Poor Prognostic Factors in Long-Term Survivors of Resected Pancreatic Ductal Adenocarcinoma: An International, Multicenter Cohort Study.

OBJECTIVE: To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS. SUMMARY BACKGROUND DATA: Long-term survival (>5 y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear. METHODS: An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression. RESULTS: 3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features. CONCLUSIONS: This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS.

Total versus Partial Pancreatectomy in Patients with Pancreatic Cancer Arising from Multifocal or Diffuse Intraductal Papillary Mucinous Neoplasia - A Multicenter Observational Study.

AIM: To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer. SUMMARY BACKGROUND DATA: Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients. METHODS: This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS. RESULTS: Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007). CONCLUSION: Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence.

Informing Decision-making for Transected Margin Reresection in Intraductal Papillary Mucinous Neoplasm-derived PDAC: An International Multicenter Study.

OBJECTIVE: To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section. SUMMARY BACKGROUND DATA: The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable. METHODS: Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002-2022) from six international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival (RFS). RESULTS: Overall, 832 patients with IPMN-derived PDAC were included with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared to those with an R1 status (65.8 vs. 26.3 mo P<0.001). Patients without dysplasia at the pancreatic neck margin had similar OS compared to those with low-grade dysplasia (mOS: 78.8 vs. 66.8 months, P=0.344). However, high-grade dysplasia (mOS: 26.1 mo, P=0.001) and invasive cancer (mOS: 25.0 mo, P<0.001) were associated with significantly worse OS compared to no or low-grade dysplasia. Patients who underwent conversion of high-risk margins (high-grade or invasive cancer) to a low-risk margin (low-grade or no dysplasia) after intraoperative frozen section had significantly superior OS compared to those with a high-risk neck margin on final pathology (mOS: 76.9 vs. 26.1 mo P<0.001). CONCLUSIONS: In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible.

Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results From an International Multicenter Study.

PURPOSE: The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS: This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS: In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION: Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

Evaluation of AJCC Nodal Staging for Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The American Joint Committee on Cancer (AJCC) eighth edition is based on pancreatic intraepithelial neoplasia-derived pancreatic ductal adenocarcinoma (PDAC), a biologically distinct entity from intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer. The role of nodal disease and the AJCC's prognostic utility for IPMN-derived pancreatic cancer are unclear. This study aimed to evaluate the prognostic role of nodal disease and the AJCC eighth-edition N-staging for IPMN-derived pancreatic cancer. METHODS: Upfront-surgery patients with IPMN-derived PDAC from four centers were stratified according to the AJCC eighth-edition N stage. Disease characteristics were compared using descriptive statistics, and both overall survival (OS) and recurrence-free survival (RFS) were evaluated using log-rank tests. Multivariable Cox regression was performed to determine the prognostic value of N stage for OS, presented as hazard ratios with 95 % confidence intervals (95 % CIs). A lowest p value log-rank statistic was used to derive the optimal cutoff for node-positive disease. RESULTS: For 360 patients, advanced N stage was associated with worse T stage, grade, tubular histology, and perineural and lymphovascular invasion (all p < 0.05). The median OS was 98.3 months (95 % CI 82.8-122.0 months) for N0 disease, 27.8 months (95 % CI 24.4-41.7 months) for N1 disease, and 18.1 months (95 % CI 16.2-25.9 months) for N2 disease (p < 0.001). The AJCC N stage was validated and associated with worse OS (N1 [HR 1.64; range, 1.05-2.57], N2 [HR2.42; range, 1.48-3.96]) and RFS (N1 [HR 1.81; range, 1.23-2.68], N2 [HR 3.72; range, 2.40-5.77]). The optimal cutoff for positive nodes was five nodes. CONCLUSION: The AJCC eighth-edition N-staging is valid and prognostic for both OS and RFS in IPMN-derived PDAC.

The Significance of Circulating Tumor Cells in Pancreatic Cancer.

The notion that technically resectable pancreatic ductal adenocarcinoma presents as localized disease is now known to be inaccurate. Evidence supports that most patients have subclinical systemic dissemination at the time of diagnosis. It is now widely accepted that both a local and systemic component of disease coexist, each requiring treatment of improved survival and potential cure. The advent of multiagent chemotherapy regimens has resulted in a modest improvement in survival. Consequently, this article will emphasize the expanding potential and significance of circulating tumor cells in the prognostication and management of patients with pancreatic cancer.

Outcomes in intraductal papillary mucinous neoplasm-derived pancreatic cancer differ from PanIN-derived pancreatic cancer.

