Neuroendocrine tumors (NETs) associated with the intrapancreatic bile duct are rare and poorly characterized. Their relationship to conventional pancreatic neuroendocrine tumors (PanNETs) and to neuroendocrine cells of the periampullary and peribiliary regions remains unclear. A total of 199 resected NETs from the pancreas were evaluated for anatomical location and intrapancreatic bile duct narrowing. Transcription factor and hormone expression were assessed by whole-slide immunohistochemistry. For comparison, 22 duodenal NETs, 6 ampullary NETs and non-neoplastic duodenal, ampullary, and bile duct tissues were examined. Nineteen tumors (10%) were associated with bile duct narrowing, including 11 lower (periampullary) and 8 upper bile duct lesions. Compared with NETs without bile duct narrowing, these tumors were exclusively non-functioning, occurred more frequently in women and exhibited higher Ki-67 indices. Lower bile duct-narrowing tumors were associated with shorter progression-free survival. All but one bile duct-narrowing tumor expressed PDX1 (18/19, 95%), whereas CDX2 expression was observed in 73% (8/11) of lower bile duct-narrowing tumors. These tumors frequently expressed gastrin (73%) and somatostatin (73%), occasionally serotonin (27%), and lacked glucagon and insulin expression. Their transcription factor and hormone expression profiles closely resembled those of duodenal NETs and neuroendocrine cells of periampullary and peribiliary glands and differed from those of conventional PanNETs. Bile duct-narrowing NETs from the pancreas, particularly those involving the lower bile duct, represent a distinct clinicopathological subgroup characterized by a PDX1-positive, frequently CDX2-positive phenotype and enrichment for gastrin and somatostatin expression. Their resemblance to duodenal NETs and periampullary/peribiliary neuroendocrine cells supports a shared differentiation program and suggests a possible non-islet cell origin.

Recent studies have shown that pulmonary neuroendocrine tumor (NET) subgroups, defined by the transcription factors OTP and ASCL1, correlate with age, sex, and tumor location. Their relationships with histology and hormone production, however, remain unclear. We analyzed 170 pulmonary NETs classified by OTP (O) and ASCL1 (A) expression into four groups: O + /A + , O + /A-, O-/A + , and O-/A-. Subgroups were assessed for histology, hormone expression, therapy-related markers, outcomes, and matched metastases. Among 152 resected primaries, O + /A + tumors (38%) were most frequent, occurring mainly in females (median age 72 years), and typically showed central or peripheral location, solid/spindle morphology with diffuse gastrin-releasing peptide (GRP), and focal ACTH/calcitonin. They also showed strong DLL3 expression and pronounced neuroendocrine cell hyperplasia. O + /A- tumors (23%) occurred predominantly in females (median age 56 years) with solid/trabecular patterns, occasional/ACTH, and strong SSTR2A/5 expression. O-/A- tumors (25%) were more common in males (median age 70 years), often central with solid/trabecular or oncocytic histology, serotonin expression (24%), and frequently SSTR2A-positivity. O-/A + tumors (14%) occurred across both sexes (median age 58 years), were centrally located, and solid, sometimes oncocytic features with moderate DLL3/SSTR2A expression. Metastases mirrored their primaries in transcription factor and hormone profiles. In the univariate analysis, OTP-negative tumors were associated with poorer disease-free survival (DFS). However, the multivariate analysis identified Ki67-based WHO grades (G1-G3) as the only independent prognostic factors. In conclusion, integrating OTP and ASCL1 refines pulmonary NET classification into four histologically and biologically distinct subgroups, providing additional insight into tumor heterogeneity. O + /A + tumors showed solid-spindle features and diffuse GRP and frequent ACTH expression, trabecular patterns characterized ASCL1-negative tumors, while oncocytic histology predominated in OTP-negative tumors, highlighting their role in defining tumor heterogeneity.

OBJECTIVE:This preclinical study investigates a novel targeted collagen type IV nanoparticle formulation, Ac2-26 coated with chitosan and pectin ((pc)-Col-IV-Ac2-26-NPs), to promote anastomotic healing in a model of acute Crohn's disease (CD) with distal colo-colonic anastomosis, using intraperitoneal, oral and rectal delivery to optimize therapeutic effects while minimizing systemic immunosuppression. SUMMARY BACKGROUND DATA:Surgery remains critical for CD-patients due to irreversible tissue damage, with anti-inflammatory therapies increasing the risk of postoperative complications like anastomotic leaks. METHOD:Female BALB/c mice (n=152) with CD-like colitis (2,4,6-Trinitrobenzenesulfonic acid) were randomized to receive (pc)-Col-IV-Ac2-26-NPs or scrambled NPs intraperitoneally, orally, or rectally every 3.5 days pre- and postoperatively, followed by distal end-to-end colo-colonic anastomosis. Perioperative outcomes (weight loss, disease activity index (DAI)), anastomotic healing scores (endoscopic, histologic), and immunohistochemical (IHC) markers were assessed on postoperative days (POD) 3 and 7. RESULTS:NPs accumulated selectively at the anastomosis in a route-dependent manner and associated with higher collagen expression (P<0.0001), reduced pro-inflammatory (nuclear RelA; iNOS+-M1 macrophages, all P<0.0001) and increased pro-resolving markers (ANXA1; Arg-1+-M2 Macrophages, all P<0.0001) at the anastomotic site. These effects were most pronounced with rectal delivery, corresponding with improved preoperative DAI (P=0.03) and both endoscopic (POD3:P<0.0103; POD7:P<0.0077) and histologic (POD3:P<0.0112; POD7:P<0.0170) healing scores. While intraperitoneal delivery produced similar outcomes, oral delivery showed the weakest effect. CONCLUSION:(pc)-Col-IV-Ac2-26-NPs promote anastomotic healing during CD-colitis through targeted, route-dependent immunomodulation and tissue repair, with rectal delivery showing the highest local efficacy. These findings support their potential as locally acting, non-immunosuppressive therapy for high-risk CD-patients undergoing intestinal surgery.