RARE DISEASE
Rare pancreatic disease
Rare pancreatic disease
Rare pancreatic disease
Drug discovery
1
drug
With orphan designation
Overview
Rare pancreatic cancers encompass distinct histologic subtypes such as acinar cell, adenosquamous, colloid, medullary, and signet ring cell carcinomas, representing <15% of pancreatic malignancies [1][15]. These tumors exhibit non-overlapping molecular profiles and clinical behaviors compared to pancreatic ductal adenocarcinoma (PDAC), with some requiring tailored therapeutic approaches due to differential aggressiveness, drug sensitivity, or genetic drivers [1][15]. Diagnosis relies on histopathology and molecular testing to guide management.
Population
Burden
Aggressive clinical courses: >60% present with metastases, contributing to 5-year survival <10% for most subtypes [1][15]
Significant healthcare costs: Late diagnosis and complex treatments account for elevated economic burden [9][14]
Projected 2-fold increase in pancreatic cancer mortality by 2060, with rare subtypes under-represented in epidemiological data [4][12]
Categories: rare gastroenterological diseases
Research Papers
2,345 drug discovery papers about Rare pancreatic disease, with 5 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
2,345 drug discovery papers about Rare pancreatic disease, with 5 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | VIPoma Presenting With Obstructive Jaundice: A Case Report.
VIPoma is a rare pancreatic neuroendocrine tumor characterized by the overproduction of vasoactive intestinal peptide (VIP), typically manifesting as watery diarrhea, hypokalaemia and metabolic acidosis. Its presentation can be atypical, complicating diagnosis. We report the case of a 30-year-old male who initially presented with obstructive jaundice and fatigue, with imaging revealing a pancreatic head mass and liver metastases. Histopathological analysis confirmed a lowgrade pancreatic neuroendocrine tumor. The clinical course was complicated by portal vein thrombosis and metastatic spread. Six months later, the patient developed persistent, refractory watery diarrhea with associated hypokalaemia. Elevated serum VIP levels and Gallium-68 DOTATATE positron-emission tomography and computed tomography (PET-CT) supported the diagnosis of VIPoma. Symptom resolution was achieved with subcutaneous octreotide, followed by transition to monthly long-acting release (LAR) octreotide. Approximately 60% of VIPoma cases are metastatic at the time of diagnosis, as demonstrated in this patient. The case highlighted the diagnostic challenges of VIPoma in the presence of atypical symptoms such as jaundice and absence of initial diarrhea. It also underscores the need for close multidisciplinary collaboration to determine the best course of action and to optimize patient outcomes.
2026-09-25 | Concurrent EGFR exon 19 deletion-insertion and germline BRCA1 alteration in KRAS-wild-type pancreatic ductal adenocarcinoma: A case report and review of therapeutic implications.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, with a dismal prognosis and a 5-year overall survival rate of 5-10%. Owing to the absence of specific symptoms at early stages, the majority of patients are first diagnosed with already locally advanced or metastatic disease. Consequently, such patients are ineligible for curative surgery, resulting in limited therapeutic options and poor outcomes. With advances in molecular profiling and next-generation sequencing, precision medicine has emerged as an important therapeutic approach for advanced PDAC. Targeted therapies directed against specific molecular alterations, including BRCA1/2, HER2 and KRAS, have demonstrated clinical benefit in selected patient populations. However, current evidence predominantly focuses on single gene alterations. There is a lack of data and consensus regarding the optimal treatment strategies for PDAC harboring concurrent multiple genomic aberrations. In the present report, a rare case of KRAS wild-type PDAC harboring a somatic EGFR exon 19 deletion-insertion mutation, a heterozygous germline BRCA1 splice-site mutation and an additional somatic synonymous TP53 variant identified by molecular testing was documented. The patient developed clinically suspected postoperative recurrence and subsequently achieved durable disease control following individualized exploratory treatment with aumolertinib and olaparib. The present case provides a clinically documented observation of individualized targeted therapy in a rare KRAS wild-type PDAC molecular context and may help inform future hypothesis-driven investigations in selected molecularly defined patients. However, further studies are required to clarify the functional relevance of these molecular alterations and the clinical value of this treatment approach in selected patients with molecularly unique PDAC.
2026-09-25 | Functioning pancreatic neuroendocrine neoplasms: Diagnosis and current treatment.
Pancreatic functioning neuroendocrine neoplasms (PanNENs) are rare and characterized by variable and heterogeneous clinical manifestations, comprising both symptoms and signs of tumor growth and systemic manifestations of hormonal hypersecretion. The diagnosis is challenging due to their rarity, neoplasm localization and diverse secretory profile. A subset of these neoplasms may develop in the context of inherited syndromes and harbor specific genetic alterations requiring genetic counseling of other family members. These particular features make the management of patients with a functioning PanNEN syndrome requiring a multidisciplinary approach. Surgical resection of local disease, antisecretory medical treatment, locoregional treatment and systemic treatments are employed on an individualized basis. The treatment landscape of advanced NENs progressing after systemic treatment or after exhibiting intolerance to sequential lines of treatment is rapidly evolving supporting the introduction of additional therapies with promising results.
2026-09-24 | Pathological complete response after nanoliposomal irinotecan plus fluorouracil/leucovorin and conversion surgery in borderline resectable pancreatic head adenocarcinoma: a case report.
Nanoliposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has become an established regimen for pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy; however, complete response remains exceptionally rare. Here, we describe a 70-year-old female patient under surveillance for branch-duct intraductal papillary mucinous neoplasm who developed a new hypovascular pancreatic head mass (~ 30 mm) with > 180° contact to the portal vein, consistent with borderline resectable PDAC. Adenocarcinoma was confirmed by endoscopic ultrasound-guided tissue acquisition. Initial therapy comprised gemcitabine plus nab-paclitaxel, but the patient showed radiographic and biochemical progression. Modified FOLFIRINOX (oxaliplatin, irinotecan, leucovorin (LV), and 5-fluorouracil (5-FU)) was attempted as second-line therapy, but discontinued after one cycle due to Grade 3 myelosuppression and severe fatigue. Subsequently, nal-IRI + 5-FU/LV was administered as third-line therapy for 10 cycles and toxicity was manageable. Follow-up contrast-enhanced computed tomography revealed marked tumor regression and resolution of previously observed right lower-lobe pulmonary opacity. Following multidisciplinary reassessment and with informed consent, subtotal stomach-preserving pancreaticoduodenectomy was performed. The resected specimen showed a 13 mm fibrotic scar without residual viable carcinoma and no lymph node metastasis was identified, meeting criteria for pathological complete response. At 25-month follow-up, the patient remained disease-free. This case provides evidence that nal-IRI + 5-FU/LV may induce profound tumor regression in carefully selected patients with preserved performance status and favorable baseline factors, enabling potentially curative resection after failure or intolerance to standard first-line regimens.
2026-09-13 | Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring.
Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers. We describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans. She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m2, annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55-59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response. Persistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.
cell therapies
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.
