RARE DISEASE
Rare tumor of pancreas
Rare tumor of pancreas
Rare tumor of pancreas
Synonyms: Rare pancreatic tumor
Synonyms: Rare pancreatic tumor
Synonyms: Rare pancreatic tumor
Drug discovery
24
drugs
With orphan designations
Overview
Rare pancreatic tumors, constituting <5% of pancreatic cancers, include adenosquamous carcinoma, acinar cell carcinoma, pancreatic neuroendocrine tumors (PNETs), and pancreatoblastoma [1][2][5]. These tumors often present with nonspecific symptoms, leading to late diagnoses (frequently advanced stages) [1][12][17]. Prognosis varies by subtype but is generally poor due to aggressive biology and limited treatment efficacy [1][18]. Multidisciplinary care at specialized centers is critical for optimizing outcomes [9].
Population
Incidence: Affects <15/100,000 individuals, meeting rare cancer criteria [2][5][6].
Demographics: Gender/age vary by subtype (e.g., adenosquamous carcinoma favors women; pancreatoblastoma occurs in children) [1][15][18].
Risk Factors: Genetic mutations (BRCA, PALB2) play roles in select subtypes [3][11].
Burden
Mortality: 5-year survival <10% for most subtypes; median survival for unresectable disease is 6–12 months [1][6][14].
Diagnostic Challenges: Requires expert pathology review to avoid misclassification [1][13].
Healthcare Impact: High morbidity, frequent recurrence, and limited evidence due to underrepresentation in trials [8][12][18].
Therapies
Surgery: Primary modality for resectable tumors; outcomes depend on stage and subtype [4][7][12].
Chemotherapy: Adjuvant FOLFIRINOX or gemcitabine-based regimens for advanced/metastatic cases, with poor response rates [3][7][10].
Targeted Agents: PARP inhibitors for BRCA/PALB2 variants; clinical trials testing immunotherapy combinations [3][11][13].
Categories: rare gastroenterological diseases, rare neoplastic diseases
Research Papers
1,876 drug discovery papers about Rare tumor of pancreas, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,876 drug discovery papers about Rare tumor of pancreas, with 5 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-16 | To eat, or not to eat… dietary patterns and the clinical recognition of insulinoma: a case report.
Insulinoma is a rare pancreatic neuroendocrine tumor causing endogenous hyperinsulinemic hypoglycemia. Its heterogeneous clinical presentation often delays diagnosis. Dietary patterns, particularly ketogenic or high-carbohydrate regimens, may influence glucose homeostasis and modify the clinical manifestations of insulinoma. A 70-year-old woman was admitted with recurrent documented hypoglycemia. She reported a 10-year history of seizure-like episodes and intermittent neurological symptoms that began after starting a ketogenic diet. Symptoms later became less frequent during a high-calorie, carbohydrate-rich diet but recurred after adopting a Mediterranean diet. Biochemical evaluation confirmed endogenous hyperinsulinemic hypoglycemia. A supervised fasting test documented symptomatic hypoglycemia with plasma glucose of 17 mg/dL, fulfilling Whipple's triad. Magnetic resonance imaging revealed a 4 cm pancreatic tail lesion, and ˆ68 Ga-DOTATATE PET/CT showed intense uptake consistent with a somatostatin receptor-positive neuroendocrine tumor. As the patient declined surgery, diazoxide and dietary modifications were started, improving symptoms and glycemic control. This case suggests that dietary habits may influence the clinical presentation of insulinoma. Marked carbohydrate restriction may unmask hypoglycemia, whereas high-carbohydrate intake may attenuate symptoms and contribute to delayed diagnosis. Careful assessment of dietary habits should be part of the evaluation of patients with recurrent unexplained hypoglycemia suggestive of insulinoma.
2026-09-10 | Biomarker discovery and patient stratification in pancreatic cancer using incomplete multi-omics data.
Pancreatic ductal adenocarcinoma (PDAC), with a 12% 5-year survival rate, is the most aggressive type of cancer. Early diagnosis for this pathology is rare, and conventional treatments such as surgery, radio- or chemotherapy, have little to no effect on reducing mortality. Machine learning (ML) approaches could be used to identify biomarkers that help clinicians stratify patients and improve treatment outcomes. However, most ML techniques perform poorly with incomplete data, which is usually the case in real-world settings, often forcing researchers to discard valuable information. In this study, unsupervised ML algorithms capable of dealing with missing modalities were applied to incomplete multi-omics data from PDAC patients to identify clinically meaningful patient subgroups. Through a large-scale clustering benchmark including six omics layers, we discovered two novel subgroups with statistically significant differences in survival and recurrence after surgery, particularly within the first two years, when most patient deaths occur, as well as distinct tumor mutational burden. Comprehensive multi-omics analyses revealed substantial molecular differences between patients in both groups, identified three methylation biomarkers to stratify patients, and highlighted dysregulation in key oncogenic pathways. Importantly, the identified groups are different from previous PDAC classifications, both in their patient composition, prognosis, and in the oncogenic gene pathway profiles exhibited. Using an independent cohort, we further demonstrated that both the prognostic value of these subtypes and their underlying biological characteristics are reproducible. These results could lead to better stratified treatment regimens to improve the prognosis of PDAC patients.
2026-09-03 | Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.
Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the KRAS oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor's specific tissue context.
2026-08-27 | Pancreatoblastoma: A Descriptive and Comparative Analysis with Pancreatic Ductal Adenocarcinoma Using SEER Data.
Pancreatoblastoma (PB) is an exceptionally rare malignant epithelial neoplasm of the pancreas that recapitulates the developing pancreatic anlage. It is defined histologically by acinar-predominant differentiation with characteristic squamoid nests, and it may also show ductal and endocrine differentiation within the same tumor, features that distinguish it from acinar cell carcinoma and solid pseudopapillary neoplasm but that are readily overlooked. It occurs predominantly in young children, although adult-onset disease is well documented. We provide a population-based characterization of PB across the full age spectrum and benchmark it against pancreatic ductal adenocarcinoma (PDAC). Cases diagnosed between 2000 and 2021 were identified in the Surveillance, Epidemiology, and End Results (SEER) 17-registry database using site and histology codes. Cancer-specific survival (CSS) was estimated and compared, and Cox proportional hazards regression was used to explore associations with cancer-specific mortality. Thirty-nine cases of PB were identified, compared with 155,924 cases of PDAC. The median age at diagnosis was 17 years (range, under 1 to 78 years); 12.8% (n = 5) were younger than 1 year. Males accounted for 69.2% (n = 27) of cases. The cohort was divided at the conventional pediatric-to-adult threshold of 18 years into a pediatric subgroup (age < 18 years; n = 20) and an adult subgroup (age ≥ 18 years; n = 19). CSS at 1 and 5 years was 95.0% and 83.5% in the pediatric subgroup, versus 67.7% and 24.6% in the adult subgroup (log-rank p < 0.001). Five-year CSS was 44.8% in males and 75.0% in females. In an exploratory multivariable model, older age was associated with higher cancer-specific mortality both as a dichotomous variable (adjusted hazard ratio [HR] for age ≥ 18 years 10.7, 95% confidence interval [CI] 2.4-48.2; p = 0.002) and, in a parallel model, as a continuous variable (adjusted HR 1.4 per 10-year increment, 95% CI 1.1-1.8; p = 0.002), indicating an age-mortality gradient. Male sex showed an association in the same direction that did not reach statistical significance (adjusted HR 3.3, 95% CI 0.96-11.6; p = 0.06). Relative to PDAC, PB was more frequently diagnosed in males and was associated with markedly superior survival (1- and 5-year CSS 81.8% and 54.9%, versus 28.8% and 4.0%). Pancreatoblastoma is predominantly a malignancy of young males and carries a substantially more favorable prognosis than PDAC, but outcomes differ markedly across the age spectrum, with adult-onset disease showing considerably poorer survival. Translationally, these population-level estimates support age-stratified prognostic counseling, argue for the referral of adults to centers experienced in rare pancreatic tumors, and provide a rationale for prospective molecular profiling to determine whether adult and pediatric PBs are biologically distinct and whether Wnt/beta-catenin pathway activation is therapeutically actionable.
2026-08-27 | Genetically determined ABO blood group, secretor status, Lewis antigens, and panNEN risk.
