BACKGROUND:The World Health Organization (WHO) classification for pancreaticobiliary cytopathology stratifies risk of malignancy (ROM) and outcome for pancreatic fine-needle aspirations (FNAs). ROM for biliary cytology, particularly for WHO categories Pan-low (IV) and Pan-high (V), has not been well examined. METHODS:Retrospective data of biliary cytology diagnosed from 2016 to 2019 were collected. WHO classification was assigned. Malignant outcome was determined by histologic correlation or clinical progression/death. Excluding clinical follow-up <3 months (if no histology), the ROM, odds ratio, performance characteristics, and overall survival were calculated. RESULTS:A total of 1056 biliary cytology cases (from 789 patients) were included. Sample types were: 757 (72%) biliary brush/wash, 115 (11%) FNA, and 184 (17%) other. Same-site histologic correlation was 292 (28%) and histology of metastasis in 124 (12%). The median follow-up (for benign) was 1431 days. Malignant outcome occurred in 704 (n = 789, 89%) of patients. Absolute ROM (%) for WHO I to VII by biliary brush/wash and FNA were: 92, 72, 87, 0, 100, 94, 100, and 50, 46, 73, N/A, 100, 80, 100, respectively. A high-tier (V-VII) category had significantly higher odds of malignancy regardless of biopsy modality, presence of stent, or autoimmune cholangitis. CONCLUSION:Absolute ROM for biliary lesions is high for WHO I through III and is at least partly because of difficulty in sampling cancers, particularly those extrinsically obstructing the bile duct. The rarity of low-grade biliary lesions impedes AROM assessment for Pan-low (WHO IV). The clinical value of biliary Pan-high (WHO V) remains uncertain because of rarity of high-grade noninvasive lesions and difficulty in cytology diagnosis.

PURPOSE The choice of adjuvant chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is mainly guided by patients' general condition. We hypothesized that tumor morphology may predict differential treatment benefit and tested whether deep learning applied to histology images could derive a biomarker of relative benefit from gemcitabine (GEM) versus modified FOLFIRINOX (mFOLFIRINOX) in resected PDAC. PATIENTS AND METHODS Standard whole-slide images from a retrospective multicentric series of 231 patients who underwent curative-intent pancreatectomy and received adjuvant mFOLFIRINOX (n = 54) or GEM (n = 177) were used to train regimen-specific histology models on disease-free survival (DFS), which were then combined into PANCprAId, a biomarker estimating personalized relative benefit from adjuvant GEM versus mFOLFIRINOX. External validation was performed in the randomized PRODIGE-24/CCTG PA6 trial (n = 313). RESULTS In PRODIGE-24/CCTG PA6, the treatment-specific histology scores used to construct PANCprAId stratified outcomes among patients treated with GEM (hazard ratio [HR], 1.69 [95% CI, 1.04 to 2.73]; P = .03) and mFOLFIRINOX (HR, 2.02 [95% CI, 1.4 to 3.0]; P < .001). When combined into PANCprAId, the biomarker identified subgroups with differential relative benefit from adjuvant GEM versus mFOLFIRINOX, with significant treatment interactions for DFS (interaction P = .003) and cancer-specific survival (interaction P = .001). Predicted sensitivity to each regimen was associated with distinct epithelial and stromal features. CONCLUSION Histology-based deep learning can derive a predictive biomarker of relative benefit from adjuvant GEM versus mFOLFIRINOX in resected PDAC.

