Background and objectives Treatment of hepatocellular carcinoma (HCC) >5 cm is problematic, as patients are often outside transplantation criteria, and cirrhosis compromises curative resection. The purpose of this study was to evaluate survival following treatment with ablation compared to chemotherapy in large HCC. Methods This was a retrospective cohort study of the National Cancer Database (NCDB) Participant User File from 2004 to 2017. Patients with HCC >5 cm in diameter treated with ablation versus chemotherapy alone were compared. Inverse probability-weighted propensity scores were used to model treatment assignments in the Cox proportional hazards model. Results A total of 14,783 HCC patients with tumors >5 cm and <9 cm were treated with chemotherapy (N=14,127) or ablation (n=656). After adjustment for stage, comorbidity, insurance status, facility type, and race, survival was significantly improved with ablation. The treatment effect of ablation was estimated using inverse-probability-weighted propensity scores, and the survival advantage was 19 months longer (p<0.001; 95% CI: 10.1-28.2) compared to chemotherapy. Conclusions Despite the reluctance to use ablation in lesions >5 cm, our analysis suggests a survival advantage when compared to chemotherapy. These results are promising, and future trials should evaluate ablation in combination with other local and systemic therapies.

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) flank tumor model, we show that serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8+ T cells and natural killer cells, and was abrogated by CD8+ T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1-driven myeloid response consistent with adaptive immune resistance. Although CSF1R inhibition alone was insufficient to improve tumor control, combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1-dependent myeloid resistance program that constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is defined by a profoundly immunosuppressive tumor microenvironment (TME). In the majority of cases, treatment is palliative as there are few effective therapeutic options shown to improve clinical outcomes. We previously demonstrated that a single radiofrequency ablation (RFA) session is safe, induces tumor necrosis, enhances immune cell infiltration, including an abscopal effect, and synergizes with immune checkpoint blockade (ICB) to further suppress tumor growth. Hypothesis: We proposed that repeated RFA sessions would more effectively restrain tumor progression, amplify immune cell recruitment, and enhance responsiveness to immunotherapy. Methods: Using a bilateral tumor-bearing KrasG12D;Trp53R172H/+;Pdx1:Cre syngeneic PDAC model, we compared tumor responses following single versus 3 repeated RFA sessions. Single-cell RNA sequencing and cytokine profiling were used to characterize TME remodeling. Given our prior findings with a single RFA session + ICB, we evaluated repeated RFA in combination with ICB and tested whether adding CSF1R blockade (PLX3397) could counteract RFA-induced myeloid immune suppression. Results: Repeated RFA significantly reduced tumor growth rates and increased tumor necrosis in both treated and contralateral lesions compared to a single RFA session. scRNA-seq and cytokine analysis revealed that repeated RFA elevated Csf1 levels, promoting differentiation of immune suppressive Csf1r+ M2-like macrophages via the Csf1/Csf1r axis. While repeated RFA combined with ICB improved tumor control compared with either therapy alone, the addition of CSF1R inhibition further enhanced efficacy. The triple combination (repeated RFA + ICB + anti-CSF1R) produced the greatest reduction in tumor volume and weight and yielded the most pronounced remodeling of the TME. Conclusions: Repeated RFA intensifies tumor necrosis, suppresses tumor progression, and remodels the PDAC TME, but concurrently induces a compensatory Csf1/Csf1r-driven M2-like macrophage response. Macrophage reprogramming through CSF1R blockade enhances both RFA- and ICB-mediated anti-tumor immunity. These findings support integrating repeated local ablative therapy with myeloid-targeting agents and checkpoint blockade to improve immunologic control of pancreatic cancer. Citation Format: Lincoln Strickland, Wendao Liu, Casey Van Kirk, Shwetapadma Dash, MacKenzie Demmel, Alyssa Waller, Nicolette R. Mardik, Jesse Cox, Curtis J. Wray, Zhongming Zhao, Nirav Thosani, Jennifer Bailey-Lundberg. Repeated RFA remodels the PDAC microenvironment and synergizes with CSF1R blockade and checkpoint inhibition to enhance anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2857.