Pancreatic neuroendocrine neoplasms (panNENs) are rare endocrine malignancies with poorly defined risk factors, in contrast to the more common pancreatic ductal adenocarcinoma (PDAC), for which non-O ABO blood group is a well-established susceptibility marker. To determine whether ABO and related glycosylation markers associated with PDAC risk extend to panNENs, we conducted a case-control study of 1,059 pathologically confirmed panNEN cases from the Mayo Clinic Biospecimen Resource for Pancreas Research and 33,018 cancer-free controls from the Mayo ClinicBiobank. Using germline genotype data, we inferred ABO blood group, FUT2-defined secretor status, and FUT3-defined Lewis antigen phenotypes and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression adjusted for age, sex, and ancestry principal components. ABO blood group was not associated with panNEN risk: compared with blood group O, the OR for non-O was 0.98 (95% CI: 0.87-1.11), with similarly null findings for blood groups A, B, and AB individually. Secretor status (OR = 0.98, 95% CI: 0.84-1.14) and Lewis-positive phenotypes (OR = 0.91, 95% CI: 0.75-1.13) were also not associated with risk, and no interactions were observed between blood group and secretor status or Lewis antigen phenotypes. Given our high statistical power to detect previously reported PDAC effect sizes for non-O blood group, these null findings are informative, indicating that the ABO-linked glycosylation, inflammatory, and host-microbe interaction pathways implicated in PDAC are unlikely to be major determinants of panNEN susceptibility. This study therefore sharpens the etiologic distinction between pancreatic exocrine and neuroendocrine cancers, redirecting panNEN research beyond PDAC paradigms toward alternative mechanisms of endocrine tumorigenesis.
proteins
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.
2026-06-19 | Insulinoma in pregnancy: a case report and literature review of diagnostic challenges, multidisciplinary management, and therapeutic dilemmas.
Insulinoma during pregnancy is exceedingly rare, with fewer than 30 cases reported worldwide. Diagnosis is often delayed due to overlapping physiological and gestational symptoms, posing significant risks to both mother and fetus. We report a case of a 36-year-old gravida 4 para 2 + 1 woman presenting at 7 weeks' gestation with recurrent symptomatic hypoglycaemia. She re-presented at 12 weeks' gestation with persistent neuroglycopenic symptoms and weight loss. Biochemical evaluation demonstrated inappropriately non-suppressed insulin and C-peptide levels during hypoglycaemia, raising suspicion for endogenous hyperinsulinaemia. Ultrasound was non-diagnostic while magnetic resonance imaging identified a 2.3 x 2.5 cm pancreatic lesion consistent with insulinoma. A multidisciplinary team (MDT) approach involving Endocrinology, Obstetrics & Gynecology (Maternal-Fetal Medicine), Hepatobiliary Surgery, and Radiology guided the management. Due to the tumor size and procedural risks during pregnancy, definitive intervention was deferred while medical therapy with octreotide was initiated, achieving partial glycaemic control. The pregnancy was complicated by fetal growth restriction, necessitating delivery at 34 weeks. Postpartum, she underwent endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), requiring two sessions before achieving glycaemic stabilization. This case highlights the diagnostic challenges of insulinoma in pregnancy and underscores the importance of MDT-guided individualized management. It also illustrates the limitations of EUS-RFA and medical therapy, particularly in larger tumors, and raises important considerations regarding fetal outcomes.
2026-01-09 | Transcriptomic landscape of transposable elements reveals LTR7-PLAAT4 as a potential oncogene and therapeutic target in pancreatic adenocarcinoma.
Eukaryotic genomes contain numerous transposable elements (TEs), whose dysregulation threatens genome stability and may contribute to cancer. Pancreatic adenocarcinoma (PAAD) is among the deadliest cancers, marked by abundant stroma that obscures tumor-specific molecular signals, complicating bulk-tissue analyses. Here, using 71 patient-derived PAAD organoids, we show that TE activities may potentially promote tumorigenesis and provide a source of novel immunotherapeutic targets. We identify 16 new TE-derived transcripts fused with 15 known oncogenes, exhibiting potential oncogenic function and prognostic value. Notably, LTR7-PLAAT4, present in 29% of tumors, encodes a protein variant transcriptionally regulated by FOXM1 binding to the LTR7 promoter. LTR7-PLAAT4 isoform 2 is associated with increased cholesterol ester accumulation and lipid droplet formation mediated through BSCL2 coexpression, potentially fostering tumor progression. On the immunogenic front, HLA-I immunopeptidomics of AsPC-1 cells and DAC13 organoids identify over 11,000 peptides respectively. Althought mutation-derived neoantigens are rare, several peptides are originated from TE-chimeric transcripts, including four predicted by TEprof2. The peptide FLIQHLPLV, detected in 27% of organoids, exhibits robust immunogenicity, validated by T2 binding, mass spectrometry and ELISPOT assays with HLA-genotyped PBMCs. Together, these findings suggest that TE activities may contribute to PAAD progression and diversify its immunopeptidome, providing new opportunities for molecular subtyping and potential immunotherapeutic intervention.
2025-10-23 | Progression of intracardiac metastases from gastroenteropancreatic neuroendocrine tumors.
Intracardiac metastases from gastroenteropancreatic neuroendocrine tumors (NETs) are rare and challenging to diagnose. Lutetium (Lu)-177 DOTATATE therapy has demonstrated significant benefit in patients with metastatic NET; however, there are limited data regarding the direct impact on cardiac metastases. Patients with intracardiac metastasis from NET were evaluated. Patients were stratified by treatment with Lu-177 DOTATATE. Quantitative assessments of the progression of cardiac metastatic size (maximal diameter) and metabolic activity, as measured by maximal standardized uptake value (SUV max ), were performed on serial 68 Ga-DOTATATE PET imaging. In a cohort of 23 patients, 11 patients (47.8%) received Lu-177 DOTATATE therapy. Through a median of 2.2 years of follow-up, these patients showed some reduction in metastatic burden with a median reduction in maximal diameter of 1.0 mm (IQR: 0.0-3.0) and a median change in SUV max of -1.6 (IQR: -4.4 to 1.5). In contrast, patients who did not receive Lu-177 DOTATATE had some increase in maximal diameter of 0.5 mm (-2.0 to 2.0) and an increase in SUV max of 1.4 (-6.2 to 2.3). Overall, Lu-177 DOTATATE therapy may result in modest regression of intracardiac metastases as assessed by molecular imaging, whereas patients with cardiac metastases who did not receive therapy appeared to show progression.
2025-08-15 | Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.
cell therapies
2026-08-21 | Giant Necrotic Axillary Metastasis From Pancreatic Neuroendocrine Carcinoma Treated With Palliative Resection and Breast Reconstruction: A Case Report.
Neuroendocrine tumors of the pancreas are rare and can present with atypical metastatic patterns. Axillary involvement is extremely uncommon and requires a diagnosis of exclusion. Furthermore, it can be a therapeutic challenge. We present the case of a 78-year-old woman with a medical history of arterial hypertension, type 2 diabetes mellitus, and Parkinson's disease. She was diagnosed with pancreatic carcinoma with metastatic disease to axillary nodes. The patient developed a massive necrotic axillary tumor, measuring approximately 30 × 30 cm clinically, also associated with erythema, pain, exudate, and local infection. Laboratory tests showed severe anemia (Hb 7.4 g/dL), neutrophilia (95.1%), hyponatremia (Na 132 mmol/L), and hypokalemia (K 2.3 mmol/L). Imaging (contrast-enhanced CT and angio-CT) revealed a well-defined mass displacing the pectoral, deltoid, and serratus muscles; partially compressing the brachial artery with distal recanalization; and measuring approximately 25 cm x 20 cm. Three months after the first diagnosis, the patient underwent a palliative surgery including a block resection of the axillary tumor measuring 26 × 21 × 8 cm and weighing 3000 g. Histopathology results showed a poorly differentiated metastatic neuroendocrine carcinoma with rhabdoid features, extensive necrosis throughout the whole tumor, and positive margins. Immunohistochemistry was also performed and revealed focal enolase positivity, while CD56, p53, and chromogranin were negative. Pancreatic neuroendocrine tumors usually metastasize to the liver, peritoneum, or lymph nodes. Axillary metastasis is extremely rare and has been documented in only a few cases. The presence of a large, necrotic, infected tumor in this location significantly impacts quality of life. Surgical resection, although not curative, may provide substantial pain relief, control local complications, reduce infectious sequelae, and improve quality of life. This particular case highlights an uncommon metastatic site of pancreatic neuroendocrine carcinoma. Awareness of atypical metastatic patterns is essential for more precocious management, and surgical resection can provide substantial palliative benefit in selected patients.