2026-05-28 | Successful treatment with plasmapheresis of severe hypertriglyceridemic acute pancreatitis complicated by fat overload syndrome caused by lipid injectable emulsion: a case report and review of the literature.
Hypertriglyceridemic acute pancreatitis (HTG-AP) and fat overload syndrome caused by lipid injectable emulsion (ILE) are rare in clinical practice. Although the treatment of HTG-AP with plasmapheresis has previously been reported, only a few reports describe the application of plasmapheresis to treat HTG-AP and fat overload syndrome caused by ILE. We report a case diagnosed with severe HTG-AP and fat overload syndrome, based on laboratory findings and abdominal computed tomography, caused by intravenous infusion of ILE for about 3 weeks without monitoring of serum triglyceride (TG) levels in a 78-year-old Chinese female patient with a history of esophageal cancer. Conventional treatments were attempted; however, the patient progressively developed worsening abdominal pain and notably elevated inflammatory biomarkers, including C-reactive protein and procalcitonin levels. Plasmapheresis treatment was performed immediately to lower serum TG levels and prevent the complication of acute pancreatitis (AP) due to hypertriglyceridemia. After two consecutive plasmapheresis sessions, the patient's TG and total cholesterol levels remarkably decreased to 13.57 and 8.62 mmol/L, respectively. She also showed considerable improvement in her abdominal symptoms. HTG-AP and fat overload syndrome can be associated with intravenous infusion of ILE. Monitoring serum TG levels while utilizing ILE is necessary. Plasmapheresis should be considered an effective treatment measure for severe HTG-AP or fat overload syndrome caused by ILE, because it rapidly lowers serum TG levels and may prevent to be useful in ameliorating the course of acute pancreatitis.
2026-04-17 | One-step knock-in CAR constructs in human NK cells enable scalable, TGFβ1-resistant immunotherapy for solid tumors.
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising modality for cancer immunotherapy, yet their efficacy in solid tumors is limited by immunosuppressive cues from the tumor microenvironment (TME), particularly, transforming growth factor β (TGFβ). Primary human NK cells were cytokine-activated (IL-12/15/18) and engineered via a one-step electroporation that delivered Cas9 ribonucleoprotein and a dsDNA donor (1 kb homology arms, SFFV promoter, poly(A), GRE element) to knock out TGFBR2 and knock in a mesothelin CAR. We compared against a two-step AAV method, and treated dexamethasone (Dex) during manufacture. Anti-tumor function was assessed using AsPC-1 cancer killing assays, patient-derived pancreatic cancer organoids (caspase-3/7 imaging, luciferase viability, live/dead FACS), and multi-omics profiling (RNA-seq, ATAC-seq, GSEA) to evaluate metabolic and transcriptional modifications. We report a streamlined, one-step strategy that simultaneously disrupts the TGFβ receptor II (TGFβRII) and integrates a mesothelin-targeting CAR transgene into primary NK cells via electroporation. By optimizing single-guide RNAs, donor DNA templates incorporating glucocorticoid response elements, and electroporation parameters, we achieved markedly improved knock-in efficiency. Transient Dex treatment during genome editing enhanced CAR expression and cytotoxic function in both electroporation- and AAV-mediated platforms. Dex augmented the cytotoxic activity of CAR-NK cells by promoting oxidative phosphorylation and ATP production. We designed robust, TGFβ1-resistant allogeneic CAR-NK cells using a virus-free, one-step engineering strategy, establishing a versatile, clinically scalable method for engineering metabolically fortified CAR-NK cells capable of overcoming TME-mediated suppression in solid tumors.
2026-02-19 | CD177+ neutrophils alleviate acute pancreatitis-associated lung injury by protecting colonic barrier and restoring gut microbiota.
Altered neutrophil infiltration and function are associated with the deterioration of acute pancreatitis (AP) and even AP-associated lung injury. Although CD177 is a marker of neutrophil activation, its role in AP remains largely unknown. To determine whether ablation of Cd177 could deteriorate colonic barrier dysfunction, changes in the gut microbiota, and AP-associated lung injury, Cd177 knock-out (KO), Cd177 conditional knock-out (cKO) in circulating neutrophils and pseudo-germ-free (antibiotic therapy, or ABX-treated) mouse models were used in this study. AP was induced in mice through injection of sodium taurocholate retrogradely into the pancreatic duct, then peripheral blood, pancreas, lung, colon tissues and fecal samples were collected at 24 h after induction, respectively. The mRNA and protein expression of certain genes and gut microbiota of mice were measured. Results indicated that both Cd177 KO and cKO increased serum amylase and lipase levels, exacerbated pathological damage, and impaired the integrity of the colonic mucosal barrier in AP mice, suggesting a protective role of neutrophil-derived CD177 in AP progression. In addition, ABX-treated mice alleviated AP-associated lung injury, demonstrating that gut microbiota dysbiosis may contribute to the deterioration of phenotypes. Moreover, ablation of Cd177 was associated with reduced abundance of gut microbiota species g_Atopostipes, downregulated Nos1ap expression in the lung and Sorbs1 expression in the colon, consequently aggravating the damage of colon and lung of mice with AP. It is concluded that Cd177+ neutrophils may ameliorate AP-associated lung injury through protecting colonic barrier and modulating certain gut microbiota and associated genes in mice.
proteins
2026-09-15 | Pediatric Gastroenteropancreatic Neuroendocrine Tumors in Jordan: A 19-Year Experience From a Tertiary Oncology Center.
Pediatric gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are exceedingly rare. Data from Jordanian and Arab world populations are absent from international registries, with only limited data available from Türkiye, leaving management strategies largely extrapolated from adult and Western literature. This study documents the clinical features, management, and outcomes at a tertiary oncology center in Jordan. We conducted a retrospective, single-center cohort study of patients 18 years or younger diagnosed with GEP-NETs at the King Hussein Cancer Center (January 2006 to May 2025). We analyzed demographics, presentation, tumor characteristics, treatment, and survival. Ten patients were identified (8 male, median age 13 y). Primary sites were the appendix (8/10) and pancreatic head (2/10). Nine patients presented with abdominal pain; one with a pancreatic primary presented with obstructive jaundice. Histologically, 9 were low- or intermediate-grade (grade 1 to 2) and 9 were localized. Nine patients underwent surgery (8 appendectomy±hemicolectomy; 1 Whipple procedure). One patient with metastatic pancreatic NET was managed nonsurgically. Two patients with advanced/metastatic pancreatic NETs received systemic therapy. Appendiceal tumors were universally indolent with excellent outcomes postsurgery, whereas pancreatic tumors exhibited aggressive clinical behavior, including nodal involvement and distant metastasis. After a median follow-up of 46.6 months, 1 patient died of metastatic disease and 1 developed recurrence; both had pancreatic primaries. Pediatric appendiceal NETs carry excellent prognoses following conservative surgery. Pancreatic NETs represent a high-risk subgroup with aggressive behavior. As the first documented GEP-NET from Jordan and the Arab world, these findings align with international patterns and support site-specific, risk-adapted management while highlighting the need for multicenter collaboration across the region.