BACKGROUND:Data on antibody-drug conjugates (ADCs) target expression prevalence, intertumoral heterogeneity, genomic concordance, and its effect on clinical outcomes is limited in biliary tract cancers (BTC). METHODS:Resected primary BTC specimens, and when available, matched metastatic samples were assembled into tissue microarrays and tested for CLDN18.2, c-MET, Nectin-4, TROP2, and HER2 expression by immunohistochemistry (IHC). A subset underwent targeted next-generation sequencing using MSK-IMPACT (NCT01775072). Exploratory associations of target expression with clinicopathologic parameters, genomic alterations, recurrence-free (RFS), and overall (OS) survival were evaluated. RESULTS:65 patients with resected BTC and 18 paired metastatic sites were identified-43% extrahepatic cholangiocarcinoma, 40% intrahepatic cholangiocarcinoma, and 17% gallbladder cancer. All evaluated target antigens were expressed; percent positivity and H-score ≥200 were: TROP2 (83%, 26%), c-MET (75%, 26%), Nectin-4 (66%, 35%), and CLDN18.2 (46%, 7.7%). HER2 overexpression occurred in 3.1% of tumors. Overall agreement among paired primary and metastatic samples on calling either positive or negative ranged from 43% to 75% with the highest observed for HER2 [75%; κ=0.29 (95%CI: -0.32 to 0.91)] and TROP2 (71%; κ not available) and lowest for c-MET, CLDN18.2, and Nectin-4. Frequently altered genes included TP53 (36%), SMAD4 (27%), ELF3 (21%). We observed no significant association between target antigen expression with genomics, RFS, or OS. CONCLUSIONS:BTC displays frequent but heterogeneous expression of multiple ADC targets. These hypothesis generating findings suggest inherent complexity of target protein quantification, target threshold determination, and target sampling discordance. Future studies will be required to refine our understanding the utlitiy of ADCs in BTC.

Background Real-time methods are needed for intraprocedural detection of residual tumors and incomplete thermal ablation (TA) to allow immediate retreatment and tumor eradication. Purpose To validate a TA workflow for detecting and immediately ablating residual viable colorectal liver metastases (CLMs). Materials and Methods This prospective single-center trial enrolled participants who underwent PET/CT-guided microwave CLM ablation from November 2019 to February 2023. The minimal ablation margin (MM) was calculated in all directions. Biopsies were obtained from the ablation zone (AZ) center and margin, with rapid tissue assessment for viable tumor (VT) cells using imprint cytology and fluorescent viability staining. Immediate reablation was performed if any of the following criteria were met: MM less than 5 mm at contrast-enhanced CT, residual PET-avid tumor, and/or VT cells at rapid tissue assessment. Gray-model statistics quantified the MM and VT impact on local tumor progression subdistribution hazard amid the competing risk of death. Results Seventy-seven participants (median age, 56 years [IQR, 47-64.5 years]; 39 male participants) underwent ablation in 104 CLMs. Overall, 15 of 104 (14%) CLMs underwent immediate reablation per the criteria (12 of 15, VT; seven of 15, MM <5 mm; and four of 15, residual fluorodeoxyglucose avidity). After reablation, all 12 initially VT-positive AZs underwent repeat biopsies with negative findings. Five of seven MMs less than 5 mm in AZs increased to greater than 5 mm after reablation. All four CLMs that underwent reablation due to PET/CT findings had AZs positive for VT, and one had MM less than 5 mm. MM greater than 5 mm protected against local tumor progression (LTP) (subdistribution hazard ratio, 0.12; 95% CI: 0.05, 0.30; P < .001). There was no LTP for MMs greater than 10 mm. The cumulative LTP incidence at 1, 2, and 3 years for participants with biopsy-proven completely ablated CLMs with MM greater than 5 mm was 7%, 12%, and 12%, respectively. Conclusion MM remained a critical technical factor affecting tumor control; the proposed multimodal comprehensive AZ assessment enabled immediate onsite reablation of 14% of CLMs with initially insufficient ablation treatment and improved local tumor control after thermal ablation. ClinicalTrials.gov identifier: NCT04143516 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