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.
2026-07-08 | Long term survival in three pancreatic cancer patients following Whipple's procedure and allogeneic hematopoietic cell transplantation.
Pancreatic ductal adenocarcinoma (PDAC) is associated with an extremely poor prognosis, with long-term survival being exceedingly rare. Here, we follow-up on three long-term survivors. This study initially included eight patients with PDAC who underwent radical resection via Whipple's procedure with no evidence of distant metastases. Two of these patients received allogeneic hematopoietic cell transplantation (HCT) in a previously published trial. The remaining six patients, who served as controls and did not receive HCT, died of progressive PDAC within one to four years. Additionally, a 60-year-old male with PDAC who underwent partial pancreatectomy and gastrectomy received HCT from a matched unrelated donor. Patient 1 developed mild acute graft-versus-host disease (GVHD) of the skin, followed by chronic GVHD. He subsequently underwent surgery for oral cancer and remains alive 21 years after the initial PDAC diagnosis, with no evidence of recurrence. Patient 2 experienced severe acute gastrointestinal GVHD and recurrent chronic bronchiolitis obliterans. He died of esophageal cancer 19 years after PDAC diagnosis. Patient 3 experienced graft rejection and multiple medical complications, including radical surgery for colorectal cancer, yet remains cancer-free 15 years after PDAC diagnosis. In conclusion, HCT may confer anticancer effects in patients with radically resected PDAC. Further investigations are warranted to confirm its therapeutic value.ClinicalTrials.gov Identifier: NCT02207985.
2026-06-16 | Robotic subtotal pancreatectomy for multifocal neuroendocrine tumour of the pancreas.
Pancreatic neuroendocrine tumours (pNETs) are rare and can be difficult to manage due to their variable presentations. Surgical resection remains the standard treatment for symptom control and reduced risk of recurrence. Minimally invasive robotic surgery has become an alternative to open approaches due to its enhanced three-dimensional visualisation and precision. Most documented cases, however, involve solitary tumours or multifocal disease in patients with genetic syndromes such as MEN-1. We present the case of a woman in her 20s who underwent robotic subtotal pancreatectomy for multifocal pNETs, without evidence of an underlying genetic syndrome. After an uneventful postoperative recovery, the patient was discharged home on day 3. This case contributes to the limited descriptive literature on the presentation and surgical management of sporadic insulinomas.
2026-05-18 | Robot-Assisted Spleen-Preserving Distal Pancreatectomy for an Epithelial Cyst Arising from an Intrapancreatic Accessory Spleen: A Case Report.
Epithelial cysts arising from an intrapancreatic accessory spleen (ECIPAS) are rare and often misdiagnosed as pancreatic cystic neoplasms because their imaging features frequently overlap. When malignancy cannot be ruled out, surgical resection is generally indicated, and minimally invasive approaches have become an appropriate treatment option. We report a case of ECIPAS initially suspected to be a mucinous cystic neoplasm (MCN), successfully treated with spleen-preserving distal pancreatectomy using the hinotori Surgical Robot System. A 63-year-old woman was incidentally found to have an 18-mm cystic lesion in the pancreatic tail during preoperative imaging for laparoscopic cholecystectomy 2 years earlier. The lesion gradually enlarged to 30 mm over 2 years of serial follow-up. MRI demonstrated a "cyst-in-cyst" morphology without communication with the main pancreatic duct. Contrast-enhanced CT revealed a thick-walled cyst with internal septal calcifications but no solid components. Serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were within normal limits. Based on the imaging features and lesion growth, we suspected MCN and indicated surgical resection. Consequently, robot-assisted spleen-preserving distal pancreatectomy (Robo-SPDP) was performed using the hinotori system, following the Kimura technique. The procedure was completed safely without any intraoperative complications. Histopathological examination revealed a cyst lined by flattened to columnar epithelium, with an underlying splenic sinus structure confirmed by CD8 immunostaining. Ovarian-type stroma was absent, excluding MCN and establishing a diagnosis of ECIPAS. The postoperative course was uneventful, and the patient was discharged on POD 10. This case highlights the importance of considering ECIPAS in the differential diagnosis of pancreatic cystic lesions, particularly when imaging findings resemble cystic neoplasms. When malignancy cannot be ruled out, surgical resection is recommended and minimally invasive spleen-preserving distal pancreatectomy is a reasonable therapeutic option. Furthermore, robotic assistance appeared to be a safe and effective surgical approach facilitating precise dissection and reliable preservation of the splenic vessels.
antibodies
2026-09-17 | Undifferentiated Carcinoma of the Pancreas With Osteoclast-Like Giant Cells: A Comprehensive Review of Clinical Features, Molecular Pathology, and Therapeutic Advances.
Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells is a rare variant of malignant pancreatic tumor, accounting for less than 1% of all pancreatic tumors. The efficacy of neoadjuvant and adjuvant chemotherapy in patients with undifferentiated carcinoma of the pancreas with osteoclast-like giant cells remains unclear. Preliminary case reports have suggested pembrolizumab may be effective in some metastatic patients, though this requires validation in larger studies. Furthermore, patients with pure undifferentiated carcinoma of the pancreas with osteoclast-like giant cells demonstrate better overall survival rates than those with mixed-type undifferentiated carcinoma of the pancreas with osteoclast-like giant cells containing a pancreatic ductal adenocarcinoma histopathological subtype. Programmed cell death ligand-1 (PD-L1) expression has been identified as a significant determinant that shortens survival in patients with undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, suggesting that anti-PD-1/PD-L1 agents may represent a potential therapeutic approach for this tumor type. This article reviews recent advances in the diagnosis, differential diagnosis, treatment, and prognosis of undifferentiated carcinoma of the pancreas with osteoclast-like giant cells to enhance understanding of this rare tumor entity.
2026-09-11 | Splenic hilum nodal involvement in resected left-sided pancreatic cancer: meta-analysis.
Splenectomy is standard of care during left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) to obtain adequate lymphadenectomy. However, evidence supporting this approach is lacking. Splenic preservation would reduce short-term morbidity and is essential for emerging oncological adjunctive therapies, including immunotherapy and personalized cancer vaccines. This study reviewed the incidence of splenic hilum nodal involvement (SHNI) in left-sided PDAC. A systematic review of the PubMed, Embase, and Cochrane databases was performed, identifying studies published from inception to July 2026. Outcomes of interest were the rate of SHNI (station 10), overall survival, and the rate of splenic artery nodal involvement (SANI; station 11). Meta-analyses were conducted using random-effects models. Subgroup analyses for SHNI were performed per tumour localization (pancreatic neck, body, tail). Among 2776 screened studies, 22 with 2260 patients undergoing left pancreatectomy for PDAC were included. The pooled prevalence of SHNI was 3.7% (95% confidence interval (c.i.) 2.2% to 6.2%); 1.1% for pancreatic body PDAC (95% c.i. 0.3% to 4.3%) and 9.7% for pancreatic tail PDAC (95% c.i. 3.5% to 24.0%). SHNI was not significantly associated with survival (pooled hazard ratio 2.05; 95% c.i. 0.89% to 4.72; P = 0.072). The pooled prevalence of SANI was 39.1% (95% c.i. 25.1% to 55.1%). In patients undergoing left pancreatectomy for PDAC, the presence of SHNI is rare, particularly in pancreatic body cancer (1.1%). These findings suggest that the relevance of routine splenectomy remains unclear, especially for pancreatic body PDAC. However, because the quality of current evidence is low, further investigation in prospective studies is required.
2026-08-27 | DLL3 expression in neuroendocrine carcinomas: a comparative analysis across tumor origins.
Neuroendocrine carcinomas (NECs) are rare and highly aggressive tumors, characterized by a dismal prognosis. Their underlying biology remains insufficiently understood, highlighting an urgent need for the identification of disease markers to enhance diagnostic and prognostic assessments, as well as to identify potential druggable targets. DLL3, an inhibitory regulator of the Notch signalling pathway, has emerged as a promising candidate in this context. We investigated DLL3 prevalence and pattern of expression in immunohistochemistry in NECs from multiple anatomical sites, with a focus on lung and gastroenteropancreatic (GEP) neoplasms. DLL3 was found to be highly expressed in 68.8% of NECs overall, with the highest prevalence observed in GEP-NECs (85.7%). Immunohistochemical analysis revealed predominantly cytoplasmic localization, with a dot-like staining pattern particularly evident in gastrointestinal cases, suggestive of potential localization in neurosecretory granules. DLL3 levels did not significantly correlate with tumor proliferation index nor with overall survival. A correlation with chromogranin A expression was found. Given its high prevalence in extrapulmonary NECs, particularly those of GEP origin, it may have potential as a disease marker and therapeutic target in a clinical context where effective options are currently limited.