2026-09-03 | Size alone is not enough: Ki-67 and invasion patterns identify high-risk pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine tumors (pNETS) constitute a heterogeneous and rare disease worldwide. Diagnosis rates have been increasing, and the evaluation of prognostic factors has become even more important in the treatment decision-making process. To present results and prognostic factors in patients undergoing surgical treatment for pNETS at a single Brazilian center. The most frequently performed surgical procedure was PCC+S 60.0%. The median hospital stay was 8 (5-13) days, and postoperative mortality occurred in 1.7%. Overall survival in 3 and 5 years was 93.8 and 92.1%, respectively. Disease-free survival at 3 and 5 years was 87.1 and 71.8%, respectively. Patients with tumors smaller than 2.0 cm did not present with lymph node disease or recurrence, and patients with tumors measuring 2.1-2.5cm had lymph node disease in 11.1% and recurrence in 11.1%. In univariate and multivariate analysis, the presence of lymphatic and perineural invasion and Ki67 (3-20) were strongly correlated with positive lymph node disease and recurrence, respectively. The presence of lymphatic and perineural invasion, Ki67 (3 to 20), and tumors larger than 2.5 cm correlated with positive lymph node disease and recurrence.
2026-08-21 | Solid Pseudopapillary Neoplasm of the Pancreas: Diagnostic Concordance and Clinicopathologic Correlation of Fine-Needle Aspiration and Long-Term Outcomes.
Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor with low malignant potential and unclear cell of origin and pathogenesis. Fine-needle aspiration (FNA) is frequently used for preoperative diagnosis, yet correlation with resection specimens and long-term follow-up remains limited in the literature. We retrospectively identified all patients diagnosed with SPN by pancreatic FNA at a single institution (2016-2025). Cytology preparations included smears with or without rapid on-site evaluation and ancillary immunohistochemistry performed on cell blocks when available. Surgical pathology, when performed, was reviewed for diagnostic concordance and adverse features. Clinical outcomes were assessed by chart review. Seven patients were identified (female-to-male ratio = 6:1; median age = 29 years, range = 18-53 years). Tumors most commonly involved the tail (5/7) and measured a median of 6.0 cm (range = 2.6-14.0). Pancreatic FNA rendered a definitive diagnosis of SPN in six cases (6/7). Six patients underwent resection, and surgical pathology confirmed SPN in all resected tumors (6/6). Lymphovascular invasion was absent in all resected cases; perineural invasion was present in one case. At last follow-up (median = 41 months, range = 4-119), all patients were alive. One patient developed liver metastasis eight years after the initial diagnosis. Pancreatic FNA demonstrated excellent diagnostic concordance and clinicopathologic correlation for SPN with available resections. Despite overall indolent behavior, late metastatic disease can occur, supporting the need for long-term surveillance.
2026-08-07 | SMARCB1 (INI1)-deficient Rhabdoid Pancreatic Carcinoma: A Rare Subtype of Pancreatic Cancer
Rhabdoid pancreatic carcinoma (RPC) is a rare and highly aggressive subtype of undifferentiated pancreatic carcinoma characterized by rhabdoid morphology and frequent loss of SWItch/sucrose non-fermentable chromatin-remodeling complex-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), integrase interactor 1 (INI1) expression.Due to its rarity, its clinicopathological characteristics and optimal management remain poorly defined.A 56-year-old woman with an Eastern Cooperative Oncology Group performance status of 1 presented with a one-month history of abdominal and back pain.Contrast-enhanced computed tomography revealed an infiltrative pancreatic head mass measuring 125×52×75 mm, with vascular involvement and multiple metastatic lymph nodes.Histopathological examination demonstrated RPC, with complete loss of nuclear SMARCB1 (INI1) expression by immunohistochemistry. Comprehensive next-generation sequencing showed KRAS wild-type status.The patient received modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) chemotherapy and achieved partial regression of metastatic abdominal lymph nodes after six cycles.Treatment was continued for a total of 12 cycles before disease progression was documented.This case highlights the aggressive clinical behavior and distinctive molecular profile of SMARCB1 (INI1)-deficient RPC.The observed partial response to mFOLFIRINOX suggests that selected patients may derive temporary benefit from systemic chemotherapy; however, durable disease control remains challenging.Increased recognition of this rare entity and further investigation of molecularly targeted and immunotherapeutic strategies are needed to improve outcomes.
2026-07-28 | Drug-specific differences in fatal adverse events among PARP inhibitors: a FAERS pharmacovigilance study.
Poly(ADP-ribose) polymerase inhibitors (PARPi) are widely used in the treatment of multiple malignancies; however, their fatal adverse event profiles remain incompletely characterized in real-world settings. Evidence regarding drug-specific differences in fatal toxicity is limited. This study aimed to comprehensively evaluate fatal adverse events associated with PARPi, focusing on the overall fatal burden across individual agents, drug-specific fatal toxicity signatures at system organ class (SOC) and preferred term (PT) levels, and the temporal dynamics of fatal events. Adverse event reports associated with olaparib, niraparib, rucaparib, and talazoparib were extracted from the FDA Adverse Event Reporting System (FAERS) database. Fatal and non-fatal cases were compared in terms of demographic and clinical characteristics. The proportion of fatal reports and reporting odds ratios (RORs) were calculated to assess drug-specific differences. SOC distribution and PT-level disproportionality analyses (cases ≥ 30, ROR > 1.5, FDR < 0.05) were performed to identify fatal toxicity signatures. Principal component analysis (PCA) and hierarchical clustering were used to evaluate similarity patterns. Time-to-onset (TTO) was analyzed using violin plots and kernel density estimation. A total of 25,413 reports were included, comprising 5,930 fatal and 19,483 non-fatal cases. Fatal reports were more common in older patients and in those with prostate and pancreatic cancers. The proportion and reporting odds of fatal events varied across PARPi, with olaparib showing a higher fatal reporting odds (OR = 1.29, 95% CI: 1.03-1.63) compared with talazoparib, whereas niraparib and rucaparib demonstrated significantly lower odds. Hematologic toxicities were consistently enriched across agents, supporting a class effect, while non-hematologic toxicities showed substantial heterogeneity. Olaparib was characterized by rare but highly enriched fatal events (e.g., interstitial lung disease, pneumonitis, thrombosis), whereas niraparib exhibited more frequent but moderately increased risks. PCA revealed clear separation of toxicity profiles among agents. Fatal events generally occurred later than non-fatal events, particularly for olaparib (median TTO: 84 vs 48 days, p < 0.001). Fatal adverse event profiles differ across PARPi, reflecting both shared class effects and drug-specific heterogeneity. These findings highlight the importance of individualized safety assessment and sustained monitoring during PARPi therapy.
antibodies
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.
2026-08-28 | Biomarker-driven immunotherapy and adoptive cell therapy in recurrent pancreatic ductal adenocarcinoma.