BACKGROUND & AIMS:Systemic therapy is the standard of care for unresectable intrahepatic cholangiocarcinoma (iCCA), but overall survival (OS) remains poor. Hepatic artery infusion pump (HAIP) chemotherapy with floxuridine (FUDR) has shown prolonged survival but is limited to expert centers. We assessed long-term OS among patients with unresectable, liver-confined iCCA treated with HAIP chemotherapy. METHODS:Individual patient data from four phase II trials were pooled, including 142 patients with unresectable, liver-confined iCCA, with or without resectable regional lymph node metastases. Patients received HAIP chemotherapy with FUDR, with or without systemic therapy. The primary outcome was OS. Cox models examined associations between preselected covariates and OS. RESULTS:Multifocal disease was found in 92 patients (65%) and 58 (41%) had tumors larger than 10 cm. Twenty-five patients (18%) received prior systemic treatment. Partial response on imaging was achieved in 73/139 patients (53%), with a disease control rate of 96%. Thirteen patients (9%) underwent resection; 4 achieved complete pathological response. The pooled median OS was 26 months (95% CI: 22-30), 3-year OS rate was 28% (95% CI: 22%-37%), and 5-year OS rate was 15% (95% CI: 10%-23%). OS was similar across trials (p=0.95). The intention to treat 3-year and 5-year OS rates were 26% and 14%, respectively, which included 12 patients (7.8%) who did not undergo HAIP chemotherapy due to peritoneal disease. Hepatic disease progression was independently associated with worse OS (HR: 4.46, 95% CI: 2.69-7.40; p<0.001). CONCLUSIONS:Patients with unresectable, liver-confined iCCA who underwent HAIP with systemic chemotherapy had a 3-year OS rate of 28% and 5-year OS rate of 15% across four phase II trials. These results provide long-term benchmark results for a selected patient population. IMPACT AND IMPLICATIONS:Unresectable, locally advanced intrahepatic cholangiocarcinoma remains a disease with poor long-term survival, and evidence supporting liver-directed strategies is limited to small, heterogeneous single-arm studies. By pooling individual patient data from all prospective phase II trials of hepatic artery infusion pump chemotherapy with extended follow-up, this study provides the most comprehensive and mature long-term survival benchmarks. These findings inform multidisciplinary decision-making at specialized centers and support further prospective evaluation of hepatic artery infusion pump chemotherapy within modern multimodality treatment strategies.

BACKGROUND:The influence of obesity and sex on outcomes in pancreatic adenocarcinoma (PDAC) remains unclear. The association between obesity (body mass index [BMI], ≥30) and biologic sex (male or female) for outcomes in patients with PDAC undergoing a surgery-first approach was investigated. METHODS:A prospectively maintained pancreatic cancer database at the Memorial Sloan Kettering Cancer Center was queried to identify all patients undergoing surgery with a pathologic diagnosis of PDAC. Clinicodemographic variables, outcomes, and tumor mutational analyses for all available patients were collected. Cumulative incidence of first recurrence involving the liver was estimated via a cumulative incidence function. Multivariable Cox regression was used to investigate the association between BMI and sex for overall survival. RESULTS:From 2012 to 2022, 939 patients were identified who underwent surgery with a final pathologic diagnosis of PDAC. Median age was 70 years, 52% were male, and 24% were obese (BMI, ≥30). When dichotomized by sex and obesity status (BMI, <30 or ≥30), females with obesity had the lowest cumulative incidence of liver recurrence at 12 and 24 months postsurgery compared to all other groups (13% [95% CI, 7.2%-20%] and 15% [8.7%-23%], respectively). Females with obesity had the longest median overall survival at 37 months. CONCLUSIONS:After curative surgery for pancreatic cancer, females with obesity have a significantly lower rate of liver recurrence and the longest median overall survival. This does not appear to be related to surgical quality, receipt of adjuvant therapy, or tumor mutational profile. Investigation into host immune, metabolic, and hormonal parameters is paramount to understanding these differences.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) often presents with poorly defined lesions and low imaging contrast, which impedes accurate assessment of therapeutic response. Current non-invasive clinical markers are limited to RECIST and blood-based biomarkers CA19-9 and CEA, which are widely regarded to be insufficient descriptors of PDAC response to therapy. We propose a contrast-independent and modality-independent biomechanical image registration workflow for characterizing therapeutic response by leveraging the Eshelby inclusion problem to estimate the transformation strain of the tumor from whole pancreas segmentations across the treatment interval. Methods: An Eshelby inclusion model was constructed to parameterize pancreatic mass effect that arises due to transformation strain of the tumor. This model was integrated into a biomechanical image registration framework to simultaneously resolve changes in tumor and parenchymal shape between baseline and restaging imaging. In 25 patients with measured pathologic response to a standardized neoadjuvant chemotherapy regimen, Eshelby transformation strain was compared to RECIST v1.1 score and changes in serum CA19-9 and CEA as indicators for therapeutic response. Correlations between each variable and pathologic response were assessed using Spearman's., and prognostic value towards stratifying pathologic response was evaluated via Wilcoxon rank sum tests at a significance level of alpha=0.05. Results: Tumor transformation strain was significantly associated with pathologic response (rho=0.55, p=0.008), whereas the change in CA19-9 (rho=0.29, p=0.19), RECIST score (rho=0.09, p=0.71), and change in CEA (rho=0.07, p=0.75) did not exhibit significant correlation. Current clinical markers for therapeutic response were not able to stratify pathologic response based on above- versus below-median values of each marker (RECIST: p=0.49;.Delta A19-9: p=0.24;Delta CEA: p=0.54), whereas the Eshelby transformation strain effectively distinguished patients who achieved more favorable pathologic response (p=0.009). Conclusions: The Eshelby biomechanical model of tumor transformation strain offers a modality- and intensity-independent mechanism for characterizing therapeutic response that surpasses current clinical markers for PDAC.