BACKGROUND AND AIM: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) management is generally extrapolated from pancreatic intraepithelial neoplasia (PanIN)-derived PDAC guidelines. However, these are biologically divergent, and heterogeneity further exists between tubular and colloid subtypes. METHODS: Consecutive upfront surgery patients with PanIN-derived and IPMN-derived PDAC were retrospectively identified from international centers (2000-2019). One-to-one propensity score matching for clinicopathologic factors generated three cohorts: IPMN-derived versus PanIN-derived PDAC, tubular IPMN-derived versus PanIN-derived PDAC, and tubular versus colloid IPMN-derived PDAC. Overall survival (OS) was compared using Kaplan-Meier and log-rank tests. Multivariable Cox regression determined corresponding hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: The median OS (mOS) in 2350 PanIN-derived and 700 IPMN-derived PDAC patients was 23.0 and 43.1 months (P < 0.001), respectively. PanIN-derived PDAC had worse T-stage, CA19-9, grade, and nodal status. Tubular subtype had worse T-stage, CA19-9, grade, nodal status, and R1 margins, with a mOS of 33.7 versus 94.1 months (P < 0.001) in colloid. Matched (n = 495), PanIN-derived and IPMN-derived PDAC had mOSs of 30.6 and 42.8 months (P < 0.001), respectively. In matched (n = 341) PanIN-derived and tubular IPMN-derived PDAC, mOS remained poorer (27.7 vs 37.4, P < 0.001). Matched tubular and colloid cancers (n = 112) had similar OS (P = 0.55). On multivariable Cox regression, PanIN-derived PDAC was associated with worse OS than IPMN-derived (HR: 1.66, 95% CI: 1.44-1.90) and tubular IPMN-derived (HR: 1.53, 95% CI: 1.32-1.77) PDAC. Colloid and tubular subtype was not associated with OS (P = 0.16). CONCLUSIONS: PanIN-derived PDAC has worse survival than IPMN-derived PDAC supporting distinct outcomes. Although more indolent, colloid IPMN-derived PDAC has similar survival to tubular after risk adjustment.

The impact of metastatic sites on survival Rates and predictors of extended survival in patients with metastatic pancreatic cancer.

BACKGROUND OBJECTIVES: The aim of this study was to determine the role of site-specific metastatic patterns over time and assess factors associated with extended survival in metastatic PDAC. Half of all patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. The site of metastasis plays a crucial role in clinical decision making due to its prognostic value. METHODS: We examined 56,757 stage-IV PDAC patients from the National Cancer Database (2016-2019), categorizing them by metastatic site: multiple, liver, lung, brain, bone, carcinomatosis, or other. The site-specific prognostic value was assessed using log-rank tests while time-varying effects were assessed by Aalen's linear hazards model. Factors associated with extended survival (>3years) were assessed with logistic regression. RESULTS: Median overall survival (mOS) in patients with distant lymph node-only metastases (9.0 months) and lung-only metastases (8.1 months) was significantly longer than in patients with liver-only metastases (4.6 months, p < 0.001). However, after six months, the metastatic site lost prognostic value. Logistic regression identified extended survivors (3.6 %) as more likely to be younger, Hispanic, privately insured, Charlson-index <2, having received chemotherapy, or having undergone primary or distant site surgery (all p < 0.001). CONCLUSION: While synchronous liver metastases are associated with worse outcomes than lung-only and lymph node-only metastases, this predictive value is diminished after six months. Therefore, treatment decisions beyond this time should not primarily depend on the metastatic site. Extended survival is possible in a small subset of patients with favorable tumor biology and good conditional status, who are more likely to undergo aggressive therapies.

What is the optimal surgical approach for ductal adenocarcinoma of the pancreatic neck? - a retrospective cohort study.

BACKGROUND: The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS: Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS: Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION: While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.