2026-07-16 | Solid pseudopapillary neoplasm of the pancreas: A retrospective single-center cohort study of 1,058 consecutive patients.
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, low-grade malignant tumor, predominantly affecting young women. Although the overall prognosis of SPN is good, the understanding of its pathophysiological characteristics and the selection of treatment strategies remain insufficient. A retrospective analysis of 1058 consecutive patients with pathologically confirmed SPN was performed at a single institution. Clinicopathological characteristics, immunohistochemical profiles, targeted sequencing data, and overall survival were systematically evaluated. The median age of the patients at diagnosis was 33 years, with females being the majority (78.1%). Most tumors were located in the body/tail (70.2%), larger than 3 cm (61.9%), while invasive features such as vascular invasion (1.6%), nerve invasion (7.0%), and lymph node metastasis (0.7%) were rare. Early-stage (stage I, II) patients were more common (99.1%). In recent years, the surgical procedures have significantly shifted towards minimally invasive and parenchyma-sparing surgery. The prognosis of SPN was excellent, with a 5-year survival of 97.9%. Molecular analysis revealed nearly universal CTNNB1 mutations (97%). High expression of progesterone receptor (PR, 97.2%) and low expression of estrogen receptor (ER, 7.7%) supported hormone dependence. This large single-center cohort study confirms that SPN is a tumor with low malignant potential, and identifies the key clinicopathological and molecular factors associated with malignant features. Different hormone receptor profiles provide a theoretical basis for exploring hormone receptor-targeted therapy for advanced patients.
2026-06-05 | EWSR1::BEND2 gene fusions characterize a majority of ACTH-producing neuroendocrine neoplasms of the pancreas: A follow-up study and brief review of the recent literature.
ACTH-producing pancreatic neuroendocrine neoplasms (PanNENs) are a rare aggressive subset of panNETs associated with clinical symptoms of ectopic Cushing syndrome. Until recently, their molecular pathogenesis remained poorly understood. Following our prior study highlighting high frequency of gene fusions (mostly EWSR1::BEND2) in them, we herein document our experience with 5 new tumors occurring in 4 women (one of unspecified sex) aged 36 to 79 (median, 45). All presented with clinical and biochemical signs of ectopic Cushing syndrome. Histologically, the tumors corresponded to NET grade 2 (n = 3) and grade 3 (n = 2). At last follow-up, three patients were alive with metastatic disease at 36, 48 and 72 months from initial diagnosis, one died of disease at 50 months and one was disease-free at 15 months. Targeted RNA sequencing revealed an EWSR1::BEND2 fusion in two cases and a possible CSE1L::TAF15 fusion in one. Two tumors were negative for fusions. This small series and review of the recent literature further confirm the significant association between the EWSR1::BEND2 fusions and ectopic ACTH-production in PanNETs with an overall frequency of ectopic Cushing among EWSR1::BEND2 fusion tumors of 70%. Given their highly aggressive course, recognition of this molecular subtype of panNETs is mandatory. Emerging BEND2 IHC represents a promising screening tool for recognizing these tumors.
other
2026-08-22 | Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.
Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic 'feed-forward' axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.
2026-07-09 | An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups.
Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.
2026-07-01 | Transcriptomic-based molecular classification of ampullary adenocarcinoma.
Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy with markedly variable clinical outcomes, underscoring the urgent need for molecularly informed classification and personalized therapeutic strategies. Current AMPAC classification relies primarily on morphological and immunohistochemical criteria, which lack prognostic accuracy and fail to capture the underlying molecular and tumor microenvironment heterogeneity. In this study, we integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and clinicopathological data to elucidate the molecular architecture of AMPAC and introduced a transcriptomic-based molecular classification (AMS). The AMS categorized patients into two molecular subtypes: mesenchymal AMPAC (AMS-M) and classical AMPAC (AMS-C). The AMS-M demonstrated increased epithelial-mesenchymal transition (EMT) and stromal activation, correlating with basal-like subtypes associated with unfavorable prognosis. In contrast, AMS-C tumors exhibited metabolic and differentiation programs with relatively preserved immune infiltration. Importantly, we identified MUC16 as a pivotal biomarker specifically overexpressed in AMS-M tumors. MUC16 knockout markedly reversed EMT, attenuated invasive and migratory capacities, and restored chemosensitivity in both cell lines and their xenograft models. Collectively, our findings establish AMS as a prognostically and therapeutically informative molecular classification framework for AMPAC, unveil the critical role of the tumor microenvironment in AMPAC heterogeneity, and provide a translational foundation for precision oncology in this rare tumor.
2025-10-10 | Late-stage hepatoid adenocarcinoma of the pancreatic head with a long survival after surgery: a case report.
Hepatoid adenocarcinoma of the pancreas is a rare primary malignant tumor. According to few previous reports, with poor prognosis and atypical clinical features, hepatoid adenocarcinoma of the pancreas is easily misdiagnosed. Its pathological examination often shows similar morphological and immunohistochemical features to those of hepatocellular carcinoma. There is also insufficient clinical experience in the diagnosis and treatment of hepatoid adenocarcinoma. A 45-year-old Asian woman, initially suspected to have late-stage pancreatic ductal adenocarcinoma, was admitted to our clinic with abdominal pain and jaundice. The magnetic resonance imaging scan showed a pancreatic head mass with enlarged retroperitoneal and portal lymph nodes. To confirm the diagnosis, a thorough evaluation of her medical history, clinical presentation, imaging findings, and laboratory tests was conducted. An endoscopic ultrasound-guided biopsy was performed, and the initial biopsy report suggested a neuroendocrine tumor. Based on this finding, a multidisciplinary team discussion was held, and the decision was made to proceed with radical surgery. Postoperative pathological examination unexpectedly revealed hepatoid adenocarcinoma of the pancreas, which led to a revision of the final clinical diagnosis. Following surgery, she received three cycles of postoperative adjuvant chemotherapy with a regimen of gemcitabine plus albumin-bound paclitaxel. Postoperative follow-up at 4 months indicated liver metastasis, for which she underwent microwave ablation. Subsequently, she was supplemented with adjuvant therapy combining durvalumab and S-1. At the time of writing, 16 months after her initial clinic visit, the patient remains alive without evidence of abdominal metastasis. This case of hepatoid adenocarcinoma of the pancreas achieved a better prognosis through a comprehensive treatment based on surgery after multidisciplinary team discussion, giving the patient hope for long-term survival. The multidisciplinary team, in the form of multidisciplinary experts coming together to discuss the patient's condition, changed the patient's treatment decision, which may be another option when it comes to complex cases.
2025-08-08 | Gastric ectopic pancreatic ductal adenocarcinoma coexisted with endometriosis mimick advanced disease: a case report and literature review.
Ectopic pancreas (EP) is most commonly located in the upper gastrointestinal tract, particularly in the stomach. Malignant transformation of EP is exceptionally rare, and due to its very low incidence, the response to drug therapy and overall prognosis remain poorly understood. This report presents a case of gastric ectopic pancreatic ductal adenocarcinoma. Unusually, the patient also had concurrent endometriosis, which caused the tumor to resemble advanced cancer on imaging. Although over 50 cases of malignant transformation of EP have been documented. Nevertheless, it has not been definitively established which drug therapeutic regimens is effective for this disease. This is the first to detail the tumor's response to anti-tumor drug therapy. Pancreatic cancer is generally resistant to anti-tumor drugs. However, in this case, the tumor arising from EP regressed following treatment with immune checkpoint inhibitors (ICIs) combined with chemotherapy. This observation highlights differences in the biological behavior of these two tumor types.
small molecules
2026-09-16 | To eat, or not to eat… dietary patterns and the clinical recognition of insulinoma: a case report.