Various mutations in hepatocellular carcinoma (HCC) carry prognostic implications. The objective of this study is to assess CT and MRI imaging features associated with Catenin Beta-1 (CTNNB1) mutation in HCC. This retrospective, IRB- approved multi-reader, single-center study included treatment-naive, pathologic-proven HCC that underwent contrast-enhanced CT, MRI or both, with subsequent targeted tumor sequencing test. Preoperative CT and MRI were reviewed for the Liver Imaging Reporting and Data System (LI-RADS, LR) features and prognostic imaging features. Fisher’s exact test and multiple testing adjustment were used to assess the association of imaging features and CTNNB1 mutation status. Of the 160 HCCs included (median age 69 [IQR: 62, 75], 125 men), 58 (36

The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib in 63 participants with metastatic pancreatic cancer with disease control on platinum-based chemotherapy. Participants were prospectively stratified into three cohorts by type of HRD: Cohort A (homologous recombination deficient [HRD] by BRCA1/2 or PALB2 mutations, N=33), Cohort B (non-core HRD mutations, N=15), and Cohort C (platinum-sensitive without HRD mutations, N=15). Cohort A used a two-stage design with co-primary endpoints of objective response rate (ORR) ≥43% and 6-month progression-free survival ≥77% per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For Cohort A, ORR was 35% (95% CI: 15-59) and 6-month-PFS rate was 64% (95% CI: 49-82), not meeting the primary endpoint. Among surviving participants (N=17), the median follow-up was 26.0 months (range: 1.4-52.5), and the 2-year overall survival rate was 56% (95% CI: 41-76). Median PFS for Cohort A was 8.3 months (95% CI: 5.3-not reached), 4.8 months (95% CI: 4-12) for Cohort B, and 3.3 months (95% CI: 1.9-4.8) for Cohort C. Pre-planned translational profiling demonstrated that molecular response by circulating cell-free DNA (cfDNA), high tumor-infiltrating lymphocyte (TIL) density, and increased abundance of frameshift indels and neoantigens were associated with durable benefit, particularly in HRD tumors. These findings support a precision immunotherapy approach for biomarker-defined subsets of pancreatic cancer. ClinicalTrials.gov identifier: NCT04666740.

Pancreatic cancer is a uniformly deadly disease. Prediction of response to neoadjuvant therapy is critical in determining which patients should undergo invasive surgery. Non-invasive biomarkers of response would address gaps in the management of patients. This study employs pre-trained convolutional neural networks (CNNs) to predict response from baseline computed tomography (CT) scans alone, prior to neoadjuvant therapy. ResNet50, InceptionV3, VGG16, and Xception were trained on a dataset of annotated CT scans of patients with pancreatic ductal adenocarcinoma (PDAC). Our results demonstrate that the ResNet50 model achieves the highest performance among the models predicting response, with an average (average +/- margin of error at 95% confidence level) accuracy of 0.679 +/- 0.057, an F1-score of 0.665 +/- 0.072, recall of 0.717 +/- 0.081, precision of 0.698 +/- 0.074, and an area under the receiver operating characteristic curve (AUC-ROC) of 0.781 +/- 0.162 across 5-fold cross-validation. These findings highlight the potential for non-invasive imaging biomarkers in predicting response to neoadjuvant therapy in PDAC.

