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ObjectivesSerous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality.DesignRetrospective multinational study including SCN diagnosed between 1990 and 2014.Results2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1).ConclusionsAfter a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN.Trial registration numberIRB 00006477.

Background Intra-tumor microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) development, treatment response and post-treatment survivorship. Moreover, therapeutic interventions targeting microbiota may improve the response to chemotherapy and immunotherapy, further emphasizing the critical need to understand the origins of and growth of bacteria within the pancreatic tumor microenvironment. Here, we studied the role of several clinical factors on the bacterial colonization of PDAC. Results We obtained matched tumor and normal pancreatic tissue specimens from 27 patients who had undergone surgical resection for PDAC between 2011 and 2015 from the University of Minnesota Biological Materials Procurement Network (BioNet). We found that 26 (48%) out of 54 pancreatic tissue samples harbored detectable bacterial communities using real-time PCR targeting the 16S rRNA gene. Bacterial colonization was detected significantly more frequently in samples from patients who had pancreatic head tumors, underwent Whipple procedure, or had preoperative biliary stent placement. There was also a significantly greater relative abundance of microbiota from the family Enterobacteriaceae among samples from patients who underwent biliary stent placement or neoadjuvant treatment with a combination of Gemcitabine and Paclitaxel. Conclusions These findings suggest that biliary stent placement and neoadjuvant chemotherapy are associated with specific alterations that promote the infiltration and growth of intra-tumor bacteria in the setting of PDAC. Further studies exploring whether specific bacterial communities could contribute to increased chemoresistance will be essential for optimizing medical therapies in the future.

Background Recent studies have suggested the important roles of CD47 and tumor-associated macrophages in the prognosis and immunotherapy of various human malignancies. However, the clinical significance of CD47 expression and CD163+ TAMs in pancreatic neuroendocrine tumor (PanNET) remains unclear. Methods In this study, 47 well-differentiated PanNET resection specimens were collected. CD47 expression and CD163+ macrophages were evaluated using immunohistochemistry and correlated with clinicopathologic properties. Results Positive CD47 staining was seen in all PanNETs as well as adjacent normal islets. Compared to normal islets, CD47 overexpressed in PanNETs ( p  = 0.0015). In the cohort, lymph node metastasis (LNM), lymphovascular invasion (LVI), and perineural invasion (PNI) were found in 36.2, 59.6, and 48.9% of the cases, respectively. Interestingly, PanNETs with LNM, LVI, or PNI had significantly lower H-score of CD47 than those without LNM ( p  = 0.035), LVI ( p  = 0.0005), or PNI ( p  = 0.0035). PanNETs in patients with disease progression (recurrence/death) also showed a significantly lower expression of CD47 than those without progression ( p  = 0.022). In contrast, CD163+ macrophage counts were significantly higher in cases with LNM, LVI, and PNI. Conclusions Our data suggest relative low CD47 expression and high CD163+ TAMs may act as indicators for poor prognosis of PanNETs.

Background Pancreatoduodenectomy (PD) has a considerable surgical risk for complications and late metabolic morbidity. Parenchyma-sparing resection of benign tumors has the potential to cure patients associated with reduced procedure-related short- and long-term complications. Materials and Methods Pubmed, Embase, and Cochrane libraries were searched for studies reporting surgery-related complications following PD and duodenum-preserving total (DPPHRt) or partial (DPPHRp) pancreatic head resection for benign tumors. A total of 38 cohort studies that included data from 1262 patients were analyzed. In total, 729 patients underwent DPPHR and 533 PD. Results Concordance between preoperative diagnosis of benign tumors and final histopathology was 90.57% for DPPHR. Cystic and neuroendocrine neoplasms (PNETs) and periampullary tumors (PATs) were observed in 497, 89, and 31 patients, respectively. In total, 34 of 161 (21.1%) patients with intraepithelial papillar mucinous neoplasm exhibited severe dysplasia in the final histopathology. The meta-analysis, when comparing DPPHRt and PD, revealed in-hospital mortality of 1/362 (0.26%) and 8/547 (1.46%) patients, respectively [OR 0.48 (95% CI 0.15–1.58); p = 0.21], and frequency of reoperation of 3.26 % and 6.75%, respectively [OR 0.52 (95% CI 0.28–0.96); p = 0.04]. After a follow-up of 45.8 ± 26.6 months, 14/340 patients with intraductal papillary mucinous neoplasms/mucinous cystic neoplasms (IPMN/MCN, 4.11%) and 2/89 patients with PNET (2.24%) exhibited tumor recurrence. Local recurrence at the resection margin and reoccurrence of tumor growth in the remnant pancreas was comparable after DPPHR or PD [OR 0.94 (95% CI 0.178–5.34); p = 0.96]. Conclusions DPPHR for benign, premalignant neoplasms provides a cure for patients with low risk of tumor recurrence and significantly fewer early surgery-related complications compared with PD. DPPHR has the potential to replace PD for benign, premalignant cystic and neuroendocrine neoplasms.

