Starr, Jason

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

Abstract Background: [212Pb]VMT-a-NET is a novel, next generation alpha therapy agent for advanced somatostatin receptor 2 positive (SSTR2+) neuroendocrine tumors (NETs). Here, we present safety and efficacy update from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: Adults with well-differentiated unresectable or metastatic NETs, who were peptide receptor radionuclide therapy-naïve, showed progressive disease after at least one prior line of systemic therapy and demonstrated SSTR2-expression on PET images were treated with up to four cycles of study therapy at the assigned dose level. Participants were followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy was evaluated by investigators according to RECIST criteria v1.1. Results: As of 10-Dec-2025 (data cut-off [DCO]) a total of 56 participants were enrolled into Cohorts 1, 2 and 3, and received at least 1 dose of [212Pb]VMT-a-NET (n=2 in Cohort 1, n=46 in Cohort 2, and n=8 in Cohort 3 at a dose level of 2.5 mCi, 5 mCi, and 6 mCi, respectively). For data analysis purposes, participants were categorized into two different groups: a safety group and an efficacy group. The safety group included all participants treated by the DCO (n=56), while the efficacy group included only the Cohort 1 participants (n=2) and the first half of participants treated in Cohort 2 (n=23). Among all participants treated with at least 1 dose of [212Pb]VMT-a-NET (n=56), no DLTs, no grade 5 adverse events (AEs), no treatment-related discontinuations, no serious renal complications, no dysphagia and no clinically significant treatment-related myelosuppression were observed. Median follow-up time for all patients treated was 40 weeks (range: 6-97). Among the 25 participants followed for efficacy (n=2 in Cohort 1 and n=23 in Cohort 2), 19 out of 25 were with no progression as of the DCO. Median follow-up time for participants included in the efficacy group was 49 weeks (range: 6-97). Investigator-assessed RECIST v1.1 objective responses were observed in 9 out of 23 participants (39%) enrolled in the first half of Cohort 2 (8 confirmed). The 2 patients enrolled in Cohort 1 at 2.5 mCi still have stable disease after 2 years of follow up. Updated safety outcomes for all participants along with updated efficacy findings for participants in Cohorts 1 and 2 with sufficient maturity will be presented during the congress. Conclusions: Treatment with [212Pb]VMT-α-NET continues to be well-tolerated among all patients treated (n=56), and to show promising efficacy at the dose levels of 2.5 mCi and 5 mCi. The study is ongoing with Cohort 3 (6 mCi) currently open for enrollment. Citation Format: Thorvardur R. Halfdanarson, Richard L. Wahl, Vineeth Sukrithan, Brandon R. Mancini, Seyed A. Mosallaie, Savitha Balaraman, Gregory S. Sibley, Jason Starr, Lowell B. Anthony, Chih Y. Liao, Samuel H. Mehr, Jared Weiss, Robert A. Ramirez, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen M. Keefe, Markus Puhlmann, Vikas Prasad. [212Pb]VMT-a-NET in advanced SSTR2+ neuroendocrine tumors: safety and preliminary efficacy results from dose-finding cohorts 1,2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT088.

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm3 serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery.

Primary central nervous system (PCNSL) lymphoma is an aggressive extranodal non-Hodgkin lymphoma, and most cases are classified as diffuse large B-cell lymphoma (DLBCL) by histology. T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) represents a distinct subtype of diffuse large B-cell lymphoma and is characterized by the presence of scattered large neoplastic B-cells in a background of abundant T-cells and histiocytes. This is in contrast to the dense perivascular cuffing of neoplastic B-cells in classic DLBCL. T-cell/histiocyte-rich large B-cell lymphoma should be considered in PCNSL cases in which neoplastic B-cells are sparse and scattered. Immunohistochemistry will help identify the B-cells and surrounding infiltrate rich in Tlymphocytes and histiocytes. Future studies exploring the biology of TCRLBCL and the crosstalk between the neoplastic cells and the surrounding inflammatory infiltrate may provide exciting prospects for future therapies for TCRLBCL.