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.

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.

Radiation response assessment of organoids derived from patients with pancreatic cancer.

Background: The effectiveness of radiotherapy for pancreatic cancer is debated. Patient-derived organoids (PDOs) already mimicked clinical radiation response in other cancer types, which could be valuable in pancreatic cancer as well. This study aimed to investigate whether PDOs can be used to model RT response in pancreatic cancer and to explore the presence of a dose-response correlation. Methods: PDOs derived from two pancreatic cancer patients (HUB-08-B2-022A and HUB-08-B2-026B) were irradiated with doses ranging from 0 to 40 Gray. Viability assessments were conducted after seven and 10 days by measuring ATP-levels. Results were normalized, defining the viability at 0 Gray as 100 % and an absolute viability of 0 as 0 %. The relative area under the curve (rAUC) was calculated (0 = total sensitivity, 1 = total resistance). Results: With a readout time of seven days, both HUB-08-B2-022A and HUB-08-B2-026B exhibited viability above 50 % at the highest dose of 12 Gy (rAUC of 0.79 and 0.69, respectively). With a readout time of 10 days, both PDOs showed a dose-response relation although HUB-08-B2-022A was more sensitive than HUB-08-B2-026B (rAUC of 0.37 and 0.51, respectively). Increasing the radiation dose to 40 Gy did not further affect viability, but the dose-response relation remained present (rAUC of 0.13 and 0.26, respectively). In the final experiment with a readout time of 10 days and a maximum dose of 14 Gy, the dose-response correlation was paramount in both PDOs (rAUC 0.28 and 0.45, respectively), with HUB-08-B2-022A being most sensitive. Conclusions: In this setup, both pancreatic cancer PDOs showed an irradiation dose-response correlation. These preliminary findings suggest that pancreatic cancer PDOs are suitable for assessing radiation response in vitro. Further experiments are needed to eventually simulate treatment responses to personalized treatment strategies.

The Effect of Radiation Treatment of Solid Tumors on Neutrophil Infiltration and Function: A Systematic Review.

Radiation therapy (RT) initiates a local and systemic immune response which can induce antitumor immunity and improve immunotherapy efficacy. Neutrophils are among the first immune cells that infiltrate tumors after RT and are suggested to be essential for the initial antitumor immune response. However, neutrophils in tumors are associated with poor outcomes and RT-induced neutrophil infiltration could also change the composition of the tumor microenvironment (TME) in favor of tumor progression. To improve RT efficacy for patients with cancer it is important to understand the interplay between RT and neutrophils. Here, we review the literature on how RT affects the infiltration and function of neutrophils in the TME of solid tumors, using both patients studies and preclinical murine in vivo models. In general, it was found that neutrophil levels increase and reach maximal levels in the first days after RT and can remain elevated up to 3 weeks. Most studies report an immunosuppressive role of neutrophils in the TME after RT, caused by upregulated expression of neutrophil indoleamine 2,3-dioxygenase 1 and arginase 1, as well as neutrophil extracellular trap formation. RT was also associated with increased reactive oxygen species production by neutrophils, which can both improve and inhibit antitumor immunity. In addition, multiple murine models showed improved RT efficacy when depleting neutrophils, suggesting that neutrophils have a protumor phenotype after RT. We conclude that the role of neutrophils should not be overlooked when developing RT strategies and requires further investigation in specific tumor types. In addition, neutrophils can possibly be exploited to enhance RT efficacy by combining RT with neutrophil-targeting therapies.

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.

Late cholangitis after pancreatoduodenectomy: A common complication with or without anatomical biliary obstruction.