Recurrent pancreatic ductal adenocarcinoma (PDAC) includes circulating tumor DNA (ctDNA)-defined molecular residual disease (MRD), isolated or oligometastatic relapse, disseminated measurable recurrence, and heavily pretreated refractory disease. These states differ in tumor burden, treatment urgency, tissue accessibility, and immune competence and should not be treated as one population. Immune checkpoint blockade has minimal activity in unselected PDAC, and randomized trials have not shown consistent benefit from adding checkpoint inhibitors to chemotherapy. However, rare microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors and selected antigen- or human leukocyte antigen (HLA)-defined subgroups support precision immune intervention. This Mini Review evaluates biomarkers for immunotherapy and adoptive cell therapy, including ctDNA kinetics, tumor mutational burden, KRAS and neoantigen profiles, antigen presentation and target-antigen density, effector immune state, myeloid and fibroblast-mediated suppression, and spatial immune exclusion. It compares checkpoint blockade, personalized and KRAS-directed vaccines, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor natural killer-cell (CAR-NK), and T-cell receptor (TCR)-engineered therapies by recurrence setting, evidence maturity, feasibility, and failure mechanisms. Checkpoint blockade is currently most defensible for MSI-H/dMMR disease; vaccines and cell therapies remain investigational and are best tested in biomarker-selected trials, especially in low-burden or molecular recurrence. We propose a five-step workflow to classify recurrence, identify actionable biomarkers, match evidence-appropriate interventions, assess feasibility, and monitor response and immune escape. This framework supports trial design and disciplined clinical translation rather than empiric immunotherapy in unselected recurrent PDAC.
2026-08-14 | Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies.
Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
2026-07-17 | Neutrophil extracellular traps induced by tumour-derived NGAL reprogram CAF subtypes via ITGA5 to promote tumour progression in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to immune checkpoint blockade, owing to its immunosuppressive tumour microenvironment. Neutrophil extracellular traps (NETs) accumulate in PDAC and correlate with disease progression, yet whether NETs reprogram cancer-associated fibroblast (CAF) heterogeneity and the upstream tumour-intrinsic signals that sustain pathological NETosis remain undefined. To delineate how NETs instruct CAF subtype specification and immunosuppression in PDAC, identify upstream NETosis drivers and evaluate combinatorial therapeutic strategies targeting this axis. Quantitative spatial analysis of human PDAC specimens, NETs-pancreatic stellate cell and patient-derived CAF cocultures, biotinylated DNA pull-down with liquid chromatography-tandem mass spectrometry, live-cell integrin-blocking assays, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing, orthotopic and hepatic colonisation models, CD8+ T-cell functional assays and single-cell RNA sequencing of an eight-arm therapeutic study were employed. NETs-DNA directly engaged integrin α5β1 (ITGA5) on fibroblasts via its N-terminal domain, initiating a FAK (focal adhesion kinase)/SRC (Src family tyrosine kinase)-YAP (Yes-associated protein)-IL-6 (interleukin-6)-JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) autocrine cascade specifying inflammatory CAF (iCAF) differentiation. Tumour-derived neutrophil gelatinase-associated lipocalin (NGAL), induced by IL-17, drove extracellular signal-regulated kinase (ERK)-reactive oxygen species-mediated NETosis. NETs-reprogrammed iCAFs accelerated tumour growth, hepatic colonisation and CD8+ T-cell exhaustion, with exhausted T cells spatially enriched in iCAF-rich regions. A composite NETs/ITGA5 signature stratified overall survival in patients with PDAC. Single-cell transcriptomics demonstrated that triple therapy (anti-IL-17+AV3+anti-PD-1) shifted fibroblasts from iCAF towards myofibroblastic CAF dominance, restored CD8+ T-cell effector programmes and achieved the greatest tumour suppression and survival benefit. We define an IL-17/NGAL/NETs/ITGA5 axis linking neutrophil-derived extracellular DNA to iCAF specification and immunosuppression in PDAC. Cotargeting IL-17 and ITGA5 synergises with PD-1 blockade, providing a rationale for combinatorial immunotherapy.
2026-07-06 | A Case of Pancreatic Cancer with High Tumor Mutation Burden Showing a Remarkable Response to Pembrolizumab.
Pancreatic cancer (PC) is an aggressive malignancy with limited therapeutic options and generally poor responsiveness to immune checkpoint inhibitors (ICIs). Microsatellite instability-high (MSI-High) and tumor mutation burden-high (TMB-High) phenotypes are rare, each occurring in approximately 1% of PC cases, but may predict improved response to ICIs. We report a case of recurrent PC harboring both MSI-High and markedly elevated TMB, in which pembrolizumab achieved an exceptional and durable response. A 72-year-old man presented with appetite loss, and contrast-enhanced CT revealed a large pancreatic tail tumor invading the stomach, colon, spleen, and left kidney. Fine-needle biopsy confirmed adenocarcinoma. Despite initial modified FOLFIRINOX therapy showing progressive disease, subsequent gemcitabine plus nab-paclitaxel achieved partial response (PR). However, gastrointestinal bleeding due to gastric invasion necessitated surgery. The patient underwent extensive resection, including distal pancreatectomy with splenectomy, total gastrectomy, partial colectomy, nephrectomy, adrenalectomy, and portal vein resection and reconstruction using the left renal vein. Pathology demonstrated well-differentiated ductal adenocarcinoma with multiorgan invasion and portal vein tumor thrombus (ypT3N1M0, Stage IIB, Evans Grade IIb). Although adjuvant chemotherapy was considered, it could not be initiated because of persistent postoperative diarrhea and delayed recovery of the patient's general condition. Four months after surgery, recurrence was detected in the para-aortic lymph nodes, with suspected peritoneal dissemination causing right hydronephrosis, accompanied by elevated carbohydrate antigen 19-9 (CA19-9). Comprehensive genomic profiling using the surgically resected tumor specimen revealed MSI-High status and extremely high TMB (75 mutations/Mb), and genomic alterations in MSH2, MSH3, KRAS, TP53, ARID1A, ATR, and SMAD2. Pembrolizumab was initiated, leading to rapid normalization of CA19-9 and continuous tumor shrinkage. The best overall response was classified as PR, and this PR has been maintained. At 26 months after surgery, the patient remains on pembrolizumab with sustained clinical benefit and no significant immune-related adverse events. This case highlights the potential for exceptional and durable response to pembrolizumab in PC characterized by concurrent MSI-High and markedly elevated TMB. Given the rarity of these biomarkers and the typically poor prognosis of PCs, early genomic profiling may facilitate personalized treatment strategies and improve outcomes in selected patients.
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.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-04-22 | Severe Familial Chylomicronemia Syndrome With Refractory Hypertriglyceridemia and Multisystem Complications Managed With Chronic Plasmapheresis and Olezarsen: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease.
2026-03-28 | A clinically relevant retrograde intraductal injection (RIDI) for lipid nanoparticles-mediated base editing in the pancreas.