Insulinoma is a rare pancreatic neuroendocrine tumor causing endogenous hyperinsulinemic hypoglycemia. Its heterogeneous clinical presentation often delays diagnosis. Dietary patterns, particularly ketogenic or high-carbohydrate regimens, may influence glucose homeostasis and modify the clinical manifestations of insulinoma. A 70-year-old woman was admitted with recurrent documented hypoglycemia. She reported a 10-year history of seizure-like episodes and intermittent neurological symptoms that began after starting a ketogenic diet. Symptoms later became less frequent during a high-calorie, carbohydrate-rich diet but recurred after adopting a Mediterranean diet. Biochemical evaluation confirmed endogenous hyperinsulinemic hypoglycemia. A supervised fasting test documented symptomatic hypoglycemia with plasma glucose of 17 mg/dL, fulfilling Whipple's triad. Magnetic resonance imaging revealed a 4 cm pancreatic tail lesion, and ˆ68 Ga-DOTATATE PET/CT showed intense uptake consistent with a somatostatin receptor-positive neuroendocrine tumor. As the patient declined surgery, diazoxide and dietary modifications were started, improving symptoms and glycemic control. This case suggests that dietary habits may influence the clinical presentation of insulinoma. Marked carbohydrate restriction may unmask hypoglycemia, whereas high-carbohydrate intake may attenuate symptoms and contribute to delayed diagnosis. Careful assessment of dietary habits should be part of the evaluation of patients with recurrent unexplained hypoglycemia suggestive of insulinoma.
2026-09-10 | Biomarker discovery and patient stratification in pancreatic cancer using incomplete multi-omics data.
Pancreatic ductal adenocarcinoma (PDAC), with a 12% 5-year survival rate, is the most aggressive type of cancer. Early diagnosis for this pathology is rare, and conventional treatments such as surgery, radio- or chemotherapy, have little to no effect on reducing mortality. Machine learning (ML) approaches could be used to identify biomarkers that help clinicians stratify patients and improve treatment outcomes. However, most ML techniques perform poorly with incomplete data, which is usually the case in real-world settings, often forcing researchers to discard valuable information. In this study, unsupervised ML algorithms capable of dealing with missing modalities were applied to incomplete multi-omics data from PDAC patients to identify clinically meaningful patient subgroups. Through a large-scale clustering benchmark including six omics layers, we discovered two novel subgroups with statistically significant differences in survival and recurrence after surgery, particularly within the first two years, when most patient deaths occur, as well as distinct tumor mutational burden. Comprehensive multi-omics analyses revealed substantial molecular differences between patients in both groups, identified three methylation biomarkers to stratify patients, and highlighted dysregulation in key oncogenic pathways. Importantly, the identified groups are different from previous PDAC classifications, both in their patient composition, prognosis, and in the oncogenic gene pathway profiles exhibited. Using an independent cohort, we further demonstrated that both the prognostic value of these subtypes and their underlying biological characteristics are reproducible. These results could lead to better stratified treatment regimens to improve the prognosis of PDAC patients.
2026-09-03 | Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.
Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the KRAS oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor's specific tissue context.
2026-08-27 | Pancreatoblastoma: A Descriptive and Comparative Analysis with Pancreatic Ductal Adenocarcinoma Using SEER Data.
Pancreatoblastoma (PB) is an exceptionally rare malignant epithelial neoplasm of the pancreas that recapitulates the developing pancreatic anlage. It is defined histologically by acinar-predominant differentiation with characteristic squamoid nests, and it may also show ductal and endocrine differentiation within the same tumor, features that distinguish it from acinar cell carcinoma and solid pseudopapillary neoplasm but that are readily overlooked. It occurs predominantly in young children, although adult-onset disease is well documented. We provide a population-based characterization of PB across the full age spectrum and benchmark it against pancreatic ductal adenocarcinoma (PDAC). Cases diagnosed between 2000 and 2021 were identified in the Surveillance, Epidemiology, and End Results (SEER) 17-registry database using site and histology codes. Cancer-specific survival (CSS) was estimated and compared, and Cox proportional hazards regression was used to explore associations with cancer-specific mortality. Thirty-nine cases of PB were identified, compared with 155,924 cases of PDAC. The median age at diagnosis was 17 years (range, under 1 to 78 years); 12.8% (n = 5) were younger than 1 year. Males accounted for 69.2% (n = 27) of cases. The cohort was divided at the conventional pediatric-to-adult threshold of 18 years into a pediatric subgroup (age < 18 years; n = 20) and an adult subgroup (age ≥ 18 years; n = 19). CSS at 1 and 5 years was 95.0% and 83.5% in the pediatric subgroup, versus 67.7% and 24.6% in the adult subgroup (log-rank p < 0.001). Five-year CSS was 44.8% in males and 75.0% in females. In an exploratory multivariable model, older age was associated with higher cancer-specific mortality both as a dichotomous variable (adjusted hazard ratio [HR] for age ≥ 18 years 10.7, 95% confidence interval [CI] 2.4-48.2; p = 0.002) and, in a parallel model, as a continuous variable (adjusted HR 1.4 per 10-year increment, 95% CI 1.1-1.8; p = 0.002), indicating an age-mortality gradient. Male sex showed an association in the same direction that did not reach statistical significance (adjusted HR 3.3, 95% CI 0.96-11.6; p = 0.06). Relative to PDAC, PB was more frequently diagnosed in males and was associated with markedly superior survival (1- and 5-year CSS 81.8% and 54.9%, versus 28.8% and 4.0%). Pancreatoblastoma is predominantly a malignancy of young males and carries a substantially more favorable prognosis than PDAC, but outcomes differ markedly across the age spectrum, with adult-onset disease showing considerably poorer survival. Translationally, these population-level estimates support age-stratified prognostic counseling, argue for the referral of adults to centers experienced in rare pancreatic tumors, and provide a rationale for prospective molecular profiling to determine whether adult and pediatric PBs are biologically distinct and whether Wnt/beta-catenin pathway activation is therapeutically actionable.
2026-08-27 | Genetically determined ABO blood group, secretor status, Lewis antigens, and panNEN risk.
Pancreatic neuroendocrine neoplasms (panNENs) are rare endocrine malignancies with poorly defined risk factors, in contrast to the more common pancreatic ductal adenocarcinoma (PDAC), for which non-O ABO blood group is a well-established susceptibility marker. To determine whether ABO and related glycosylation markers associated with PDAC risk extend to panNENs, we conducted a case-control study of 1,059 pathologically confirmed panNEN cases from the Mayo Clinic Biospecimen Resource for Pancreas Research and 33,018 cancer-free controls from the Mayo ClinicBiobank. Using germline genotype data, we inferred ABO blood group, FUT2-defined secretor status, and FUT3-defined Lewis antigen phenotypes and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression adjusted for age, sex, and ancestry principal components. ABO blood group was not associated with panNEN risk: compared with blood group O, the OR for non-O was 0.98 (95% CI: 0.87-1.11), with similarly null findings for blood groups A, B, and AB individually. Secretor status (OR = 0.98, 95% CI: 0.84-1.14) and Lewis-positive phenotypes (OR = 0.91, 95% CI: 0.75-1.13) were also not associated with risk, and no interactions were observed between blood group and secretor status or Lewis antigen phenotypes. Given our high statistical power to detect previously reported PDAC effect sizes for non-O blood group, these null findings are informative, indicating that the ABO-linked glycosylation, inflammatory, and host-microbe interaction pathways implicated in PDAC are unlikely to be major determinants of panNEN susceptibility. This study therefore sharpens the etiologic distinction between pancreatic exocrine and neuroendocrine cancers, redirecting panNEN research beyond PDAC paradigms toward alternative mechanisms of endocrine tumorigenesis.
proteins
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.
2026-06-19 | Insulinoma in pregnancy: a case report and literature review of diagnostic challenges, multidisciplinary management, and therapeutic dilemmas.
Insulinoma during pregnancy is exceedingly rare, with fewer than 30 cases reported worldwide. Diagnosis is often delayed due to overlapping physiological and gestational symptoms, posing significant risks to both mother and fetus. We report a case of a 36-year-old gravida 4 para 2 + 1 woman presenting at 7 weeks' gestation with recurrent symptomatic hypoglycaemia. She re-presented at 12 weeks' gestation with persistent neuroglycopenic symptoms and weight loss. Biochemical evaluation demonstrated inappropriately non-suppressed insulin and C-peptide levels during hypoglycaemia, raising suspicion for endogenous hyperinsulinaemia. Ultrasound was non-diagnostic while magnetic resonance imaging identified a 2.3 x 2.5 cm pancreatic lesion consistent with insulinoma. A multidisciplinary team (MDT) approach involving Endocrinology, Obstetrics & Gynecology (Maternal-Fetal Medicine), Hepatobiliary Surgery, and Radiology guided the management. Due to the tumor size and procedural risks during pregnancy, definitive intervention was deferred while medical therapy with octreotide was initiated, achieving partial glycaemic control. The pregnancy was complicated by fetal growth restriction, necessitating delivery at 34 weeks. Postpartum, she underwent endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), requiring two sessions before achieving glycaemic stabilization. This case highlights the diagnostic challenges of insulinoma in pregnancy and underscores the importance of MDT-guided individualized management. It also illustrates the limitations of EUS-RFA and medical therapy, particularly in larger tumors, and raises important considerations regarding fetal outcomes.