BACKGROUND: Postoperative cholangitis is a common complication after pancreatoduodenectomy that can occur with or without anatomical biliary obstruction. This study aimed to investigate the incidence, diagnosis, treatment, and risk factors of cholangitis after pancreatoduodenectomy. METHODS: We performed a retrospective cohort study of consecutive patients who underwent pancreatoduodenectomy in 2 Dutch tertiary pancreatic centers (2010-2019). Primary outcome was postoperative cholangitis, defined as systemic inflammation with abnormal liver tests without another focus of infection, at least 1 month after resection. Diagnostic and therapeutic strategies were evaluated. Two types of postoperative cholangitis were distinguished; obstructive cholangitis (benign stenosis of the hepaticojejunostomy) and nonobstructive cholangitis. Potential risk factors were identified using logistic regression analysis. RESULTS: Postoperative cholangitis occurred in 93 of 900 patients (10.3%). Median time to first episode of cholangitis was 8 months (interquartile range 4-16) after pancreatoduodenectomy. Multiple episodes of cholangitis occurred in 44 patients (47.3%) and readmission was necessary in 83 patients (89.2%). No cholangitis-related mortality was observed. Obstructive cholangitis was seen in 37 patients (39.8%) and nonobstructive cholangitis in 56 patients (60.2%). Surgery was performed for cholangitis in 7 patients (7.5%) and consisted of revision of the hepaticojejunostomy or elongation of the biliary limb. Postoperative biliary leakage (odds ratio 2.56; 95% confidence interval 1.42-4.62; P = .0018) was independently associated with postoperative cholangitis. CONCLUSION: Postoperative cholangitis unrelated to cancer recurrence was seen in 10% of patients after pancreatoduodenectomy. Nonobstructive cholangitis was more common than obstructive cholangitis. Postoperative biliary leakage was an independent risk factor.

Patient-Reported Outcomes Following Magnetic Resonance-Guided Radiation Therapy for Prostate Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review provides an overview of literature on the impact of magnetic resonance-guided radiation therapy (MRgRT) on patient-reported outcomes (PROs) in patients with prostate cancer (PC). METHODS AND MATERIALS: A systematic search was performed in October 2023 in PubMed, EMBASE, and Cochrane Library. The Patient, Intervention, Comparison, Outcomes, and Study design (PICOS) framework was used to determine eligibility criteria. Included were studies assessing PROs following MRgRT for PC with a sample size >10. Methodological quality was assessed using the Cochrane's Risk of Bias in Nonrandomized Studies - of Interventions and Cochrane's risk of bias tool for randomized trials. Relevant mean differences (MDs) compared with pre-RT were interpreted using minimal important differences. Meta-analyses were performed using random-effects models. Between-study heterogeneity was assessed using the I2 statistic. RESULTS: Eleven observational studies and 1 randomized controlled trial (n = 897) were included. Nine studies included patients with primary PC with MRgRT as first-line treatment (n = 813) and 3 with MRgRT as second-line treatment (n = 84). Substantial risk of bias was found in 5 studies. European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ) core 30 (C30) and EORTC QLQ prostate cancer module (PR25) scores were pooled from 3 studies, and Expanded Prostate Cancer Index Composite (EPIC)-26 scores were pooled from 4 studies. Relevant MDs for the urinary domain were found with the EPIC-26 (MD, -10.0; 95% CI, -12.0 to -8.1; I2 = 0%) and the EORTC QLQ-PR25 (MD, 8.6; 95% CI, -4.7 to 22.0; I2 = 97%), both at end-RT to 1-month follow-up. Relevant MDs for the bowel domain were found with the EPIC-26 (MD, -4.7; 95% CI, -9.2 to -0.2; I2 = 82%) at end-RT or 1-month follow-up, but not with the EORTC QLQ-PR25. For both domains, no relevant MDs were found after 3 months of follow-up. No relevant MDs were found in the general quality of life domains of the EORTC QLQ C30. CONCLUSIONS: MRgRT for PC results in a temporary worsening of patient-reported urinary and bowel symptoms during the first month after treatment compared with pre-RT, resolving at 3 months. No clinically relevant changes were found for general quality of life domains. These results provide important information for patient counseling and can serve as a benchmark for future studies.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Perineural Invasion is an Important Prognostic Factor in Patients With Radically Resected (R0) and Node-negative (pN0) Pancreatic Cancer.