Conversion to laparotomy during robotic pancreatoduodenectomy (RPD) carries important clinical implications, yet its incidence, predictors, and consequences in elderly and/or obese patients remain poorly characterized. This study aimed to define the conversion rate, identify preoperative predictors, and assess the impact of conversion on postoperative outcomes in elderly and/or obese surgically high-risk patients undergoing attempted RPD. A retrospective analysis was performed using a multi-institutional database. Patients were included if they underwent attempted RPD and met at least one high-risk criterion: age ≥ 80 years and/or BMI ≥ 30 kg/m2. Conversion was defined as any unplanned transition from robotic to open surgery after initiation of the robotic procedure. Reasons for conversion were assigned using a hierarchical, mutually exclusive framework: intraoperative complication, patient instability, vascular involvement, or strategic surgeon decision. Among 311 patients, 36 (11.6

e16413 Background: Standard of care (SOC) chemotherapy with either FOLFIRINOX or gemcitabine/nab-paclitaxel provides an overall response rate (ORR) < 35% in locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In preclinical and clinical publications, we previously reported that radiofrequency ablation (RFA) decreases tumor size and potentiates anti-tumor immunity. Additionally, we reported that the combination of RFA and PD-L1 inhibitor sustained anti-tumor immunity and had a greater efficacy to reduce tumor size in treated and distant tumors than RFA alone. Based on these studies, we hypothesized that trimodal therapy with chemotherapy, RFA, and immunotherapy in patients with unresectable and metastatic PDAC may synergistically improve ORR. Methods: At our center, patients with newly diagnosed locally advanced or metastatic PDAC were treated with SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) and endoscopic ultrasound-guided RFA (EUS-RFA) of the primary pancreatic tumor. Fourteen patients received pembrolizumab via compassionate care use. Patients were given 6 weeks of chemotherapy followed by EUS-RFA every 6 weeks until tumor had complete response. Pembrolizumab was administered after each EUS-RFA session and continued every 6 weeks concurrent with chemotherapy. Primary endpoint was ORR and secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: In our cohort of 14 patients, 6 patients (43%) were locally advanced PDAC (LAPC) and 8 patients (57%) had metastatic disease. Median age was 64.5 (range, 49-83 years) with 10 (71%) females and 4 males. Four patients (29%) had a CDKN2A somatic mutation, and 6 patients had CA 19-9 > 500. One patient with LAPC downstaged to resectable disease and underwent a successful Whipple surgery. Three metastatic patients (21%) had progression of disease with a median PFS of 11.5 months. The ORR (based on ultrasound-guided imaging during EUS-RFA) is 93% (13/14 patients) with median tumor shrinkage of 54% and median CA 19-9 decrease of 41%. Radiographic responses on EUS peaks after the 5th RFA treatment. Six patients (43%) who completed the 5th EUS-RFA had a smaller tumor burden on imaging studies. One patient (16%) had a complete response based on EUS, while 5 (83%) patients had more than 50% shrinkage of tumor size. Conclusions: SOC chemotherapy in combination with EUS-RFA, followed by immunotherapy was highly effective in disease control in locally advanced/metastatic PDAC and potentially prolongs PFS, compared to historical controls who received chemotherapy alone.

Gastric cancer ranks as the fifth leading cause of global cancer incidences, exhibiting varied prevalence influenced by geographical, ethnic, and lifestyle factors, as well as Helicobacter pylori infection. The ATM gene on chromosome 11q22 is vital for genomic stability as an initiator of the DNA damage response, and mutations in this gene have been associated with various cancers. Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown efficacy in cancers with homologous recombination repair deficiencies, notably in those with ATM mutations. Here, we present a case of a 66-year-old patient with germline ATM-mutated metastatic gastric cancer with very high CA 19-9 (48 000 units/mL) who demonstrated an exceptional response to the addition of olaparib to chemo-immunotherapy and subsequent olaparib maintenance monotherapy for 12 months. CA 19-9 was maintained at low level for 18 months. Despite the failure of a phase II clinical trial on olaparib in gastric cancer (NCT01063517) to meet its primary endpoint, intriguing findings emerged in the subset of ATM-mutated patients, who exhibited notable improvements in overall survival. Our case underscores the potential clinical utility of olaparib in germline ATM-mutated gastric cancer and emphasizes the need for further exploration through larger clinical trials. Ongoing research and clinical trials are essential for optimizing the use of PARP inhibitors, identifying biomarkers, and advancing personalized treatment strategies for gastric cancer.

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively.

Gastric cancer ranks as the fifth leading cause of global cancer incidences, exhibiting varied prevalence influenced by geographical, ethnic, and lifestyle factors, as well as Helicobacter pylori infection. The ATM gene on chromosome 11q22 is vital for genomic stability as an initiator of the DNA damage response, and mutations in this gene have been associated with various cancers. Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown efficacy in cancers with homologous recombination repair deficiencies, notably in those with ATM mutations. Here, we present a case of a 66-year-old patient with germline ATM-mutated metastatic gastric cancer with very high CA 19-9 (48 000 units/mL) who demonstrated an exceptional response to the addition of olaparib to chemo-immunotherapy and subsequent olaparib maintenance monotherapy for 12 months. CA 19-9 was maintained at low level for 18 months. Despite the failure of a phase II clinical trial on olaparib in gastric cancer (NCT01063517) to meet its primary endpoint, intriguing findings emerged in the subset of ATM-mutated patients, who exhibited notable improvements in overall survival. Our case underscores the potential clinical utility of olaparib in germline ATM-mutated gastric cancer and emphasizes the need for further exploration through larger clinical trials. Ongoing research and clinical trials are essential for optimizing the use of PARP inhibitors, identifying biomarkers, and advancing personalized treatment strategies for gastric cancer. Keywords olaparib , PARP inhibitor , gastric cancer , germline ATM mutation