This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Background Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare, low-grade malignancies that predominantly affect young females. Their diagnosis is often facilitated by a characteristic histomorphological pattern and immunohistochemical profile. However, diagnostic challenges persist, especially in pediatric and atypical presentations. Recent attention has focused on the diagnostic value of CD99 and LEF1 in distinguishing SPNs from other pancreatic neoplasms. Objective To evaluate the diagnostic accuracy and utility of CD99 and LEF1 as immunohistochemical markers for SPNs. Methods A retrospective analysis of 60 SPN cases diagnosed between 2015 and 2024 was performed. Histopathological features were systematically reviewed, and immunohistochemical staining for CD99, LEF1, β-catenin, Cyclin D1, PR, Ki-67 was evaluated. Immunohistochemical marker interpretation was standardized using internally validated thresholds informed by existing literature: CD99 was considered positive with ≥ 10% cytoplasmic staining exhibiting paranuclear accentuation; β-catenin positivity was defined by ≥ 5% nuclear localization; Cyclin D1 by ≥ 10% moderate-to-strong nuclear staining; and progesterone receptor (PR) expression by ≥ 1% nuclear positivity, consistent with hormone receptor evaluation guidelines. Marker expression was statistically analyzed for their associations. Results SPNs exhibited a strong female predilection (F:M ratio ≈ 7:1), with a mean age of 32.5 years. Pediatric cases ( n  = 4) displayed higher mean expression of CD99 (73.8%) and LEF1 (86.5%) compared to adults. CD99 showed cytoplasmic positivity with paranuclear accentuation in 96.7% of cases, while LEF1 demonstrated nuclear staining in 91.7%. β-catenin nuclear localization was observed in 95% of tumors, reflecting Wnt/β-catenin pathway activation. Cyclin D1 and PR were expressed in 90% and 88.3% of cases, respectively. Co-expression of β-catenin, CD99, LEF1, Cyclin D1, and PR was observed in 73.3% of tumors. CD99 and LEF1 inversely correlated with tumor size and proliferative activity (Ki-67), whereas Cyclin D1 and Ki-67 positively correlated with tumor size and lymphovascular invasion (LVI). Pediatric tumors generally exhibited favorable profiles, with limited evidence of LVI. Conclusion SPNs present with distinctive immunohistochemical signatures that are critical for accurate diagnosis, particularly in morphologically ambiguous or pediatric cases. CD99 and LEF1 are highly sensitive markers that, in combination with β-catenin and Cyclin D1, enhance diagnostic precision. These findings emphasize the central role of Wnt/β-catenin signaling in SPN pathogenesis and underscore the importance of integrating clinicopathological and molecular data for comprehensive tumor assessment.

Pancreatic neuroendocrine tumors (NETs) are rare well-differentiated neoplasms with limited therapeutic options and unknown cells of origin. The current classification of pancreatic neuroendocrine tumors is based on proliferative grading, and guides therapeutic strategies, however, tumors within grades exhibit profound heterogeneity in clinical manifestation and outcome. Manifold studies have highlighted intra-patient differences in tumors at the genetic and transcriptomic levels. Molecular classification might become an alternative or complementary basis for treatment decisions and reflect tumor biology, actionable cellular processes. Here, we provide a comprehensive review of genomic, transcriptomic, proteomic and epigenomic studies of pancreatic NETs to elucidate patterns shared between proposed subtypes that could form a foundation for new classification. We denote four NET subtypes with distinct molecular features, which were consistently reproduced using various omics technologies.