OBJECTIVE: To investigate the association between perineural invasion (PNI) and overall survival (OS) in a nationwide cohort of patients with resected pancreatic ductal adenocarcinoma (PDAC), stratified for margin negative (R0) or positive (R1) resection and absence or presence of lymph node metastasis (pN0 or pN1-N2, respectively). BACKGROUND: Patients with R0 and pN0 resected PDAC have a relatively favorable prognosis. As PNI is associated with worse OS, this might be a useful factor to provide further prognostic information for patients counselling. METHODS: A nationwide observational cohort study was performed including all patients who underwent PDAC resection in the Netherlands (2014-2019) with complete information on relevant pathological features (PNI, R status, and N status). OS was assessed using Kaplan-Meier curves, and Cox-proportional hazard analyses were performed to calculate hazard ratio's (HR) with corresponding 95% confidence intervals (CI). RESULTS: In total, 1630 patients were included with a median follow-up of 43 (interquartile range 33-58) months. PNI was independently associated with worse OS in both R0 patients (HR 1.49 [95%CI 1.18-1.88]; P<0.001) and R1 patients (HR 1.39 [95% CI 1.06-1.83]; P=0.02), as well as in pN0 patients (HR 1.75 [95%CI 1.27-2.41]; P<0.001) and pN1-N2 patients (HR 1.35 [95% CI 1.10-1.67]; P<0.01). In 315 patients with R0N0, multivariable analysis showed that PNI was the strongest predictor of OS (HR 2.24 [95% CI 1.52-3.30]; P<0.001). CONCLUSION: PNI is strongly associated with worse survival in patients with resected PDAC, in particular in patients with relatively favorable pathological features. These findings may aid patient stratification and counselling and help guide treatment strategies.

Evaluation of Short- and Long-Term Outcomes After Resection in Patients with Locally Advanced versus (Borderline) Resectable Pancreatic Cancer.

OBJECTIVE: This study aims to evaluate short- and long-term outcomes following pancreatectomy in patients with LAPC compared to (B)RPC patients. SUMMARY BACKGROUND DATA: Selected patients diagnosed with locally advanced pancreatic cancer (LAPC) are increasingly undergoing resection following induction chemotherapy. To evaluate the benefit of this treatment approach, it is helpful to compare outcomes in resected patients with primary LAPC to outcomes in resected patients with primary (borderline) resectable pancreatic cancer ((B)RPC). METHODS: Two prospectively maintained nationwide databases were used for this study. Patients with (B)RPC undergoing upfront tumor resection and patients with resected LAPC after induction therapy were included. Outcomes were postoperative pancreas-specific complications, 90-day mortality, pathological outcomes, disease-free interval (DFI), and overall survival (OS). RESULTS: Overall, 879 patients were included; 103 with LAPC (12%) and 776 with (B)RPC (88%). LAPC patients had a lower WHO performance score and CACI. Postoperative pancreas-specific complications were comparable between groups, except delayed gastric emptying grade C, which occurred more often in LAPC patients (9% vs. 3%, P=0.03). Ninety-day mortality was comparable. About half of the patients in both groups (54% in LAPC vs. 48% in (B)RPC), P=0.21) had a radical resection (R0). DFI was 13 months in both groups (P=0.12) and OS from date of diagnosis was 24 months in LAPC patients and 19 months in (B)RPC patients (P=0.34). CONCLUSIONS: In our nationwide prospective databases, pancreas-specific complications, mortality and survival in patients with LAPC following pancreatectomy are comparable with those undergoing resection for (B)RPC. These outcomes suggest that postoperative morbidity and mortality after tumor resection in carefully selected patients with LAPC are acceptable.

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.

The Difficulty of Detecting Occult Metastases in Patients with Potentially Resectable Pancreatic Cancer: Development and External Validation of a Preoperative Prediction Model.

Occult metastases are detected in 10-15% of patients during exploratory laparotomy for pancreatic cancer. This study developed and externally validated a model to predict occult metastases in patients with potentially resectable pancreatic cancer. Model development was performed within the Dutch Pancreatic Cancer Audit, including all patients operated for pancreatic cancer (January 2013-December 2017). Multivariable logistic regression analysis based on the Akaike Information Criteria was performed with intraoperative pathologically proven metastases as the outcome. The model was externally validated with a cohort from the University Hospital of Verona (January 2013-December 2017). For model development, 2262 patients were included of whom 235 (10%) had occult metastases, located in the liver (n = 143, 61%), peritoneum (n = 73, 31%), or both (n = 19, 8%). The model included age (OR 1.02, 95% CI 1.00-1.03), BMI (OR 0.96, 95% CI 0.93-0.99), preoperative nutritional support (OR 1.73, 95% CI 1.01-2.74), tumor diameter (OR 1.60, 95% CI 1.04-2.45), tumor composition (solid vs. cystic) (OR 2.33, 95% CI 1.20-4.35), and indeterminate lesions on preoperative imaging (OR 4.01, 95% CI 2.16-7.43). External validation showed poor discrimination with a C-statistic of 0.56. Although some predictor variables were significantly associated with occult metastases, the model performed insufficiently at external validation.

DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms.