An international Multi-Institutional validation of T1 Sub-staging of intraductal papillary mucinous neoplasm-derived pancreatic cancer.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) is resected at smaller sizes compared to its biologically distinct counterpart, pancreatic intraepithelial neoplasia (PanIN)-derived PDAC. Thus, experts proposed T1 sub-staging for IPMN-derived PDAC. However, this has never been validated. METHODS: Consecutive upfront surgery patients with IPMN-derived PDAC from five international high-volume centers were classified by the proposed T1 sub-staging classification (T1a ≤ 0.5, T1b > 0.5 and ≤1.0, and T1c >1.0 and ≤2.0 cm) using the invasive component size. Kaplan-Meier and log-rank tests were utilized to compare overall survival (OS). A multivariable Cox-regression was used to determine hazard ratios (HR) with confidence intervals (95%CI). RESULTS: Among 747 patients, 69 (9.2%), 50 (6.7%), 99 (13.0%), and 531 patients (71.1%), comprised the T1a, T1b, T1c, and T2-4 subgroups, respectively. Increasing T-stage was associated with elevated CA19-9, poorer grade, nodal positivity, R1-margin, and tubular subtype. Median OS for T1a, T1b, T1c, and T2-4 were 159.0 (95%CI:126.0-NR), 128.8 (98.3-NR), 77.6 (48.3-108.2), and 31.4 (27.5-37.7) months, respectively (p < .001). OS decreased with increasing T-stage for all pairwise comparisons (all p < .05). After risk-adjustment, age > 65, elevated CA19-9, T1b [HR : 2.55 (1.22-5.32)], T1c [HR : 3.04 (1.60-5.76)], and T2-4 [HR : 3.41 (1.89-6.17)] compared to T1a, nodal positivity, R1-margin, and no adjuvant chemotherapy were associated with worse OS. Disease recurrence was more common in T2-4 tumors (56.4%) compared to T1a (18.2%), T1b (23.9%), and T1c (36.1%, p < .001). CONCLUSION: T1 sub-staging of IPMN-derived PDAC is valid and has significant prognostic value. Advancing T1 sub-stage is associated with worse histopathology, survival, and recurrence. T1 sub-staging is recommended for future guidelines.

Clinical Relevance of Cancerization of Ducts in Resected Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Although prevalent in 50%-90% of pancreatic ductal adenocarcinomas, the clinical relevance of "cancerization of ducts" (COD) remains unknown. METHODS: Pathologists retrospectively reviewed slides classifying prevalence of COD. Histopathological parameters, location of first recurrence, recurrence-free survival (RFS), and overall survival (OS) were collected from the institutional pancreatectomy registry. RESULTS: Among 311 pancreatic ductal adenocarcinomas, COD was present in 216 (69.5%) and more prevalent in the cohort that underwent upfront surgery (75.3% vs 63.1%, P = 0.019). Furthermore, COD was associated with female gender (P = 0.040), advanced T stage (P = 0.007), perineural invasion (P = 0.014), lymphovascular invasion (P = 0.025), and R1 margin (P = 0.009), but not N stage (P = 0.401) or tumor differentiation (P = 0.717). In multivariable regression, COD was associated with less liver recurrence (odds ratio, 0.44; P < 0.005). This association was driven by the cohort of patients who had received preoperative treatment (odds ratio, 0.18; P < 0.001). COD was not predictive for RFS or OS. CONCLUSIONS: Cancerization of ducts was not associated with RFS or OS. Currently underrecognized, standardized implementation into histopathological reports may have merit, and further mechanistic scientific experiments need to illuminate its clinical and biologic impact.

Defining the Minimal and Optimal Thresholds for Lymph Node Resection and Examination for Intraductal Papillary Mucinous Neoplasm Derived Pancreatic Cancer: A Multicenter Retrospective Analysis.

OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+ T cells barren human pancreatic cancer.

BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

Anatomical and Biological Considerations to Determine Resectability in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains associated with poor outcomes with a 5-year survival of 12% across all stages of the disease. These poor outcomes are driven by a delay in diagnosis and an early propensity for systemic dissemination of the disease. Recently, aggressive surgical approaches involving complex vascular resections and reconstructions have become more common, thus allowing more locally advanced tumors to be resected. Unfortunately, however, even after the completion of surgery and systemic therapy, approximately 40% of patients experience early recurrence of disease. To determine resectability, many institutions utilize anatomical staging systems based on the presence and extent of vascular involvement of major abdominal vessels around the pancreas. However, these classification systems are based on anatomical considerations only and do not factor in the burden of systemic disease. By integrating the biological criteria, we possibly could avoid futile resections often associated with significant morbidity. Especially patients with anatomically resectable disease who have a heavy burden of radiologically undetected systemic disease most likely do not derive a survival benefit from resection. On the contrary, we could offer complex resections to those who have locally advanced or oligometastatic disease but have favorable systemic biology and are most likely to benefit from resection. This review summarizes the current literature on defining anatomical and biological resectability in patients with pancreatic cancer.

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 Role of Intraoperative Pancreatoscopy in the Surgical Management of Intraductal Papillary Mucinous Neoplasms: A Scoping Review.