BACKGROUND:The benefit of adjuvant chemotherapy (AC) for ampullary adenocarcinoma is unclear. The Hidden Genome model classifies prognostic subtypes with greater accuracy than standard histologic classification (intestinal [INT] vs pancreatobiliary [PB]), but its predictive capacity to guide the use of AC remains unstudied. METHODS:We applied the Hidden Genome model to an international cohort of 183 patients with resected ampullary adenocarcinoma who underwent genomic sequencing. The model quantified the predicted cell of origin (colorectal vs pancreas/distal bile duct) in all specimens. Overall survival (OS) was compared using Kaplan-Meier estimates, stratified by AC use versus surgery alone (SA). RESULTS:Most patients (n=128; 69.9%) received AC, which was not associated with a significant improvement in OS (median, 50.9 months [95% CI, 36.5-76.9] vs 53.8 months [95% CI, 32.4-119.0]; P=.816). Histologic subtype was neither associated with prognosis (P=.241) nor predictive of chemotherapy efficacy for INT-subtype (P=.379) or PB-subtype (P=.544) tumors. When stratified by genomic subtype, the colorectal group had a favorable prognosis regardless of AC use (median OS, 74.4 months [95% CI, 33.8-97.8] for AC vs 98.7 months [95% CI, 32.4-140.9] for SA; P=.889). Among patients with pancreas/distal bile duct tumors, those who received AC had longer survival compared with those who underwent SA (78.2 months [9.8-not reached] vs 22.7 months [2.3-not reached], respectively; hazard ratio, 0.17 [95% CI, 0.04-0.80]; P=.024). CONCLUSIONS:AC regimens were not associated with improved survival in histologically defined INT- or PB-subtype ampullary adenocarcinoma. However, genomic classification better stratified risk groups and identified patients more likely to benefit from AC.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare. This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts. Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95

OBJECTIVE:This study analyzed outcomes and clinical differences between patients who completed or failed TSH (cTSH or fTSH), and evaluated predictive factors for cTSH. BACKGROUND:Two-stage hepatectomy (TSH) is a well-recognized treatment for extensive colorectal liver metastases (CRLM). METHODS:A retrospective review of a prospective database identified patients who underwent TSH for extensive CRLM not amenable to a single resection. Patients who submitted to hepatectomy for recurrent CRLM and/or were treated with ablative techniques only, were excluded. RESULTS:Out of 183 (7%) CRLM patients who underwent an initial hepatectomy for TSH, 127 (69%) completed the treatment (cTSH). Median overall survival (OS) after the first hepatectomy was 45 months for the entire cohort, 20.6 months for fTSH, and 65.3 months for cTSH patients. fTSH was due to disease progression. The vast majority of cTSH patients received systemic chemotherapy between stages, including hepatic arterial infusion chemotherapy (HAIC). Compared with cTSH, fTSH patients had more frequent extrahepatic disease (EHD), larger CRLM, more frequent metachronous metastases, and lower pathologic response at first resection. CRLM >5 cm, EHD prior or at the time of the first hepatectomy, and a tumor response ≥70% to neoadjuvant chemotherapy were independently associated with a cTSH. CONCLUSION:TSH with perioperative systemic chemotherapy and HAIC in patients with extensive CRLM is associated with excellent oncologic outcomes in patients who complete the resection. EHD, larger tumor size, and lower pathologic response rate were associated with fTSH.

