PVT/SMVT at a median time of 18 months. On univariate competing risks regression, operative blood loss and venous repair with a vascular interposition graft, but not IORT dose escalation or diabetes history, were significantly associated with PVT/SMVT. The development of thrombosis in the absence of recurrence was significantly associated with a longstanding diabetes history, post-neoadjuvant treatment CA19-9, and operative blood loss. All 4 patients who underwent both IORT and vascular repair with a graft developed PVT/SMVT. PVT/SMVT in the absence of recurrence is not associated with significantly worsened overall survival but led to frequent medical interventions. CONCLUSIONS: Approximately 30% of patients who underwent neoadjuvant chemoradiation for PDAC developed PVT/SMVT a median of 18 months following surgery. This was significantly associated with venous reconstruction with vascular grafts, but not with escalating radiation dose. PVT/SMVT in the absence of recurrence was associated with significant morbidity.

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis.

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

A Clinical Guide to the Management of Intraductal Papillary Mucinous Neoplasms: the Need for a More Graded Approach in Clinical Decision-making.

Intraductal papillary mucinous neoplasms (IPMNs) have become a very common diagnosis and represent a spectrum of disease that ranges from benign to malignant lesions. Presently, clinical and radiographic features are used to predict the presence of high-grade dysplasia and invasive cancer to inform treatment decisions of whether to pursuit surgical resection or continued surveillance. However, the natural history of IPMNs is still not completely understood, with guidelines from different societies providing contradictory recommendations. This underscores the challenge in balancing the risk of missing cancer with long-term surveillance and the morbidity associated with surgical resection. In this review, we aim to reconcile the differences in the guidelines' recommendations and provide a clinical framework to the management of IPMNs with hopes of adding clarity to how treatment decisions should be made. We also highlight recent advances made in the field and future efforts that can minimize rates of missing cancer while also reducing the number of unnecessary operations.

Association Between Biliary Pathogens, Surgical Site Infection, and Pancreatic Fistula: Results of a Randomized Trial of Perioperative Antibiotic Prophylaxis in Patients Undergoing Pancreatoduodenectomy.

OBJECTIVE: To establish the association between bactibilia and postoperative complications when stratified by perioperative antibiotic prophylaxis. BACKGROUND: Patients undergoing pancreatoduodenectomy experience high rates of surgical site infection (SSI) and clinically relevant postoperative pancreatic fistula (CR-POPF). Contaminated bile is known to be associated with SSI, but the role of antibiotic prophylaxis in mitigation of infectious risks is ill-defined. METHODS: Intraoperative bile cultures (IOBCs) were collected as an adjunct to a randomized phase 3 clinical trial comparing piperacillin-tazobactam with cefoxitin as perioperative prophylaxis in patients undergoing pancreatoduodenectomy. After compilation of IOBC data, associations between culture results, SSI, and CR-POPF were assessed using logistic regression stratified by the presence of a preoperative biliary stent. RESULTS: Of 778 participants in the clinical trial, IOBC were available for 247 participants. Overall, 68 (27.5%) grew no organisms, 37 (15.0%) grew 1 organism, and 142 (57.5%) were polymicrobial. Organisms resistant to cefoxitin but not piperacillin-tazobactam were present in 95 patients (45.2%). The presence of cefoxitin-resistant organisms, 92.6% of which contained either Enterobacter spp. or Enterococcus spp., was associated with the development of SSI in participants treated with cefoxitin [53.5% vs 25.0%; odds ratio (OR)=3.44, 95% CI: 1.50-7.91; P =0.004] but not those treated with piperacillin-tazobactam (13.5% vs 27.0%; OR=0.42, 95% CI: 0.14-1.29; P =0.128). Similarly, cefoxitin-resistant organisms were associated with CR-POPF in participants treated with cefoxitin (24.1% vs 5.8%; OR=3.45, 95% CI: 1.22-9.74; P =0.017) but not those treated with piperacillin-tazobactam (5.4% vs 4.8%; OR=0.92, 95% CI: 0.30-2.80; P =0.888). CONCLUSIONS: Previously observed reductions in SSI and CR-POPF in patients that received piperacillin-tazobactam antibiotic prophylaxis are potentially mediated by biliary pathogens that are cefoxitin resistant, specifically Enterobacter spp. and Enterococcus spp.