2026-01-09 | Transcriptomic landscape of transposable elements reveals LTR7-PLAAT4 as a potential oncogene and therapeutic target in pancreatic adenocarcinoma.
Eukaryotic genomes contain numerous transposable elements (TEs), whose dysregulation threatens genome stability and may contribute to cancer. Pancreatic adenocarcinoma (PAAD) is among the deadliest cancers, marked by abundant stroma that obscures tumor-specific molecular signals, complicating bulk-tissue analyses. Here, using 71 patient-derived PAAD organoids, we show that TE activities may potentially promote tumorigenesis and provide a source of novel immunotherapeutic targets. We identify 16 new TE-derived transcripts fused with 15 known oncogenes, exhibiting potential oncogenic function and prognostic value. Notably, LTR7-PLAAT4, present in 29% of tumors, encodes a protein variant transcriptionally regulated by FOXM1 binding to the LTR7 promoter. LTR7-PLAAT4 isoform 2 is associated with increased cholesterol ester accumulation and lipid droplet formation mediated through BSCL2 coexpression, potentially fostering tumor progression. On the immunogenic front, HLA-I immunopeptidomics of AsPC-1 cells and DAC13 organoids identify over 11,000 peptides respectively. Althought mutation-derived neoantigens are rare, several peptides are originated from TE-chimeric transcripts, including four predicted by TEprof2. The peptide FLIQHLPLV, detected in 27% of organoids, exhibits robust immunogenicity, validated by T2 binding, mass spectrometry and ELISPOT assays with HLA-genotyped PBMCs. Together, these findings suggest that TE activities may contribute to PAAD progression and diversify its immunopeptidome, providing new opportunities for molecular subtyping and potential immunotherapeutic intervention.
2025-10-23 | Progression of intracardiac metastases from gastroenteropancreatic neuroendocrine tumors.
Intracardiac metastases from gastroenteropancreatic neuroendocrine tumors (NETs) are rare and challenging to diagnose. Lutetium (Lu)-177 DOTATATE therapy has demonstrated significant benefit in patients with metastatic NET; however, there are limited data regarding the direct impact on cardiac metastases. Patients with intracardiac metastasis from NET were evaluated. Patients were stratified by treatment with Lu-177 DOTATATE. Quantitative assessments of the progression of cardiac metastatic size (maximal diameter) and metabolic activity, as measured by maximal standardized uptake value (SUV max ), were performed on serial 68 Ga-DOTATATE PET imaging. In a cohort of 23 patients, 11 patients (47.8%) received Lu-177 DOTATATE therapy. Through a median of 2.2 years of follow-up, these patients showed some reduction in metastatic burden with a median reduction in maximal diameter of 1.0 mm (IQR: 0.0-3.0) and a median change in SUV max of -1.6 (IQR: -4.4 to 1.5). In contrast, patients who did not receive Lu-177 DOTATATE had some increase in maximal diameter of 0.5 mm (-2.0 to 2.0) and an increase in SUV max of 1.4 (-6.2 to 2.3). Overall, Lu-177 DOTATATE therapy may result in modest regression of intracardiac metastases as assessed by molecular imaging, whereas patients with cardiac metastases who did not receive therapy appeared to show progression.
2025-08-15 | Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.
cell therapies
2026-08-21 | Giant Necrotic Axillary Metastasis From Pancreatic Neuroendocrine Carcinoma Treated With Palliative Resection and Breast Reconstruction: A Case Report.
Neuroendocrine tumors of the pancreas are rare and can present with atypical metastatic patterns. Axillary involvement is extremely uncommon and requires a diagnosis of exclusion. Furthermore, it can be a therapeutic challenge. We present the case of a 78-year-old woman with a medical history of arterial hypertension, type 2 diabetes mellitus, and Parkinson's disease. She was diagnosed with pancreatic carcinoma with metastatic disease to axillary nodes. The patient developed a massive necrotic axillary tumor, measuring approximately 30 × 30 cm clinically, also associated with erythema, pain, exudate, and local infection. Laboratory tests showed severe anemia (Hb 7.4 g/dL), neutrophilia (95.1%), hyponatremia (Na 132 mmol/L), and hypokalemia (K 2.3 mmol/L). Imaging (contrast-enhanced CT and angio-CT) revealed a well-defined mass displacing the pectoral, deltoid, and serratus muscles; partially compressing the brachial artery with distal recanalization; and measuring approximately 25 cm x 20 cm. Three months after the first diagnosis, the patient underwent a palliative surgery including a block resection of the axillary tumor measuring 26 × 21 × 8 cm and weighing 3000 g. Histopathology results showed a poorly differentiated metastatic neuroendocrine carcinoma with rhabdoid features, extensive necrosis throughout the whole tumor, and positive margins. Immunohistochemistry was also performed and revealed focal enolase positivity, while CD56, p53, and chromogranin were negative. Pancreatic neuroendocrine tumors usually metastasize to the liver, peritoneum, or lymph nodes. Axillary metastasis is extremely rare and has been documented in only a few cases. The presence of a large, necrotic, infected tumor in this location significantly impacts quality of life. Surgical resection, although not curative, may provide substantial pain relief, control local complications, reduce infectious sequelae, and improve quality of life. This particular case highlights an uncommon metastatic site of pancreatic neuroendocrine carcinoma. Awareness of atypical metastatic patterns is essential for more precocious management, and surgical resection can provide substantial palliative benefit in selected patients.
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.
2026-07-08 | Long term survival in three pancreatic cancer patients following Whipple's procedure and allogeneic hematopoietic cell transplantation.
Pancreatic ductal adenocarcinoma (PDAC) is associated with an extremely poor prognosis, with long-term survival being exceedingly rare. Here, we follow-up on three long-term survivors. This study initially included eight patients with PDAC who underwent radical resection via Whipple's procedure with no evidence of distant metastases. Two of these patients received allogeneic hematopoietic cell transplantation (HCT) in a previously published trial. The remaining six patients, who served as controls and did not receive HCT, died of progressive PDAC within one to four years. Additionally, a 60-year-old male with PDAC who underwent partial pancreatectomy and gastrectomy received HCT from a matched unrelated donor. Patient 1 developed mild acute graft-versus-host disease (GVHD) of the skin, followed by chronic GVHD. He subsequently underwent surgery for oral cancer and remains alive 21 years after the initial PDAC diagnosis, with no evidence of recurrence. Patient 2 experienced severe acute gastrointestinal GVHD and recurrent chronic bronchiolitis obliterans. He died of esophageal cancer 19 years after PDAC diagnosis. Patient 3 experienced graft rejection and multiple medical complications, including radical surgery for colorectal cancer, yet remains cancer-free 15 years after PDAC diagnosis. In conclusion, HCT may confer anticancer effects in patients with radically resected PDAC. Further investigations are warranted to confirm its therapeutic value.ClinicalTrials.gov Identifier: NCT02207985.
2026-06-16 | Robotic subtotal pancreatectomy for multifocal neuroendocrine tumour of the pancreas.
Pancreatic neuroendocrine tumours (pNETs) are rare and can be difficult to manage due to their variable presentations. Surgical resection remains the standard treatment for symptom control and reduced risk of recurrence. Minimally invasive robotic surgery has become an alternative to open approaches due to its enhanced three-dimensional visualisation and precision. Most documented cases, however, involve solitary tumours or multifocal disease in patients with genetic syndromes such as MEN-1. We present the case of a woman in her 20s who underwent robotic subtotal pancreatectomy for multifocal pNETs, without evidence of an underlying genetic syndrome. After an uneventful postoperative recovery, the patient was discharged home on day 3. This case contributes to the limited descriptive literature on the presentation and surgical management of sporadic insulinomas.
2026-05-18 | Robot-Assisted Spleen-Preserving Distal Pancreatectomy for an Epithelial Cyst Arising from an Intrapancreatic Accessory Spleen: A Case Report.