BACKGROUND & AIMS: Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms. METHODS: DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin. RESULTS: After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample. CONCLUSIONS: Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting.

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis.

BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.

Dynamics of Serum CA19-9 in Patients Undergoing Pancreatic Cancer Resection.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is an established perioperative prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is unclear how CA19-9 monitoring should be used during postoperative surveillance to detect recurrence and to guide the initiation of recurrence-focused therapy. OBJECTIVE: This study aimed to elucidate the value of CA19-9 as a diagnostic biomarker for disease recurrence in patients who underwent PDAC resection. METHODS: Serum CA19-9 levels at diagnosis, after surgery, and during postoperative follow-up were analyzed in patients who underwent PDAC resection. All patients with at least two postoperative follow-up CA19-9 measurements before recurrence were included. Patients deemed to be nonsecretors of CA19-9 were excluded. The relative increase in postoperative CA19-9 was calculated for each patient by dividing the maximum postoperative CA19-9 value by the first postoperative value. Receiver operating characteristic analysis was performed to identify the optimal threshold for the relative increase in CA19-9 levels to identify recurrence in the training set using Youden's index. The performance of this cutoff was validated in a test set by calculating the area under the curve (AUC) and was compared to the performance of the optimal cutoff for postoperative CA19-9 measurements as a continuous value. In addition, sensitivity, specificity, and predictive values were assessed. RESULTS: In total, 271 patients were included, of whom 208 (77%) developed recurrence. Receiver operating characteristic analysis demonstrated that a relative increase in postoperative serum CA19-9 of 2.6× was predictive of recurrence, with 58% sensitivity, 83% specificity, 95% positive predictive value, and 28% negative predictive value. The AUC for a 2.6× relative increase in the CA19-9 level was 0.719 in the training set and 0.663 in the test set. The AUC of postoperative CA19-9 as a continuous value (optimal threshold, 52) was 0.671 in the training set. In the training set, the detection of a 2.6-fold increase in CA19-9 preceded the detection of recurrence by a mean difference of 7 months ( P <0.001) and in the test set by 10 months ( P <0.001). CONCLUSIONS: A relative increase in the postoperative serum CA19-9 level of 2.6-fold is a stronger predictive marker for recurrence than a continuous CA19-9 cutoff. A relative CA19-9 increase can precede the detection of recurrence on imaging for up to 7 to 10 months. Therefore, CA19-9 dynamics can be used as a biomarker to guide the initiation of recurrence-focused treatment.

Predicting Long-term Disease-free Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Cohort Study.

OBJECTIVE: To develop a prediction model for long-term (≥5 years) disease-free survival (DFS) after the resection of pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Despite high recurrence rates, ~10% of patients have long-term DFS after PDAC resection. A model to predict long-term DFS may aid individualized prognostication and shared decision-making. METHODS: This nationwide cohort study included all consecutive patients who underwent PDAC resection in the Netherlands (2014-2016). The best-performing prognostic model was selected by Cox-proportional hazard analysis and Akaike's Information Criterion, presented by hazard ratios (HRs) with 95% confidence intervals (CIs). Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In all, 836 patients with a median follow-up of 67 months (interquartile range 51-79) were analyzed. Long-term DFS was seen in 118 patients (14%). Factors predictive of long-term DFS were low preoperative carbohydrate antigen 19-9 (logarithmic; HR 1.21; 95% CI 1.10-1.32), no vascular resection (HR 1.33; 95% CI 1.12-1.58), T1 or T2 tumor stage (HR 1.52; 95% CI 1.14-2.04, and HR 1.17; 95% CI 0.98-1.39, respectively), well/moderate tumor differentiation (HR 1.44; 95% CI 1.22-1.68), absence of perineural and lymphovascular invasion (HR 1.42; 95% CI 1.11-1.81 and HR 1.14; 95% CI 0.96-1.36, respectively), N0 or N1 nodal status (HR 1.92; 95% CI 1.54-2.40, and HR 1.33; 95% CI 1.11-1.60, respectively), R0 resection margin status (HR 1.25; 95% CI 1.07-1.46), no major complications (HR 1.14; 95% CI 0.97-1.35) and adjuvant chemotherapy (HR 1.74; 95% CI 1.47-2.06). Moderate performance (concordance index 0.68) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: The developed prediction model, readily available at www.pancreascalculator.com, can be used to estimate the probability of long-term DFS after resection of pancreatic ductal adenocarcinoma.