Cytologic, histologic, and molecular features of pancreatic sarcomatoid undifferentiated carcinoma with heterologous osteosarcomatous transformation.

Fine-needle aspiration (FNA) is a minimally invasive and effective modality to diagnose pancreatic ductal adenocarcinoma. However, some histologic subtypes of ductal adenocarcinoma are rarely encountered and challenging to diagnose on FNA/small biopsies. To date, cytohistologic features of pancreatic sarcomatoid undifferentiated carcinoma with heterologous elements have not been thoroughly described. An 83-year-old man with lower back pain was found to have an incidental pancreatic neck mass. FNA biopsy of the mass showed rare markedly atypical, large, pleomorphic cells in a background of abundant calcifications/bone formation without areas of conventional adenocarcinoma. A diagnosis of "Malignant neoplasm with osteosarcomatous differentiation" was rendered on the FNA specimen. Subsequently, a Whipple resection revealed a 4.1 cm lobulated, calcified pancreatic mass. Microscopic examination showed a heavily calcified/ossified mass with adjacent areas of a highly cellular malignant spindle cell proliferation and admixed large, pleomorphic tumor cells; no background conventional adenocarcinoma was identified. Cytokeratin immunostains MNF116 and CK19 were positive in a large subset of the malignant spindle cells, and AE1.3/CAM5.2 showed patchy weak staining. Molecular testing revealed mutations in KRAS, TP53, BRCA2, NTRK3, EPHA2, MYD88, and CBL. No reportable fusions were detected. The final diagnosis was "Sarcomatoid undifferentiated carcinoma with heterologous elements (osteosarcomatous differentiation)." Definitive diagnosis of extremely rare subtypes of ductal adenocarcinoma is challenging on FNA biopsies. In this case, cytologic evaluation was helpful in making an early diagnosis of a malignant neoplasm with highly unusual features, prompting appropriate triage and early surgical resection of a sarcomatoid undifferentiated carcinoma with prominent osteosarcomatous differentiation.

A Simple Classification of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery.

OBJECTIVE: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. METHODS: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. RESULTS: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001). CONCLUSION: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy.

Pancreatic adenocarcinoma is a lethal cancer with poor response to chemotherapy and immune checkpoint inhibitors. Recent studies suggest that epigenetic alterations contribute to its aggressive biology and the tumor microenvironment which render it unresponsive to immune checkpoint blockade. Here, we review our current understandings of epigenetic dysregulation in pancreatic adenocarcinoma, its effect on the tumor immune microenvironment, and the potential for epigenetic therapy to be combined with immune checkpoint inhibitors.

Treatment and Prevention of Intraabdominal Bleeding in Necrotizing Pancreatitis Patients Treated With a Step-Up Approach.

OBJECTIVES: A minimally invasive step-up (MIS) approach for management of necrotizing pancreatitis (NP) has been associated with reduced morbidity and mortality compared with open surgical techniques. We sought to evaluate bleeding complications in NP patients treated with a MIS approach and to describe the management and outcomes of these events. METHODS: An observational, cohort study was performed using a prospectively maintained NP database at a tertiary referral center from 2013 to 2019. RESULTS: Of 119 NP patients, 13% suffering bleeding events, and 18% underwent an intervention. There was a 6-fold higher mortality rate in patients with bleeding events (n = 3; 18.8%) compared with those without (n = 3; 2.9%) ( P = 0.031). The most common intervention for hemorrhage control was endovascular coil embolization (75%), which was successful 88% of the time. Seven patients underwent prophylactic vascular intervention, which was 100% successful in preventing bleeding events from the embolized vessel. CONCLUSIONS: Bleeding events in NP patients treated with a MIS approach are associated with a 6-fold increase in mortality. Endovascular intervention is an effective strategy for the management of bleeding events. Prophylactic embolization may be an effective technique for reducing bleeding complications.