Epithelial cysts arising from an intrapancreatic accessory spleen (ECIPAS) are rare and often misdiagnosed as pancreatic cystic neoplasms because their imaging features frequently overlap. When malignancy cannot be ruled out, surgical resection is generally indicated, and minimally invasive approaches have become an appropriate treatment option. We report a case of ECIPAS initially suspected to be a mucinous cystic neoplasm (MCN), successfully treated with spleen-preserving distal pancreatectomy using the hinotori Surgical Robot System. A 63-year-old woman was incidentally found to have an 18-mm cystic lesion in the pancreatic tail during preoperative imaging for laparoscopic cholecystectomy 2 years earlier. The lesion gradually enlarged to 30 mm over 2 years of serial follow-up. MRI demonstrated a "cyst-in-cyst" morphology without communication with the main pancreatic duct. Contrast-enhanced CT revealed a thick-walled cyst with internal septal calcifications but no solid components. Serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were within normal limits. Based on the imaging features and lesion growth, we suspected MCN and indicated surgical resection. Consequently, robot-assisted spleen-preserving distal pancreatectomy (Robo-SPDP) was performed using the hinotori system, following the Kimura technique. The procedure was completed safely without any intraoperative complications. Histopathological examination revealed a cyst lined by flattened to columnar epithelium, with an underlying splenic sinus structure confirmed by CD8 immunostaining. Ovarian-type stroma was absent, excluding MCN and establishing a diagnosis of ECIPAS. The postoperative course was uneventful, and the patient was discharged on POD 10. This case highlights the importance of considering ECIPAS in the differential diagnosis of pancreatic cystic lesions, particularly when imaging findings resemble cystic neoplasms. When malignancy cannot be ruled out, surgical resection is recommended and minimally invasive spleen-preserving distal pancreatectomy is a reasonable therapeutic option. Furthermore, robotic assistance appeared to be a safe and effective surgical approach facilitating precise dissection and reliable preservation of the splenic vessels.
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2026-09-17 | Undifferentiated Carcinoma of the Pancreas With Osteoclast-Like Giant Cells: A Comprehensive Review of Clinical Features, Molecular Pathology, and Therapeutic Advances.
Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells is a rare variant of malignant pancreatic tumor, accounting for less than 1% of all pancreatic tumors. The efficacy of neoadjuvant and adjuvant chemotherapy in patients with undifferentiated carcinoma of the pancreas with osteoclast-like giant cells remains unclear. Preliminary case reports have suggested pembrolizumab may be effective in some metastatic patients, though this requires validation in larger studies. Furthermore, patients with pure undifferentiated carcinoma of the pancreas with osteoclast-like giant cells demonstrate better overall survival rates than those with mixed-type undifferentiated carcinoma of the pancreas with osteoclast-like giant cells containing a pancreatic ductal adenocarcinoma histopathological subtype. Programmed cell death ligand-1 (PD-L1) expression has been identified as a significant determinant that shortens survival in patients with undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, suggesting that anti-PD-1/PD-L1 agents may represent a potential therapeutic approach for this tumor type. This article reviews recent advances in the diagnosis, differential diagnosis, treatment, and prognosis of undifferentiated carcinoma of the pancreas with osteoclast-like giant cells to enhance understanding of this rare tumor entity.
2026-09-11 | Splenic hilum nodal involvement in resected left-sided pancreatic cancer: meta-analysis.
Splenectomy is standard of care during left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) to obtain adequate lymphadenectomy. However, evidence supporting this approach is lacking. Splenic preservation would reduce short-term morbidity and is essential for emerging oncological adjunctive therapies, including immunotherapy and personalized cancer vaccines. This study reviewed the incidence of splenic hilum nodal involvement (SHNI) in left-sided PDAC. A systematic review of the PubMed, Embase, and Cochrane databases was performed, identifying studies published from inception to July 2026. Outcomes of interest were the rate of SHNI (station 10), overall survival, and the rate of splenic artery nodal involvement (SANI; station 11). Meta-analyses were conducted using random-effects models. Subgroup analyses for SHNI were performed per tumour localization (pancreatic neck, body, tail). Among 2776 screened studies, 22 with 2260 patients undergoing left pancreatectomy for PDAC were included. The pooled prevalence of SHNI was 3.7% (95% confidence interval (c.i.) 2.2% to 6.2%); 1.1% for pancreatic body PDAC (95% c.i. 0.3% to 4.3%) and 9.7% for pancreatic tail PDAC (95% c.i. 3.5% to 24.0%). SHNI was not significantly associated with survival (pooled hazard ratio 2.05; 95% c.i. 0.89% to 4.72; P = 0.072). The pooled prevalence of SANI was 39.1% (95% c.i. 25.1% to 55.1%). In patients undergoing left pancreatectomy for PDAC, the presence of SHNI is rare, particularly in pancreatic body cancer (1.1%). These findings suggest that the relevance of routine splenectomy remains unclear, especially for pancreatic body PDAC. However, because the quality of current evidence is low, further investigation in prospective studies is required.
2026-08-27 | DLL3 expression in neuroendocrine carcinomas: a comparative analysis across tumor origins.
Neuroendocrine carcinomas (NECs) are rare and highly aggressive tumors, characterized by a dismal prognosis. Their underlying biology remains insufficiently understood, highlighting an urgent need for the identification of disease markers to enhance diagnostic and prognostic assessments, as well as to identify potential druggable targets. DLL3, an inhibitory regulator of the Notch signalling pathway, has emerged as a promising candidate in this context. We investigated DLL3 prevalence and pattern of expression in immunohistochemistry in NECs from multiple anatomical sites, with a focus on lung and gastroenteropancreatic (GEP) neoplasms. DLL3 was found to be highly expressed in 68.8% of NECs overall, with the highest prevalence observed in GEP-NECs (85.7%). Immunohistochemical analysis revealed predominantly cytoplasmic localization, with a dot-like staining pattern particularly evident in gastrointestinal cases, suggestive of potential localization in neurosecretory granules. DLL3 levels did not significantly correlate with tumor proliferation index nor with overall survival. A correlation with chromogranin A expression was found. Given its high prevalence in extrapulmonary NECs, particularly those of GEP origin, it may have potential as a disease marker and therapeutic target in a clinical context where effective options are currently limited.
2026-07-16 | Solid pseudopapillary neoplasm of the pancreas: A retrospective single-center cohort study of 1,058 consecutive patients.
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, low-grade malignant tumor, predominantly affecting young women. Although the overall prognosis of SPN is good, the understanding of its pathophysiological characteristics and the selection of treatment strategies remain insufficient. A retrospective analysis of 1058 consecutive patients with pathologically confirmed SPN was performed at a single institution. Clinicopathological characteristics, immunohistochemical profiles, targeted sequencing data, and overall survival were systematically evaluated. The median age of the patients at diagnosis was 33 years, with females being the majority (78.1%). Most tumors were located in the body/tail (70.2%), larger than 3 cm (61.9%), while invasive features such as vascular invasion (1.6%), nerve invasion (7.0%), and lymph node metastasis (0.7%) were rare. Early-stage (stage I, II) patients were more common (99.1%). In recent years, the surgical procedures have significantly shifted towards minimally invasive and parenchyma-sparing surgery. The prognosis of SPN was excellent, with a 5-year survival of 97.9%. Molecular analysis revealed nearly universal CTNNB1 mutations (97%). High expression of progesterone receptor (PR, 97.2%) and low expression of estrogen receptor (ER, 7.7%) supported hormone dependence. This large single-center cohort study confirms that SPN is a tumor with low malignant potential, and identifies the key clinicopathological and molecular factors associated with malignant features. Different hormone receptor profiles provide a theoretical basis for exploring hormone receptor-targeted therapy for advanced patients.
2026-06-05 | EWSR1::BEND2 gene fusions characterize a majority of ACTH-producing neuroendocrine neoplasms of the pancreas: A follow-up study and brief review of the recent literature.
ACTH-producing pancreatic neuroendocrine neoplasms (PanNENs) are a rare aggressive subset of panNETs associated with clinical symptoms of ectopic Cushing syndrome. Until recently, their molecular pathogenesis remained poorly understood. Following our prior study highlighting high frequency of gene fusions (mostly EWSR1::BEND2) in them, we herein document our experience with 5 new tumors occurring in 4 women (one of unspecified sex) aged 36 to 79 (median, 45). All presented with clinical and biochemical signs of ectopic Cushing syndrome. Histologically, the tumors corresponded to NET grade 2 (n = 3) and grade 3 (n = 2). At last follow-up, three patients were alive with metastatic disease at 36, 48 and 72 months from initial diagnosis, one died of disease at 50 months and one was disease-free at 15 months. Targeted RNA sequencing revealed an EWSR1::BEND2 fusion in two cases and a possible CSE1L::TAF15 fusion in one. Two tumors were negative for fusions. This small series and review of the recent literature further confirm the significant association between the EWSR1::BEND2 fusions and ectopic ACTH-production in PanNETs with an overall frequency of ectopic Cushing among EWSR1::BEND2 fusion tumors of 70%. Given their highly aggressive course, recognition of this molecular subtype of panNETs is mandatory. Emerging BEND2 IHC represents a promising screening tool for recognizing these tumors.
