2026-08-16 | [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial.
In the phase 3 NETTER-2 study, first-line [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) significantly improved progression-free survival in patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Median progression-free survival was 22·8 months (95% CI 19·4-not estimable [NE]) with 177Lu-DOTATATE vs 8·5 months (7·7-13·8) in the control arm. Here, we report subgroup analyses, including preplanned assessments of efficacy by NET grade (G) and site of origin; further post-hoc analyses are reported in the main text. In this open-label, parallel-group study, patients from nine countries were randomised 2:1 to receive four cycles of 177Lu-DOTATATE plus octreotide long-acting repeatable (LAR) 30 mg every 8 weeks then octreotide LAR 30 mg every 4 weeks, or high-dose octreotide LAR 60 mg every 4 weeks. The primary endpoint (progression-free survival) was previously reported. Tumours were assessed at baseline, week 16, week 24, then every 12 weeks until disease progression or death. Preplanned subgroup analyses used blinded independent centrally reviewed data. The study is registered with ClinicalTrials.gov, NCT03972488, and is completed. Between Jan 22, 2020, and Oct 13, 2022, 261 patients were screened; 35 were excluded due to screen failure, and 226 were randomised. 177Lu-DOTATATE (n = 151) reduced risk of disease progression/death vs control (n = 75) regardless of NET grade/origin (hazard ratio [95% CI]: G2 NET 0·31 [0·18-0·53]; G3 NET 0·27 [0·14-0·49]; pancreatic NET 0·34 [0·20-0·56]; gastrointestinal NET 0·23 [0·12-0·46]). Median progression-free survival in months (95% CI) with 177Lu-DOTATATE was: G2 NET 29·0 (21·8-NE); G3 NET 22·2 (13·9-27·8); pancreatic NET 19·4 (16·6-24·9); gastrointestinal NET NE (22·6-NE). 177Lu-DOTATATE improved objective response rate vs control regardless of NET grade/origin. These findings support the use of first-line 177Lu-DOTATATE for patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option, regardless of NET grade (2/3) or origin (pancreas/gastrointestinal). Advanced Accelerator Applications, a Novartis Company.
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2026-08-11 | Clinical outcomes of medical therapy, EUS-guided ethanol ablation, and surgical resection in insulinoma: a clinical epidemiology study.
Insulinoma is a rare pancreatic neuroendocrine tumor causing hypoglycemia. Surgery is the standard treatment, while endoscopic ultrasound (EUS)-guided ethanol ablation and medical therapy are alternatives in some patients. In this retrospective study, we recruited 19 patients with insulinoma treated between 2011 and 2025 at National Taiwan University Hospital. The final treatment strategies were surgery (n = 13), EUS-guided ethanol ablation (n = 3), and medical therapy (n = 3). The study outcomes included post-procedure stays (PPS), treatment-related complications, and follow-up results. New-onset diabetes and complete remission rates for insulinoma were examined and compared across treatment modalities. A Firth's bias-reduced logistic regression analysis was performed to identify predictors of complete remission in 19 patients with insulinoma. Patients could receive more than one treatment. Among the three final treatment modalities, surgical resection achieved the highest complete remission rate (13/13; 100%) but was associated with a longer PPS (mean ± standard deviation [SD] = 13.46 ± 7.59 days) and a higher incidence of new-onset diabetes (2/13, 15.38%). EUS-guided ethanol ablation demonstrated moderate efficacy (2/3; 66.67%) with a comparable PPS (18.33 ± 27.43 days). Lastly, medical therapy relieved symptoms but yielded no complete remissions in insulinoma (0/3; 0%). Paradoxical hypoglycemia occurred in 2 of 8 patients (25.0%) during octreotide testing or after direct octreotide treatment. One patient with insulin autoimmune syndrome improved after drug withdrawal and multimodal therapy. Logistic regression analysis identified a positive linear effect of baseline glucose levels (mg/dL) on insulinoma complete remission (estimated adjusted odds ratio [aOR] = 1.2140, p = 0.0461) and ever surgery (yes vs. no) as the most effective treatment for complete remission in insulinoma (aOR = 296.0707, p = 0.0015). Although surgery was the most effective treatment, it was associated with longer recovery times and potential metabolic risks. EUS-guided ethanol ablation provided a less invasive alternative with a moderate success rate, whereas medical therapy primarily offered symptomatic control rather than a definitive complete remission. Notably, lower baseline glucose levels were associated with treatment resistance, suggesting a potential role in guiding individualized therapeutic strategies.
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2026-08-07 | RNA methyltransferase 3 drives pancreatic acinar cell carcinoma growth and is a therapeutic target.
Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.
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2026-07-28 | Pancreatic Acinar Cell Carcinoma: A Rare Pancreatic Malignancy with Distinct Biology and Emerging Therapeutic Opportunities.
Pancreatic acinar cell carcinoma (PACC) is a rare exocrine pancreatic malignancy accounting for approximately 1-2% of adult pancreatic neoplasms. Although historically grouped with pancreatic ductal adenocarcinoma (PDAC), accumulating evidence demonstrates that PACC represents a biologically distinct entity with unique clinical, pathologic, and molecular characteristics. Compared with PDAC, PACC more commonly presents as a large pancreatic mass, is less frequently associated with obstructive jaundice, and exhibits lower rates of KRAS mutations. Recent genomic studies have identified recurrent alterations involving DNA damage repair pathways, WNT/β-catenin signaling, and actionable kinase fusions, including BRAF and RAF1 rearrangements. In advanced disease, fluoropyrimidine- and platinum-based regimens appear to demonstrate greater activity than traditional gemcitabine-based approaches, although prospective comparative data are lacking. This review summarizes the current understanding of the epidemiology, clinical presentation, pathology, molecular landscape, treatment approaches, and prognostic factors associated with PACC. We highlight emerging opportunities for precision oncology and discuss ongoing challenges in the management of this uncommon pancreatic malignancy.
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2026-07-24 | Expanded GEP-NET organoid culture for personalized therapy evaluation.
Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are a rare subset of cancers with increasing incidence. Due to their slow growth and lack of targetable mutations, the identification of effective treatments remains limited. One reason behind this stagnation is the lack of applicable, accurate study models. One solution is patient tumor organoids (PTOs) that maintain tumor characteristics and can scale for high throughput assays. In this study, PTOs were generated from 35 tumors of pancreatic, small intestinal, and gastric origin, obtained from 17 patients. Important subtypes including hormone functional and MEN1/VHL mutant GEP-NETs are represented, with each demonstrating growth in culture while maintaining GEP-NET immunohistochemistry and genomic characteristics. Half of G2/G3 tumors (10 of 20) could be cultured past passage 6, whereas G1 tumors (n = 15) were capable of growth until passage 4. Therapeutic targeting of the PTOs displayed both tissue-origin and grade-based response to standard of care and investigational therapies while maintaining patient tumor sensitivity and resistance. Last, a successful PTO xenograft model was developed from one PTO line. This study describes GEP-NET organoid development that demonstrates feasibility for expansion, enabling their use for translational investigations.
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