Effects of a perioperative geriatric intervention for older adults with Cancer: A randomized clinical trial.

BACKGROUND: Older adults with gastrointestinal cancers undergoing surgery often experience poor outcomes, such as prolonged postoperative hospital length of stay (LOS), intensive care unit (ICU) use, hospital readmissions, and complications. Involvement of geriatricians in the care of older adults with cancer can improve outcomes. We conducted a randomized trial of a perioperative geriatric intervention (PERI-OP) in older patients with gastrointestinal cancer undergoing surgery. METHODS: From 9/2016-4/2019, we randomly assigned patients age ≥ 65 with gastrointestinal cancer planning to undergo surgical resection to receive PERI-OP or usual care. Patients assigned to PERI-OP met with a geriatrician preoperatively in the outpatient setting and postoperatively as an inpatient consultant. The primary outcome was postoperative hospital LOS. Secondary outcomes included postoperative ICU use, 90-day hospital readmission rates, and complication rates. We conducted intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: ITT analyses included 137/160 patients who underwent surgery (usual care = 68/78, intervention = 69/82). PP analyses included the 68 usual care patients and the 30/69 intervention patients who received the preoperative and postoperative intervention components. ITT analyses demonstrated no significant differences between intervention and usual care in postoperative hospital LOS (7.23 vs 8.21 days, P = 0.374), ICU use (23.2% vs 32.4%, P = 0.257), 90-day hospital readmission rates (21.7% vs 25.0%, P = 0.690), or complication rates (17.4% vs 20.6%, P = 0.668). In PP analyses, intervention patients had shorter postoperative hospital LOS (5.90 vs 8.21 days, P = 0.024), but differences in ICU use (13.3% vs 32.4%, P = 0.081), 90-day hospital readmission rates (16.7% vs 25.0%, P = 0.439), and complication rates (6.7% vs 20.6%, P = 0.137) remained non-significant. CONCLUSIONS: In this randomized trial, PERI-OP did not have a significant impact on postoperative hospital LOS, ICU use, hospital readmissions, or complications. However, the subgroup who received PERI-OP as planned experienced encouraging results. Future studies of PERI-OP should include efforts, such as telehealth, to ensure the intervention is delivered as planned.

Reassessment of the Optimal Number of Examined Lymph Nodes in Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The aim of this study was to reappraise the optimal number of examined lymph nodes (ELNs) in pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: The well-established threshold of 15 ELNs in PD for PDAC is optimized for detecting 1 positive node (PLN) per the previous 7th edition of the American Joint Committee on Cancer (AJCC) staging manual. In the framework of the 8th edition, where at least 4 PLN are needed for an N2 diagnosis, this threshold may be inadequate for accurate staging. METHODS: Patients who underwent upfront PD at 2 academic institutions between 2000 and 2016 were analyzed. The optimal ELN threshold was defined as the cut-point associated with a 95% probability of identifying at least 4 PLNs in N2 patients. The results were validated addressing the N-status distribution and stage migration. RESULTS: Overall, 1218 patients were included. The median number of ELN was 26 (IQR 17-37). ELN was independently associated with N2-status (OR 1.27, P < 0.001). The estimated optimal threshold of ELN was 28. This cut-point enabled improved detection of N2 patients and stage III disease (58% vs 37%, P = 0.001). The median survival was 28.6 months. There was an improved survival in N0/N1 patients when ELN exceeded 28, suggesting a stage migration effect (47 vs 29 months, adjusted HR 0.649, P < 0.001). In N2 patients, this threshold was not associated with survival on multivariable analysis. CONCLUSION: Examining at least 28 LN in PD for PDAC ensures optimal staging through improved detection of N2/stage III disease. This may have relevant implications for benchmarking processes and quality implementation.

Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma.