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2026-08-22 | Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.
Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic 'feed-forward' axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.
2026-07-09 | An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups.
Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.
2026-07-01 | Transcriptomic-based molecular classification of ampullary adenocarcinoma.
Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy with markedly variable clinical outcomes, underscoring the urgent need for molecularly informed classification and personalized therapeutic strategies. Current AMPAC classification relies primarily on morphological and immunohistochemical criteria, which lack prognostic accuracy and fail to capture the underlying molecular and tumor microenvironment heterogeneity. In this study, we integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and clinicopathological data to elucidate the molecular architecture of AMPAC and introduced a transcriptomic-based molecular classification (AMS). The AMS categorized patients into two molecular subtypes: mesenchymal AMPAC (AMS-M) and classical AMPAC (AMS-C). The AMS-M demonstrated increased epithelial-mesenchymal transition (EMT) and stromal activation, correlating with basal-like subtypes associated with unfavorable prognosis. In contrast, AMS-C tumors exhibited metabolic and differentiation programs with relatively preserved immune infiltration. Importantly, we identified MUC16 as a pivotal biomarker specifically overexpressed in AMS-M tumors. MUC16 knockout markedly reversed EMT, attenuated invasive and migratory capacities, and restored chemosensitivity in both cell lines and their xenograft models. Collectively, our findings establish AMS as a prognostically and therapeutically informative molecular classification framework for AMPAC, unveil the critical role of the tumor microenvironment in AMPAC heterogeneity, and provide a translational foundation for precision oncology in this rare tumor.
2025-10-10 | Late-stage hepatoid adenocarcinoma of the pancreatic head with a long survival after surgery: a case report.
Hepatoid adenocarcinoma of the pancreas is a rare primary malignant tumor. According to few previous reports, with poor prognosis and atypical clinical features, hepatoid adenocarcinoma of the pancreas is easily misdiagnosed. Its pathological examination often shows similar morphological and immunohistochemical features to those of hepatocellular carcinoma. There is also insufficient clinical experience in the diagnosis and treatment of hepatoid adenocarcinoma. A 45-year-old Asian woman, initially suspected to have late-stage pancreatic ductal adenocarcinoma, was admitted to our clinic with abdominal pain and jaundice. The magnetic resonance imaging scan showed a pancreatic head mass with enlarged retroperitoneal and portal lymph nodes. To confirm the diagnosis, a thorough evaluation of her medical history, clinical presentation, imaging findings, and laboratory tests was conducted. An endoscopic ultrasound-guided biopsy was performed, and the initial biopsy report suggested a neuroendocrine tumor. Based on this finding, a multidisciplinary team discussion was held, and the decision was made to proceed with radical surgery. Postoperative pathological examination unexpectedly revealed hepatoid adenocarcinoma of the pancreas, which led to a revision of the final clinical diagnosis. Following surgery, she received three cycles of postoperative adjuvant chemotherapy with a regimen of gemcitabine plus albumin-bound paclitaxel. Postoperative follow-up at 4 months indicated liver metastasis, for which she underwent microwave ablation. Subsequently, she was supplemented with adjuvant therapy combining durvalumab and S-1. At the time of writing, 16 months after her initial clinic visit, the patient remains alive without evidence of abdominal metastasis. This case of hepatoid adenocarcinoma of the pancreas achieved a better prognosis through a comprehensive treatment based on surgery after multidisciplinary team discussion, giving the patient hope for long-term survival. The multidisciplinary team, in the form of multidisciplinary experts coming together to discuss the patient's condition, changed the patient's treatment decision, which may be another option when it comes to complex cases.
2025-08-08 | Gastric ectopic pancreatic ductal adenocarcinoma coexisted with endometriosis mimick advanced disease: a case report and literature review.
Ectopic pancreas (EP) is most commonly located in the upper gastrointestinal tract, particularly in the stomach. Malignant transformation of EP is exceptionally rare, and due to its very low incidence, the response to drug therapy and overall prognosis remain poorly understood. This report presents a case of gastric ectopic pancreatic ductal adenocarcinoma. Unusually, the patient also had concurrent endometriosis, which caused the tumor to resemble advanced cancer on imaging. Although over 50 cases of malignant transformation of EP have been documented. Nevertheless, it has not been definitively established which drug therapeutic regimens is effective for this disease. This is the first to detail the tumor's response to anti-tumor drug therapy. Pancreatic cancer is generally resistant to anti-tumor drugs. However, in this case, the tumor arising from EP regressed following treatment with immune checkpoint inhibitors (ICIs) combined with chemotherapy. This observation highlights differences in the biological behavior of these two tumor types.
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Drug Discovery Landscape
24 orphan drug designations for Rare tumor of pancreas.
24 orphan drug designations for Rare tumor of pancreas.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
anti-tissue factor monoclonal antibody conjugated to topoisomerase I inhibitor | antibodies | FDA | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | |
Quemliclustat | small molecules | EMA | Arcus Biosciences Europe Limited | |
Daraxonrasib | small molecules | EMA | Revolution Medicines Netherlands B.V. | |
selective p53 reactivator targeting p53 Y220C mutation | small molecules | FDA | — | Changchun GeneScience Pharmaceutical Co., Ltd. |
recombinant humanized IgG1k monoclonal antibody targeting parathyroid hormone-related protein (PTHrP) | antibodies | FDA | — | BioGate Precision Medicine Corp. |
Recombinant human interleukin-7 fused to a hybrid crystallizable fragment region of a human antibody (rhIL-7-hyFc) | proteins | FDA | NeoImmuneTech | |
elraglusib | small molecules | FDA | Actuate Therapeutics, Inc. | |
Paclitaxel, polyoligo(ethylene glycol)methacrylate-co-poly(vinylbenzyldithiodibutyric acid-gemcitabine) | small molecules | EMA | — | Duo Oncology Europe B.V. |
N-hydroxy-N-(methylacylfulvene)urea | small molecules | FDA | Lantern Pharma, Inc. | |
Racemetyrosine | small molecules | FDA | Tyme Technologies, Inc. | |
anti-EGFR VHH Fragment Fused to Cytosine Deaminase | proteins | FDA | — | Lumosa Therapeutics Co., Ltd. |
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)piperidine-1-carboxylate | small molecules | FDA | Tarveda Therapeutics, Inc. | |
doranidazole | small molecules | FDA | — | Shuttle Pharmaceuticals, Inc. |
4-amino-1-[(1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl]pyrimidin-2-one | small molecules | EMA | IQVIA RDS Ireland Limited | |
pegylated recombinant human interleukin-10 | proteins | FDA | Eli Lilly and Company | |
tarextumab | antibodies | FDA | OncoMed Pharmaceuticals, Inc. | |
Istiratumab | antibodies | FDA | Merrimack Pharmaceuticals, Inc. | |
recombinant human monoclonal antibody of the IgG1 kappa class against prostate stem cell antigen | antibodies | FDA | Astellas Pharma Global Development, Inc. | |
12-A-p21 RAS(5-21). 12-C-p21 RAS(5-21). 12-D-p21 RAS(5-21). 12-Rp21 RAS(5-21). 12-S-p21 RAS(5-21). 12-V-p21 RAS(5-21). 13-D-p21 RAS(5-21) | vaccines | FDA | Targovax Solutions AS, a subsidiary of Targovax ASA | |
mycobacterium vaccae | other | FDA | Immodulon Therapeutics Ltd. | |
Replication-incompetent GM-CSF-expressing gene-modified allogeneic pancreatic cancer cell lines | cell therapies | FDA | Aduro BioTech, Inc. | |
Gastrin 17C Diphtheria Toxoid Immunogen | vaccines | FDA | Astrimmune Ltd. | |
Paclitaxel (liposomal) | small molecules | EMA | SynCore Biotechnology Europe GmbH | |
N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maystansine-Conjugated Humanized C242 Monoclonal Antibody | antibodies | FDA | — | SmithKline Beecham Pharmaceuticals |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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