Gene therapy offers potential curative strategies for many pancreatic diseases, including diabetes and inherited pancreatitis. However, their clinical translation has been hindered by the lack of an effective delivery platform. Lipid nanoparticles (LNPs) are established as a leading non-viral delivery system for nucleic acids; however, their tropism is limited to the liver following systemic administration. In this study, we evaluated retrograde intraductal injection (RIDI), a clinically relevant and routinely performed endoscopic technique, as a direct delivery route for LNPs into pancreatic tissue. RIDI of Cre mRNA-loaded LNPs resulted in the transfection of approximately 47% of acinar cells, leading to robust recombination. Extending this approach to gene editing, we observed ~20-30% of gene editing and 5% base editing in mouse models. Collectively, these findings establish RIDI as a viable strategy for pancreas-targeted LNP administration, highlighting its potential to enable gene therapy and gene editing in pancreatic diseases.
small molecules
2026-09-28 | VIPoma Presenting With Obstructive Jaundice: A Case Report.
VIPoma is a rare pancreatic neuroendocrine tumor characterized by the overproduction of vasoactive intestinal peptide (VIP), typically manifesting as watery diarrhea, hypokalaemia and metabolic acidosis. Its presentation can be atypical, complicating diagnosis. We report the case of a 30-year-old male who initially presented with obstructive jaundice and fatigue, with imaging revealing a pancreatic head mass and liver metastases. Histopathological analysis confirmed a lowgrade pancreatic neuroendocrine tumor. The clinical course was complicated by portal vein thrombosis and metastatic spread. Six months later, the patient developed persistent, refractory watery diarrhea with associated hypokalaemia. Elevated serum VIP levels and Gallium-68 DOTATATE positron-emission tomography and computed tomography (PET-CT) supported the diagnosis of VIPoma. Symptom resolution was achieved with subcutaneous octreotide, followed by transition to monthly long-acting release (LAR) octreotide. Approximately 60% of VIPoma cases are metastatic at the time of diagnosis, as demonstrated in this patient. The case highlighted the diagnostic challenges of VIPoma in the presence of atypical symptoms such as jaundice and absence of initial diarrhea. It also underscores the need for close multidisciplinary collaboration to determine the best course of action and to optimize patient outcomes.
2026-09-25 | Concurrent EGFR exon 19 deletion-insertion and germline BRCA1 alteration in KRAS-wild-type pancreatic ductal adenocarcinoma: A case report and review of therapeutic implications.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, with a dismal prognosis and a 5-year overall survival rate of 5-10%. Owing to the absence of specific symptoms at early stages, the majority of patients are first diagnosed with already locally advanced or metastatic disease. Consequently, such patients are ineligible for curative surgery, resulting in limited therapeutic options and poor outcomes. With advances in molecular profiling and next-generation sequencing, precision medicine has emerged as an important therapeutic approach for advanced PDAC. Targeted therapies directed against specific molecular alterations, including BRCA1/2, HER2 and KRAS, have demonstrated clinical benefit in selected patient populations. However, current evidence predominantly focuses on single gene alterations. There is a lack of data and consensus regarding the optimal treatment strategies for PDAC harboring concurrent multiple genomic aberrations. In the present report, a rare case of KRAS wild-type PDAC harboring a somatic EGFR exon 19 deletion-insertion mutation, a heterozygous germline BRCA1 splice-site mutation and an additional somatic synonymous TP53 variant identified by molecular testing was documented. The patient developed clinically suspected postoperative recurrence and subsequently achieved durable disease control following individualized exploratory treatment with aumolertinib and olaparib. The present case provides a clinically documented observation of individualized targeted therapy in a rare KRAS wild-type PDAC molecular context and may help inform future hypothesis-driven investigations in selected molecularly defined patients. However, further studies are required to clarify the functional relevance of these molecular alterations and the clinical value of this treatment approach in selected patients with molecularly unique PDAC.
2026-09-25 | Functioning pancreatic neuroendocrine neoplasms: Diagnosis and current treatment.
Pancreatic functioning neuroendocrine neoplasms (PanNENs) are rare and characterized by variable and heterogeneous clinical manifestations, comprising both symptoms and signs of tumor growth and systemic manifestations of hormonal hypersecretion. The diagnosis is challenging due to their rarity, neoplasm localization and diverse secretory profile. A subset of these neoplasms may develop in the context of inherited syndromes and harbor specific genetic alterations requiring genetic counseling of other family members. These particular features make the management of patients with a functioning PanNEN syndrome requiring a multidisciplinary approach. Surgical resection of local disease, antisecretory medical treatment, locoregional treatment and systemic treatments are employed on an individualized basis. The treatment landscape of advanced NENs progressing after systemic treatment or after exhibiting intolerance to sequential lines of treatment is rapidly evolving supporting the introduction of additional therapies with promising results.
2026-09-24 | Pathological complete response after nanoliposomal irinotecan plus fluorouracil/leucovorin and conversion surgery in borderline resectable pancreatic head adenocarcinoma: a case report.
Nanoliposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has become an established regimen for pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy; however, complete response remains exceptionally rare. Here, we describe a 70-year-old female patient under surveillance for branch-duct intraductal papillary mucinous neoplasm who developed a new hypovascular pancreatic head mass (~ 30 mm) with > 180° contact to the portal vein, consistent with borderline resectable PDAC. Adenocarcinoma was confirmed by endoscopic ultrasound-guided tissue acquisition. Initial therapy comprised gemcitabine plus nab-paclitaxel, but the patient showed radiographic and biochemical progression. Modified FOLFIRINOX (oxaliplatin, irinotecan, leucovorin (LV), and 5-fluorouracil (5-FU)) was attempted as second-line therapy, but discontinued after one cycle due to Grade 3 myelosuppression and severe fatigue. Subsequently, nal-IRI + 5-FU/LV was administered as third-line therapy for 10 cycles and toxicity was manageable. Follow-up contrast-enhanced computed tomography revealed marked tumor regression and resolution of previously observed right lower-lobe pulmonary opacity. Following multidisciplinary reassessment and with informed consent, subtotal stomach-preserving pancreaticoduodenectomy was performed. The resected specimen showed a 13 mm fibrotic scar without residual viable carcinoma and no lymph node metastasis was identified, meeting criteria for pathological complete response. At 25-month follow-up, the patient remained disease-free. This case provides evidence that nal-IRI + 5-FU/LV may induce profound tumor regression in carefully selected patients with preserved performance status and favorable baseline factors, enabling potentially curative resection after failure or intolerance to standard first-line regimens.
2026-09-13 | Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring.
Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers. We describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans. She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m2, annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55-59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response. Persistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.
cell therapies
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.
2026-05-28 | Successful treatment with plasmapheresis of severe hypertriglyceridemic acute pancreatitis complicated by fat overload syndrome caused by lipid injectable emulsion: a case report and review of the literature.