11122 Background: The long-term health related quality of life (QoL) after curative intent hepatectomy for high-risk colorectal liver metastases (CRLM) is not well described. Methods: This prospective single-center study enrolled patients with resectable CRLM with Clinical Risk Score ≥3. European Organization for Research and Treatment of Cancer QLQ-C30, LMC21, and EuroQol EQ-5D-5L were administered at preoperative and postoperative visits, and at 6, 12, 18, 24, and 36 months from hepatectomy. Patient characteristics at baseline along with colorectal cancer disease state were collected at each timepoint on a scale from no evidence of disease (NED) to progressive disease on best supportive care. Linear mixed models were used to examine the trajectory of QoL scores with disease state modeled as a time-varying variable. Results: From 297 consented, 146 were evaluable by completing preoperative and postoperative surveys. Median age was 52 years (IQR: 45, 63), 42% (n=61) were female, 84% (n=122) were Non-Hispanic White, 70% (n=102) had synchronous CRLM, and 80% (n=117) received hepatic artery infusion chemotherapy (HAIC). Overall, QLQ-C30 demonstrated decrease in global health from baseline at post-operative survey (p<0.05) with subsequent improvements until returning to pre-operative levels at 12 months. Similarly, self-assessed health state on EQ-VAS─ a visual analog scale from 0 to 100 that corresponds to worst and best health possible, respectively─ decreased post-operatively (p<0.05) with recovery to baseline by 6 months. Among NED patients, QLQ-C30 QoL scores recovered to pre-operative levels 6 months after hepatectomy, whereas those with recurrent cancer reported scores below baseline at every follow-up assessment (all p<0.05). On EQ-VAS, NED patients were comparable to baseline at 6 months and reported higher scores than baseline at 24 months (p=0.029). Patients with recurrence had similar EQ-VAS scores as baseline at 12 months but remained lower than NED patients at each timepoint (all p<0.05). HAIC did not impact QoL assessed by QLQ-C30 (p=0.725) or EQ-VAS (p=0.559) during follow-up. Conclusions: Health related QoL suffers in the immediate post-operative period before returning to pre-operative levels and exceeding it among patients without recurrence. While cancer recurrence significantly influenced patient experience, HAIC did not sway QoL. Comparison of self-assessed EQ-VAS scores stratified by cancer recurrence status, where 0 and 100 correspond to worst and best health possible, respectively. Time Point No Recurrence, QoL Estimate Cancer Recurrence, QoL Estimate P-value Pre-op 75.28 Post-op 66.45 6m 75.37 68.10 <0.05 12m 80.78 70.15 <0.05 18m 80.28 70.48 <0.05 24m 83.38 74.21 <0.05 36m 78.32 57.44 <0.05

OBJECTIVE:To investigate the clinicopathologic features and long-term outcomes of cystic and solid pancreatic neuroendocrine tumors (PanNETs). BACKGROUND:PanNETs uncommonly present as cystic lesions. Whether cystic PanNETs represent a distinct clinical entity compared with solid PanNETs is controversial. METHODS:Clinicopathologic data of patients with resected PanNETs were collected from 4 high-volume centers between 2000 and 2019. Clinicopathologic characteristics and outcomes of patients with cystic and solid PanNETs were compared based on a 3 cm tumor size cutoff using the χ 2 test and Mann-Whitney U test. Survival estimates were calculated with the Kaplan-Meier method and log-rank test and multivariable analysis using a Cox proportional hazard model. RESULTS:Of the 1727 patients undergoing pancreatectomy for PanNET, the median age was 58.1 years (IQR: 18.4), and 53.3% were males. Of these, 177 (10.3%) were cystic, and 1550 (89.7%) were solid. Cystic PanNETs were more prevalent in patients with hereditary syndromes, less frequently functional, and more often located in the body/tail of the pancreas. After the exclusion of patients with functional tumors, World Health Organization G3 tumors, hereditary syndromes, neoadjuvant treatment, and metastatic stage, 145 cystic PanNETs were compared with 1059 solid PanNETs, and the median follow-up period of the cohort was 64 months. Cystic PanNETs demonstrated significantly fewer high-risk histopathologic features, lymph node (LN) metastases (5.5% vs 24.0%, P < 0.001), and distant recurrence (4.1% vs 14.4%; P < 0.001). Among tumors, ≤3 cm, cystic PanNETs had a low rate of LN metastases (3.9% vs 17.8%; P < 0.001), recurrence (3.1% vs 8.4%; P = 0.041), and low propensity to recur distantly. Cystic PanNETs had favorable long-term survival regardless of tumor size. CONCLUSIONS:Cystic PanNETs have a more benign course than their solid counterparts, and conservative management can be considered for endoscopic ultrasound-guided fine needle aspiration-proven cystic PanNETs ≤3 cm. Parenchyma and LN-sparing resections are warranted in patients with cystic PanNETs >3 cm. Patients with poor baseline performance status may forego cystic PanNET resection and not affect their overall survival.

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.