Background Ki67 index changes during the treatment of metastatic pancreatic neuroendocrine tumor (PanNET) treatment. The study aimed to detect alterations of grade based on Ki67 index and immune microenvironment in PanNET responding to capecitabine/temozolomide (CapTem). Method Retrospective data of patients with PanNET were collected. In control group, 35 patients underwent surgery immediately after biopsy. In CapTem group, 38 patients received CapTem after biopsy and responded well to treatment (defined as either stable disease or partial response), and subsequently underwent surgery. All patients have pathological Ki67 index at biopsy and after surgery. CD163 + CD68 + CD206 + M2 macrophages, CD68 + CD86 + CD80 + M1 macrophages, CD11b + CD33 + myeloid-derived suppressor cells, and CD4 + CD25 + regulatory T cells were stained using multiplex immunofluorescence. Results In control group, the paired grade based on Ki67 index directly after surgery showed no upgrade or downgrade compared to biopsy. In patients who responded well to CapTem, the grade based on Ki67 index before and after CapTem was altered. Thirteen patients had upgraded Ki67 index and 11 patients had downgraded. The proportion of stable disease was higher in the upgraded group compared to downgraded group ( p  = 0.0155). And upgraded group had a significantly shorter mPFS than patients in the downgrade group (8.5 months vs. 20 months, HR 4.834, 95% CI 1.414 to 16.53, p  = 0.012). M1 macrophages was significantly lower in the downgraded group than in the Ki67 upgraded group ( p  < 0.001). Conclusion Grade based on Ki67 index and immune environment change in PanNET patients responding well to CapTem. Patients with downgraded had longer mPFS compared to those with upgraded. It is necessary to reassess the Ki67 index after CapTem treatment, even in patients responding well to CapTem.

Background The co-occurrence of type 1 autoimmune pancreatitis (AIP) and pancreatic tumor (PaT) has been previously reported. Pure AIP cases have favorable prognosis and are primarily treated with steroids, while AIP cases with PaT are associated with poor prognosis where the primary management is pancreatic resection. However, it’s a challenge to timely identify the concurrent PaT in AIP because of their similar clinical and radiological manifestations. Methods We retrospectively reviewed the data in two medical centers from January 2010 to April 2019. The inclusion criteria were as follows: 1) completion of abdominal CT imaging before invasive procedures to the pancreas, 2) a final diagnosis of type 1 AIP using the 2011 international consensus diagnostic criteria, 3) follow-up duration of at least one month unless AIP and PaT were identified simultaneously. The presence of PaT in AIP was made based on histopathological confirmation, and the absence of PaT in AIP was defined as no pathological or radiological evidence of concurrent PaT. Clinical and radiological characteristics including gender, age, surveillance period, serum IgG4 and Ca-199 levels, biopsy, extrapancreatic involvement, CT and MR (if performed) imaging characteristics were compared between AIP with and without PaT. The Fisher’s exact test was used for qualitative variables, and nonparametric Mann-Whitney test for quantitative variables. A p value ≤0.05 was considered statistically significant. Results A total of 74 patients with type 1 AIP were included, of which 5 (6.7%) had the concurrent PaT. The subtypes were pancreatic ductal adenocarcinoma (3/5), solitary extramedullary plasmacytoma in the pancreas (1/5) and cholangiocarcinoma in the pancreatic segment (1/5), respectively. Gender ( p  = 0.044), the pattern of pancreatic enlargement ( p  = 0.003), heterogeneity ( p  = 0.015), low-density ( p  = 0.004) on CT and rim enhancement on MRI ( p  = 0.050) differed significantly between AIP with and without PaT. None of the low-density characteristics on CT or other assessed MRI characteristics could significantly differentiate the two groups (p>0.05). Conclusions Female, focal pancreatic enlargement, pancreatic heterogeneity, low-density on CT and rim enhancement on MRI are suggestive of the concurrent PaT in type 1 AIP. The characteristics of low-density on CT or other MRI characteristics did not provide further diagnostic values.

Background and Aims: Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. Methods: MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I 2 = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I 2 = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I 2 = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I 2 = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I 2 = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I 2 = 0.0%) for first-degree family history of cancer. Conclusions: Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.