Hypertriglyceridemic acute pancreatitis (HTG-AP) and fat overload syndrome caused by lipid injectable emulsion (ILE) are rare in clinical practice. Although the treatment of HTG-AP with plasmapheresis has previously been reported, only a few reports describe the application of plasmapheresis to treat HTG-AP and fat overload syndrome caused by ILE. We report a case diagnosed with severe HTG-AP and fat overload syndrome, based on laboratory findings and abdominal computed tomography, caused by intravenous infusion of ILE for about 3 weeks without monitoring of serum triglyceride (TG) levels in a 78-year-old Chinese female patient with a history of esophageal cancer. Conventional treatments were attempted; however, the patient progressively developed worsening abdominal pain and notably elevated inflammatory biomarkers, including C-reactive protein and procalcitonin levels. Plasmapheresis treatment was performed immediately to lower serum TG levels and prevent the complication of acute pancreatitis (AP) due to hypertriglyceridemia. After two consecutive plasmapheresis sessions, the patient's TG and total cholesterol levels remarkably decreased to 13.57 and 8.62 mmol/L, respectively. She also showed considerable improvement in her abdominal symptoms. HTG-AP and fat overload syndrome can be associated with intravenous infusion of ILE. Monitoring serum TG levels while utilizing ILE is necessary. Plasmapheresis should be considered an effective treatment measure for severe HTG-AP or fat overload syndrome caused by ILE, because it rapidly lowers serum TG levels and may prevent to be useful in ameliorating the course of acute pancreatitis.
2026-04-17 | One-step knock-in CAR constructs in human NK cells enable scalable, TGFβ1-resistant immunotherapy for solid tumors.
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising modality for cancer immunotherapy, yet their efficacy in solid tumors is limited by immunosuppressive cues from the tumor microenvironment (TME), particularly, transforming growth factor β (TGFβ). Primary human NK cells were cytokine-activated (IL-12/15/18) and engineered via a one-step electroporation that delivered Cas9 ribonucleoprotein and a dsDNA donor (1 kb homology arms, SFFV promoter, poly(A), GRE element) to knock out TGFBR2 and knock in a mesothelin CAR. We compared against a two-step AAV method, and treated dexamethasone (Dex) during manufacture. Anti-tumor function was assessed using AsPC-1 cancer killing assays, patient-derived pancreatic cancer organoids (caspase-3/7 imaging, luciferase viability, live/dead FACS), and multi-omics profiling (RNA-seq, ATAC-seq, GSEA) to evaluate metabolic and transcriptional modifications. We report a streamlined, one-step strategy that simultaneously disrupts the TGFβ receptor II (TGFβRII) and integrates a mesothelin-targeting CAR transgene into primary NK cells via electroporation. By optimizing single-guide RNAs, donor DNA templates incorporating glucocorticoid response elements, and electroporation parameters, we achieved markedly improved knock-in efficiency. Transient Dex treatment during genome editing enhanced CAR expression and cytotoxic function in both electroporation- and AAV-mediated platforms. Dex augmented the cytotoxic activity of CAR-NK cells by promoting oxidative phosphorylation and ATP production. We designed robust, TGFβ1-resistant allogeneic CAR-NK cells using a virus-free, one-step engineering strategy, establishing a versatile, clinically scalable method for engineering metabolically fortified CAR-NK cells capable of overcoming TME-mediated suppression in solid tumors.
2026-02-19 | CD177+ neutrophils alleviate acute pancreatitis-associated lung injury by protecting colonic barrier and restoring gut microbiota.
Altered neutrophil infiltration and function are associated with the deterioration of acute pancreatitis (AP) and even AP-associated lung injury. Although CD177 is a marker of neutrophil activation, its role in AP remains largely unknown. To determine whether ablation of Cd177 could deteriorate colonic barrier dysfunction, changes in the gut microbiota, and AP-associated lung injury, Cd177 knock-out (KO), Cd177 conditional knock-out (cKO) in circulating neutrophils and pseudo-germ-free (antibiotic therapy, or ABX-treated) mouse models were used in this study. AP was induced in mice through injection of sodium taurocholate retrogradely into the pancreatic duct, then peripheral blood, pancreas, lung, colon tissues and fecal samples were collected at 24 h after induction, respectively. The mRNA and protein expression of certain genes and gut microbiota of mice were measured. Results indicated that both Cd177 KO and cKO increased serum amylase and lipase levels, exacerbated pathological damage, and impaired the integrity of the colonic mucosal barrier in AP mice, suggesting a protective role of neutrophil-derived CD177 in AP progression. In addition, ABX-treated mice alleviated AP-associated lung injury, demonstrating that gut microbiota dysbiosis may contribute to the deterioration of phenotypes. Moreover, ablation of Cd177 was associated with reduced abundance of gut microbiota species g_Atopostipes, downregulated Nos1ap expression in the lung and Sorbs1 expression in the colon, consequently aggravating the damage of colon and lung of mice with AP. It is concluded that Cd177+ neutrophils may ameliorate AP-associated lung injury through protecting colonic barrier and modulating certain gut microbiota and associated genes in mice.
proteins
2026-09-15 | Pediatric Gastroenteropancreatic Neuroendocrine Tumors in Jordan: A 19-Year Experience From a Tertiary Oncology Center.
Pediatric gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are exceedingly rare. Data from Jordanian and Arab world populations are absent from international registries, with only limited data available from Türkiye, leaving management strategies largely extrapolated from adult and Western literature. This study documents the clinical features, management, and outcomes at a tertiary oncology center in Jordan. We conducted a retrospective, single-center cohort study of patients 18 years or younger diagnosed with GEP-NETs at the King Hussein Cancer Center (January 2006 to May 2025). We analyzed demographics, presentation, tumor characteristics, treatment, and survival. Ten patients were identified (8 male, median age 13 y). Primary sites were the appendix (8/10) and pancreatic head (2/10). Nine patients presented with abdominal pain; one with a pancreatic primary presented with obstructive jaundice. Histologically, 9 were low- or intermediate-grade (grade 1 to 2) and 9 were localized. Nine patients underwent surgery (8 appendectomy±hemicolectomy; 1 Whipple procedure). One patient with metastatic pancreatic NET was managed nonsurgically. Two patients with advanced/metastatic pancreatic NETs received systemic therapy. Appendiceal tumors were universally indolent with excellent outcomes postsurgery, whereas pancreatic tumors exhibited aggressive clinical behavior, including nodal involvement and distant metastasis. After a median follow-up of 46.6 months, 1 patient died of metastatic disease and 1 developed recurrence; both had pancreatic primaries. Pediatric appendiceal NETs carry excellent prognoses following conservative surgery. Pancreatic NETs represent a high-risk subgroup with aggressive behavior. As the first documented GEP-NET from Jordan and the Arab world, these findings align with international patterns and support site-specific, risk-adapted management while highlighting the need for multicenter collaboration across the region.
2026-09-03 | Size alone is not enough: Ki-67 and invasion patterns identify high-risk pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine tumors (pNETS) constitute a heterogeneous and rare disease worldwide. Diagnosis rates have been increasing, and the evaluation of prognostic factors has become even more important in the treatment decision-making process. To present results and prognostic factors in patients undergoing surgical treatment for pNETS at a single Brazilian center. The most frequently performed surgical procedure was PCC+S 60.0%. The median hospital stay was 8 (5-13) days, and postoperative mortality occurred in 1.7%. Overall survival in 3 and 5 years was 93.8 and 92.1%, respectively. Disease-free survival at 3 and 5 years was 87.1 and 71.8%, respectively. Patients with tumors smaller than 2.0 cm did not present with lymph node disease or recurrence, and patients with tumors measuring 2.1-2.5cm had lymph node disease in 11.1% and recurrence in 11.1%. In univariate and multivariate analysis, the presence of lymphatic and perineural invasion and Ki67 (3-20) were strongly correlated with positive lymph node disease and recurrence, respectively. The presence of lymphatic and perineural invasion, Ki67 (3 to 20), and tumors larger than 2.5 cm correlated with positive lymph node disease and recurrence.