OBJECTIVES: Most patients with intraductal papillary mucinous neoplasms (IPMNs) are diagnosed with a solitary lesion; however, the presence of skip lesions, not appreciable on imaging, has been described. Postoperatively, these missed lesions can continue to grow and potentially become cancerous. Intraoperative pancreatoscopy (IOP) may facilitate detection of such skip lesions in the remnant gland. The aim of this scoping review was to appraise the evidence on the role of IOP in the surgical management of IPMNs. MATERIALS AND METHODS: Studies reporting on the use of IOP during IPMN surgery were identified through searches of the PubMed, Embase, and Scopus databases. Data extracted included IOP findings, surgical plan modifications, and patient outcomes. The primary outcome of interest was the utility of IOP in surgical decision making. RESULTS: Ten studies reporting on the use of IOP for IPMNs were identified, representing 147 patients. A total of 46 skip lesions were identified by IOP. Overall, surgical plans were altered in 37% of patients who underwent IOP. No IOP-related complications were reported. CONCLUSIONS: The current literature suggests a potential role of integration of IOP into the management of patients with IPMNs. This tool is safe and feasible and can result in changes in surgical decision making.

Accurate non-invasive grading of nonfunctional pancreatic neuroendocrine tumors with a CT derived radiomics signature.

PURPOSE: The purpose of this study was to develop a radiomics-signature using computed tomography (CT) data for the preoperative prediction of grade of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs). MATERIALS AND METHODS: A retrospective study was performed on patients undergoing resection for NF-PNETs between 2010 and 2019. A total of 2436 radiomic features were extracted from arterial and venous phases of pancreas-protocol CT examinations. Radiomic features that were associated with final pathologic grade observed in the surgical specimens were subjected to joint mutual information maximization for hierarchical feature selection and the development of the radiomic-signature. Youden-index was used to identify optimal cutoff for determining tumor grade. A random forest prediction model was trained and validated internally. The performance of this tool in predicting tumor grade was compared to that of EUS-FNA sampling that was used as the standard of reference. RESULTS: A total of 270 patients were included and a fusion radiomic-signature based on 10 selected features was developed using the development cohort (n = 201). There were 149 men and 121 women with a mean age of 59.4 ± 12.3 (standard deviation) years (range: 23.3-85.0 years). Upon internal validation in a new set of 69 patients, a strong discrimination was observed with an area under the curve (AUC) of 0.80 (95% confidence interval [CI]: 0.71-0.90) with corresponding sensitivity and specificity of 87.5% (95% CI: 79.7-95.3) and 73.3% (95% CI: 62.9-83.8) respectively. Of the study population, 143 patients (52.9%) underwent EUS-FNA. Biopsies were non-diagnostic in 26 patients (18.2%) and could not be graded due to insufficient sample in 42 patients (29.4%). In the cohort of 75 patients (52.4%) in whom biopsies were graded the radiomic-signature demonstrated not different AUC as compared to EUS-FNA (AUC: 0.69 vs. 0.67; P = 0.723), however greater sensitivity (i.e., ability to accurately identify G2/3 lesion was observed (80.8% vs. 42.3%; P < 0.001). CONCLUSION: Non-invasive assessment of tumor grade in patients with PNETs using the proposed radiomic-signature demonstrated high accuracy. Prospective validation and optimization could overcome the commonly experienced diagnostic uncertainty in the assessment of tumor grade in patients with PNETs and could facilitate clinical decision-making.

Progression of Site-Specific Recurrence of Pancreatic Cancer and Implications for Treatment.

OBJECTIVE: This study aimed to analyze post-recurrence progression in context of recurrence sites and assess implications for post-recurrence treatment. BACKGROUND: Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within two years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of post-recurrence progression and survival remains. METHODS: This retrospective analysis included surgically treated PDAC patients at the NYU-Langone Health (2010-2021). Sites of recurrence were identified at time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox-regression analyses were applied to assess survival outcomes. RESULTS: Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95%CI:12.6 to 16.5). First site of recurrence was local in 43.9% patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, while 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared to other sites (16.9 months vs. 8.49 months, P=0.003). In local recurrence, 21 (33.3%) patients were alive after one year without progression to secondary sites. This was associated with a CA19-9 of <100U/ml at time of primary diagnosis (P=0.039), nodal negative disease (P=0.023), and well-moderate differentiation (P=0.042) compared to patients with progression. CONCLUSION: Except for lung recurrence, post-recurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.