OBJECTIVE: The objective of this study was to characterize the patterns of first recurrence after curative-intent resection for pancreatic adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: We evaluated the first site of recurrence after neoadjuvant treatment as locoregional (LR) or distant metastasis (DM). To validate our findings, we evaluated the pattern from 2 phase II clinical trials evaluating neoadjuvant chemotherapy (NAC) in PDAC. METHODS: We identified site of first recurrence from a retrospective cohort of patients from 2011 to 2017 treated with NAC followed by chemoradiation and then an operation or an operation first followed by adjuvant therapy, and 2 separate prospective cohorts of patients derived from 2 phase II clinical trials evaluating patients treated with NAC in borderline-resectable and locally advanced PDAC. RESULTS: In the retrospective cohorts, 160 out of 285 patients (56.1%) recurred after a median disease-free survival (mDFS) of 17.2 months. The pattern of recurrence was DM in 81.9% of patients, versus LR in 11.1%. This pattern was consistent in patients treated with upfront resection and adjuvant chemotherapy (DM 83.0%, LR 16.9%) regardless of margin-involvement (DM 80.1%, LR 19.4%). The use of NAC did not alter pattern of recurrence; 81.7% had DM and 18.3% had LR. This pattern also remained consistent regardless of margin-involvement (DM 94.1%, LR 5.9%). In the Phase II borderline-resectable trial (NCI# 01591733) cohort of 32 patients, the mDFS was 34.2 months. Pattern of recurrence remained predominantly DM (88.9%) versus LR (11.1%). In the Phase II locally-advanced trial (NCI# 01821729) cohort of 34 patients, the mDFS was 30.7 months. Although there was a higher rate of local recurrence in this cohort, pattern of first recurrence remained predominantly DM (66.6%) versus LR (33.3%) and remained consistent independent of margin-status. CONCLUSIONS: The pattern of recurrence in PDAC is predominantly DM rather than LR, and is consistent regardless of the use of NAC and margin involvement.

Implications of Perineural Invasion on Disease Recurrence and Survival After Pancreatectomy for Pancreatic Head Ductal Adenocarcinoma.

OBJECTIVE: To describe PNI and to evaluate its impact on disease-free (DFS) and overall survival (OS) in patients with resected pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: Although PNI is a prognostic factor for survival in many GI cancers, there is limited knowledge regarding its impact on tumor recurrence, especially in ''early stage disease'' (PDAC ≤20 mm, R0/ N0 PDAC). METHODS: This multicenter retrospective study included patients undergoing PDAC resection between 2009 and 2014. The association of PNI with DFS and OS was analyzed using Cox proportional-hazards models. RESULTS: PNI was found in 87% of 778 patients included in the study, with lower rates in PDAC ≤20 mm (78.7%) and in R0/N0 tumors (70.6%). PNI rate did not differ between patients who underwent neoadjuvant therapy and upfront surgery (88% vs 84%, P = 0.08). Although not significant at multivariate analysis ( P = 0.07), patients with PNI had worse DFS at univariate analysis (median DFS: 20 vs 15 months, P < 0.01). PNI was the only independent predictor of DFS in R0/N0 tumors (hazard ratio [HR]: 2.2) and in PDAC ≤ 20 mm (HR: 1.8). PNI was an independent predictor of OS in the entire cohort (27 vs 50 months, P = 0.01), together with G3 tumors, pN1 status, carbohydrate antigen (CA) 19.9 >37 and pain. CONCLUSIONS: PNI represents a major determinant of tumor recurrence and patients' survival in pancreatic cancer. The role of PNI is particularly relevant in early stages, supporting the hypothesis that invasion of nerves by cancer cells has a driving role in pancreatic cancer progression.

The Influence of Intraoperative Blood Loss on Fistula Development Following Pancreatoduodenectomy.

OBJECTIVE: To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). BACKGROUND: Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development. METHODS: This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL; > 1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk. RESULTS: CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P < 0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P < 0.001). EBL >400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P < 0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P < 0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P < 0.001). CONCLUSION: EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.