2026-08-21 | Solid Pseudopapillary Neoplasm of the Pancreas: Diagnostic Concordance and Clinicopathologic Correlation of Fine-Needle Aspiration and Long-Term Outcomes.
Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor with low malignant potential and unclear cell of origin and pathogenesis. Fine-needle aspiration (FNA) is frequently used for preoperative diagnosis, yet correlation with resection specimens and long-term follow-up remains limited in the literature. We retrospectively identified all patients diagnosed with SPN by pancreatic FNA at a single institution (2016-2025). Cytology preparations included smears with or without rapid on-site evaluation and ancillary immunohistochemistry performed on cell blocks when available. Surgical pathology, when performed, was reviewed for diagnostic concordance and adverse features. Clinical outcomes were assessed by chart review. Seven patients were identified (female-to-male ratio = 6:1; median age = 29 years, range = 18-53 years). Tumors most commonly involved the tail (5/7) and measured a median of 6.0 cm (range = 2.6-14.0). Pancreatic FNA rendered a definitive diagnosis of SPN in six cases (6/7). Six patients underwent resection, and surgical pathology confirmed SPN in all resected tumors (6/6). Lymphovascular invasion was absent in all resected cases; perineural invasion was present in one case. At last follow-up (median = 41 months, range = 4-119), all patients were alive. One patient developed liver metastasis eight years after the initial diagnosis. Pancreatic FNA demonstrated excellent diagnostic concordance and clinicopathologic correlation for SPN with available resections. Despite overall indolent behavior, late metastatic disease can occur, supporting the need for long-term surveillance.
2026-08-07 | SMARCB1 (INI1)-deficient Rhabdoid Pancreatic Carcinoma: A Rare Subtype of Pancreatic Cancer
Rhabdoid pancreatic carcinoma (RPC) is a rare and highly aggressive subtype of undifferentiated pancreatic carcinoma characterized by rhabdoid morphology and frequent loss of SWItch/sucrose non-fermentable chromatin-remodeling complex-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), integrase interactor 1 (INI1) expression.Due to its rarity, its clinicopathological characteristics and optimal management remain poorly defined.A 56-year-old woman with an Eastern Cooperative Oncology Group performance status of 1 presented with a one-month history of abdominal and back pain.Contrast-enhanced computed tomography revealed an infiltrative pancreatic head mass measuring 125×52×75 mm, with vascular involvement and multiple metastatic lymph nodes.Histopathological examination demonstrated RPC, with complete loss of nuclear SMARCB1 (INI1) expression by immunohistochemistry. Comprehensive next-generation sequencing showed KRAS wild-type status.The patient received modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) chemotherapy and achieved partial regression of metastatic abdominal lymph nodes after six cycles.Treatment was continued for a total of 12 cycles before disease progression was documented.This case highlights the aggressive clinical behavior and distinctive molecular profile of SMARCB1 (INI1)-deficient RPC.The observed partial response to mFOLFIRINOX suggests that selected patients may derive temporary benefit from systemic chemotherapy; however, durable disease control remains challenging.Increased recognition of this rare entity and further investigation of molecularly targeted and immunotherapeutic strategies are needed to improve outcomes.
2026-07-28 | Drug-specific differences in fatal adverse events among PARP inhibitors: a FAERS pharmacovigilance study.
Poly(ADP-ribose) polymerase inhibitors (PARPi) are widely used in the treatment of multiple malignancies; however, their fatal adverse event profiles remain incompletely characterized in real-world settings. Evidence regarding drug-specific differences in fatal toxicity is limited. This study aimed to comprehensively evaluate fatal adverse events associated with PARPi, focusing on the overall fatal burden across individual agents, drug-specific fatal toxicity signatures at system organ class (SOC) and preferred term (PT) levels, and the temporal dynamics of fatal events. Adverse event reports associated with olaparib, niraparib, rucaparib, and talazoparib were extracted from the FDA Adverse Event Reporting System (FAERS) database. Fatal and non-fatal cases were compared in terms of demographic and clinical characteristics. The proportion of fatal reports and reporting odds ratios (RORs) were calculated to assess drug-specific differences. SOC distribution and PT-level disproportionality analyses (cases ≥ 30, ROR > 1.5, FDR < 0.05) were performed to identify fatal toxicity signatures. Principal component analysis (PCA) and hierarchical clustering were used to evaluate similarity patterns. Time-to-onset (TTO) was analyzed using violin plots and kernel density estimation. A total of 25,413 reports were included, comprising 5,930 fatal and 19,483 non-fatal cases. Fatal reports were more common in older patients and in those with prostate and pancreatic cancers. The proportion and reporting odds of fatal events varied across PARPi, with olaparib showing a higher fatal reporting odds (OR = 1.29, 95% CI: 1.03-1.63) compared with talazoparib, whereas niraparib and rucaparib demonstrated significantly lower odds. Hematologic toxicities were consistently enriched across agents, supporting a class effect, while non-hematologic toxicities showed substantial heterogeneity. Olaparib was characterized by rare but highly enriched fatal events (e.g., interstitial lung disease, pneumonitis, thrombosis), whereas niraparib exhibited more frequent but moderately increased risks. PCA revealed clear separation of toxicity profiles among agents. Fatal events generally occurred later than non-fatal events, particularly for olaparib (median TTO: 84 vs 48 days, p < 0.001). Fatal adverse event profiles differ across PARPi, reflecting both shared class effects and drug-specific heterogeneity. These findings highlight the importance of individualized safety assessment and sustained monitoring during PARPi therapy.
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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.
2026-08-28 | Biomarker-driven immunotherapy and adoptive cell therapy in recurrent pancreatic ductal adenocarcinoma.
Recurrent pancreatic ductal adenocarcinoma (PDAC) includes circulating tumor DNA (ctDNA)-defined molecular residual disease (MRD), isolated or oligometastatic relapse, disseminated measurable recurrence, and heavily pretreated refractory disease. These states differ in tumor burden, treatment urgency, tissue accessibility, and immune competence and should not be treated as one population. Immune checkpoint blockade has minimal activity in unselected PDAC, and randomized trials have not shown consistent benefit from adding checkpoint inhibitors to chemotherapy. However, rare microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors and selected antigen- or human leukocyte antigen (HLA)-defined subgroups support precision immune intervention. This Mini Review evaluates biomarkers for immunotherapy and adoptive cell therapy, including ctDNA kinetics, tumor mutational burden, KRAS and neoantigen profiles, antigen presentation and target-antigen density, effector immune state, myeloid and fibroblast-mediated suppression, and spatial immune exclusion. It compares checkpoint blockade, personalized and KRAS-directed vaccines, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor natural killer-cell (CAR-NK), and T-cell receptor (TCR)-engineered therapies by recurrence setting, evidence maturity, feasibility, and failure mechanisms. Checkpoint blockade is currently most defensible for MSI-H/dMMR disease; vaccines and cell therapies remain investigational and are best tested in biomarker-selected trials, especially in low-burden or molecular recurrence. We propose a five-step workflow to classify recurrence, identify actionable biomarkers, match evidence-appropriate interventions, assess feasibility, and monitor response and immune escape. This framework supports trial design and disciplined clinical translation rather than empiric immunotherapy in unselected recurrent PDAC.