Pancreatic cancer serves as the third leading cause of cancer-associated morbidity and mortality in the United States, with a 5-year survival rate of only 12% with an expected increase in incidence and mortality in the coming years. Pancreatic ductal adenocarcinomas constitute most pancreatic malignancies. Certain genetic syndromes, including Lynch syndrome, hereditary breast and ovarian cancer syndrome, hereditary pancreatitis, familial adenomatous polyposis, Peutz–Jeghers syndrome, familial pancreatic cancer mutation, and ataxia telangiectasia, confer a significantly higher risk. Screening for pancreatic malignancies currently targets patients with germline mutations or those with significant family history. Screening the general population is not currently viable owing to overall low incidence and lack of specific tests. Endoscopic ultrasound (EUS) and its applied advances are increasingly being used for surveillance, diagnosis, and management of pancreatic malignancies and have now become an indispensable tool in their management. For patients with risk factors, EUS in combination with magnetic resonance imaging/magnetic resonance cholangiopancreatography is used for screening. The role of endoscopic modalities has been expanding with the increased utilization of endoscopic retrograde cholangiopancreatography, EUS-directed therapies include EUS-guided fine-needle aspiration and EUS-fine-needle biopsy (FNB). EUS combined with FNB has the highest specificity and sensitivity for detecting pancreatic cancer amongst available modalities. Studies also recognize that artificial intelligence assisted EUS in the early detection of pancreatic cancer. At the same time, surgical resection has been historically considered the only curative treatment for pancreatic cancer, over 80% of patients present with unresectable disease. We also discuss EUS-guided therapies of physicochemicals (radiofrequency ablation, brachytherapy, and intratumor chemotherapy), biological agents (gene therapies and oncolytic viruses), and immunotherapy. We aim to perform a detailed review of the current burden, risk factors, role of screening, diagnosis, and endoscopic advances in the treatment modalities available for pancreatic cancer.

BACKGROUND AND AIMS:Emerging data suggest neoadjuvant chemotherapy (NAC) for resectable pancreatic ductal adenocarcinoma (PDAC) is associated with improved survival. However, less than 40% of patients demonstrate a meaningful radiographic response to NAC. EUS-guided radiofrequency ablation (EUS-RFA) has emerged as a new modality to treat PDAC. We hypothesize that NAC plus EUS-RFA can be used in the management of resectable PDAC. METHODS:This was a prospective review of PDAC patients meeting the criteria of resectable tumor anatomy who underwent NAC chemotherapy plus EUS-RFA followed by pancreatic resection. Radiographic imaging and perioperative and short-term outcomes were recorded. Surgical pathology specimens were analyzed for treatment response. RESULTS:Three eligible patients with resectable PDAC received 4 months of NAC plus EUS-RFA. One month after completing NAC and EUS-RFA, all 3 patients underwent standard pancreaticoduodenectomy without adverse events. After a 6-week recovery, all patients completed 2 months of postoperative adjuvant chemotherapy. CONCLUSIONS:In our institutional experience, this treatment protocol appears to be safe as patients tolerated the combination of chemotherapy and ablation. Patients underwent pancreatic resection with uneventful recovery. This novel neoadjuvant approach may provide a more effective alternative to chemotherapy alone.

This clinical practice guideline from the American Society for Gastrointestinal Endoscopy provides an evidence-based approach for the diagnosis of malignancy in patients with biliary strictures of undetermined etiology. This document was developed using the Grading of Recommendations Assessment, Development and Evaluation framework and addresses the role of fluoroscopic-guided biopsy sampling, brush cytology, cholangioscopy, and EUS in the diagnosis of malignancy in patients with biliary strictures. In the endoscopic workup of these patients, we suggest the use of fluoroscopic-guided biopsy sampling in addition to brush cytology over brush cytology alone, especially for hilar strictures. We suggest the use of cholangioscopic and EUS-guided biopsy sampling especially for patients who undergo nondiagnostic sampling, cholangioscopic biopsy sampling for nondistal strictures and EUS-guided biopsy sampling distal strictures or those with suspected spread to surrounding lymph nodes and other structures.