2026-08-14 | Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies.
Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
2026-07-17 | Neutrophil extracellular traps induced by tumour-derived NGAL reprogram CAF subtypes via ITGA5 to promote tumour progression in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to immune checkpoint blockade, owing to its immunosuppressive tumour microenvironment. Neutrophil extracellular traps (NETs) accumulate in PDAC and correlate with disease progression, yet whether NETs reprogram cancer-associated fibroblast (CAF) heterogeneity and the upstream tumour-intrinsic signals that sustain pathological NETosis remain undefined. To delineate how NETs instruct CAF subtype specification and immunosuppression in PDAC, identify upstream NETosis drivers and evaluate combinatorial therapeutic strategies targeting this axis. Quantitative spatial analysis of human PDAC specimens, NETs-pancreatic stellate cell and patient-derived CAF cocultures, biotinylated DNA pull-down with liquid chromatography-tandem mass spectrometry, live-cell integrin-blocking assays, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing, orthotopic and hepatic colonisation models, CD8+ T-cell functional assays and single-cell RNA sequencing of an eight-arm therapeutic study were employed. NETs-DNA directly engaged integrin α5β1 (ITGA5) on fibroblasts via its N-terminal domain, initiating a FAK (focal adhesion kinase)/SRC (Src family tyrosine kinase)-YAP (Yes-associated protein)-IL-6 (interleukin-6)-JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) autocrine cascade specifying inflammatory CAF (iCAF) differentiation. Tumour-derived neutrophil gelatinase-associated lipocalin (NGAL), induced by IL-17, drove extracellular signal-regulated kinase (ERK)-reactive oxygen species-mediated NETosis. NETs-reprogrammed iCAFs accelerated tumour growth, hepatic colonisation and CD8+ T-cell exhaustion, with exhausted T cells spatially enriched in iCAF-rich regions. A composite NETs/ITGA5 signature stratified overall survival in patients with PDAC. Single-cell transcriptomics demonstrated that triple therapy (anti-IL-17+AV3+anti-PD-1) shifted fibroblasts from iCAF towards myofibroblastic CAF dominance, restored CD8+ T-cell effector programmes and achieved the greatest tumour suppression and survival benefit. We define an IL-17/NGAL/NETs/ITGA5 axis linking neutrophil-derived extracellular DNA to iCAF specification and immunosuppression in PDAC. Cotargeting IL-17 and ITGA5 synergises with PD-1 blockade, providing a rationale for combinatorial immunotherapy.
2026-07-06 | A Case of Pancreatic Cancer with High Tumor Mutation Burden Showing a Remarkable Response to Pembrolizumab.
Pancreatic cancer (PC) is an aggressive malignancy with limited therapeutic options and generally poor responsiveness to immune checkpoint inhibitors (ICIs). Microsatellite instability-high (MSI-High) and tumor mutation burden-high (TMB-High) phenotypes are rare, each occurring in approximately 1% of PC cases, but may predict improved response to ICIs. We report a case of recurrent PC harboring both MSI-High and markedly elevated TMB, in which pembrolizumab achieved an exceptional and durable response. A 72-year-old man presented with appetite loss, and contrast-enhanced CT revealed a large pancreatic tail tumor invading the stomach, colon, spleen, and left kidney. Fine-needle biopsy confirmed adenocarcinoma. Despite initial modified FOLFIRINOX therapy showing progressive disease, subsequent gemcitabine plus nab-paclitaxel achieved partial response (PR). However, gastrointestinal bleeding due to gastric invasion necessitated surgery. The patient underwent extensive resection, including distal pancreatectomy with splenectomy, total gastrectomy, partial colectomy, nephrectomy, adrenalectomy, and portal vein resection and reconstruction using the left renal vein. Pathology demonstrated well-differentiated ductal adenocarcinoma with multiorgan invasion and portal vein tumor thrombus (ypT3N1M0, Stage IIB, Evans Grade IIb). Although adjuvant chemotherapy was considered, it could not be initiated because of persistent postoperative diarrhea and delayed recovery of the patient's general condition. Four months after surgery, recurrence was detected in the para-aortic lymph nodes, with suspected peritoneal dissemination causing right hydronephrosis, accompanied by elevated carbohydrate antigen 19-9 (CA19-9). Comprehensive genomic profiling using the surgically resected tumor specimen revealed MSI-High status and extremely high TMB (75 mutations/Mb), and genomic alterations in MSH2, MSH3, KRAS, TP53, ARID1A, ATR, and SMAD2. Pembrolizumab was initiated, leading to rapid normalization of CA19-9 and continuous tumor shrinkage. The best overall response was classified as PR, and this PR has been maintained. At 26 months after surgery, the patient remains on pembrolizumab with sustained clinical benefit and no significant immune-related adverse events. This case highlights the potential for exceptional and durable response to pembrolizumab in PC characterized by concurrent MSI-High and markedly elevated TMB. Given the rarity of these biomarkers and the typically poor prognosis of PCs, early genomic profiling may facilitate personalized treatment strategies and improve outcomes in selected patients.
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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.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
2026-04-22 | Severe Familial Chylomicronemia Syndrome With Refractory Hypertriglyceridemia and Multisystem Complications Managed With Chronic Plasmapheresis and Olezarsen: A Case Report.
Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease.
2026-03-28 | A clinically relevant retrograde intraductal injection (RIDI) for lipid nanoparticles-mediated base editing in the pancreas.
Gene therapy offers potential curative strategies for many pancreatic diseases, including diabetes and inherited pancreatitis. However, their clinical translation has been hindered by the lack of an effective delivery platform. Lipid nanoparticles (LNPs) are established as a leading non-viral delivery system for nucleic acids; however, their tropism is limited to the liver following systemic administration. In this study, we evaluated retrograde intraductal injection (RIDI), a clinically relevant and routinely performed endoscopic technique, as a direct delivery route for LNPs into pancreatic tissue. RIDI of Cre mRNA-loaded LNPs resulted in the transfection of approximately 47% of acinar cells, leading to robust recombination. Extending this approach to gene editing, we observed ~20-30% of gene editing and 5% base editing in mouse models. Collectively, these findings establish RIDI as a viable strategy for pancreas-targeted LNP administration, highlighting its potential to enable gene therapy and gene editing in pancreatic diseases.
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Drug Discovery Landscape
1 orphan drug designation for Rare pancreatic disease, including 1 approved therapy.
1 orphan drug designation for Rare pancreatic disease, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Synthetic porcine secretin [Secreflo] | peptides | FDA | Approved | ChiRhoClin, Inc. |
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