Background: Vulvar extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma that typically affects postmenopausal women and often mimics benign inflammatory or infectious vulvar conditions, leading to delayed diagnosis. Optimal diagnosis and therapy remain challenging due to its nonspecific presentation and variable extent of disease. Case Presentation: We report a 58-year-old Lebanese postmenopausal woman with more than one year of persistent vulvar pruritus and an erythematous lesion refractory to topical antifungal and corticosteroid therapy. Clinical evaluation revealed a 5 cm vulvar lesion without lymphadenopathy. Vulvar biopsy confirmed extramammary Paget disease, and staging work-up excluded associated malignancies. Although histology suggested non-invasive disease, the lesion was extensive with ill-defined margins and was reviewed by a multidisciplinary tumor board. A key feature of this case is the discordance between non-invasive biopsy findings and the decision to proceed with radical surgery due to concern for occult invasion. The patient underwent radical vulvectomy with left superficial and deep inguinal lymph node dissection. Final histopathology confirmed disease confined to the epidermis with negative margins and no nodal involvement (0/8). Postoperative imaging at 6 months showed no recurrence or metastasis. Conclusions: This case highlights prolonged diagnostic delay despite multiple treatments and the management challenge posed by extensive clinical disease with non-invasive biopsy findings. It underscores the importance of considering EMPD in chronic refractory vulvar lesions. Management should be individualized in multidisciplinary settings. Given the short follow-up, long-term outcomes cannot be established, and careful surveillance remains essential due to the risk of late recurrence.

The CAPTRANE trial evaluated the efficacy of randomly assigned high-concentration capsaicin patch (HCCP) versus daily oral pregabalin (PGB) in adults with chronic neuropathic pain (DN4 ≥ 4) post-breast cancer surgery. The objective of its 4-month open-label extension following patient's self-selection of their second treatment (HCCP, PGB, or none) was to explore efficacy and safety of various strategies.

The study was conducted in France between March 2019 and November 2022. At each clinic visit, we assessed pain intensity (NRS, 0-10), painful area (cm²), mood (HADS), and quality of life (EQ-5D-5L). Standard statistical tests were used.

Data from 116 patients (all females; 76% aged < 65 years) were collected. At Month 2, 71% (46/65) of HCCP-treated patients received a second HCCP application and none switched to PGB, whereas 27% (14/51) continued on PGB and 49% (25/51) of PGB-treated patients switched to HCCP. At Month 6, NRS scores had decreased in HCCP-treated patients, including PGB/HCCP-treated patients, with a reduction of -2.0 [-4.0; 0.0] and -3.0 [-4.0; -2.0] in the HCCP/HCCP and PGB/HCCP group, respectively (median[interquartile]). Adverse events aligned with those expected with HCCP and PGB; none were serious.

This first study to examine switching between PGB and HCCP treatments for chronic intercostobrachial neuropathic pain after breast cancer surgery showed patients' preference for HCCP, confirmed the benefit of repeated HCCP applications, and indicated that HCCP could be preceded by PGB without compromising efficacy or safety. These findings suggest that HCCP may be used early in this population, and PGB initiated before HCCP to relieve patients waiting for HCCP application.

Vitamin D deficiency is common in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Whether vitamin D status influences tumor aggressiveness and clinical outcomes remains uncertain. This review examines current evidence on the prevalence, determinants, clinical associations, and clinical relevance of vitamin D deficiency in GEP-NENs.

A narrative and critical review of the literature was conducted using the PubMed/MEDLINE, Scopus, and Web of Science databases. Clinical studies, observational cohorts, translational research, selected mechanistic studies, and current clinical guidelines addressing vitamin D metabolism and neuroendocrine neoplasms were evaluated.

Vitamin D deficiency has been reported in approximately 60-80% of patients with GEP-NENs. Low serum 25-hydroxyvitamin D concentrations likely reflect multiple disease-related factors, including malabsorption, pancreatic exocrine insufficiency, chronic diarrhea, previous gastrointestinal surgery, and nutritional impairment. Several observational studies have linked lower vitamin D status with markers of more aggressive disease, including higher Ki-67 proliferation index values and shorter progression-free survival. Nevertheless, the available data are heterogeneous, predominantly observational, and do not support a causal relationship between vitamin D deficiency and tumor progression. At present, the main clinical rationale for assessing vitamin D status is to support metabolic care, preserve bone health, and prevent osteoporosis.

Vitamin D deficiency is a frequent and clinically relevant comorbidity in patients with GEP-NENs. Although lower vitamin D status has been associated with markers of more aggressive disease, current findings do not support vitamin D supplementation as an anticancer treatment strategy. Prospective clinical and translational studies are needed to clarify the biological and clinical significance of vitamin D signaling in GEP-NENs.

Background/Objectives: Metastasizing pleomorphic adenoma (MPA) is a rare salivary gland tumor characterized by benign pleomorphic adenoma morphology despite regional or distant metastatic behavior. Because most evidence derives from case reports and small series, this systematic review and pooled case-report analysis aimed to summarize published patient-level data and to explore clinicopathologic features, metastatic distribution, treatment, and survival without inferring causal treatment effects. Methods: PubMed, Scopus, Google Scholar, and reference lists were searched for English-language reports published up to 1 August 2025. Eligible reports described primary pleomorphic adenoma and metastatic disease reported as MPA with benign morphology; carcinoma ex pleomorphic adenoma and other malignant pleomorphic adenoma variants were excluded. The primary pooled analysis was restricted to 122 published case-report patients. Institutional cases are presented separately as illustrative cases and were not included in the primary pooled statistical analyses. Unknown, not reported, NA, and unclear values were treated as missing, and denominators are reported. Because only 16 deaths were available, survival analyses were exploratory and no multivariable Cox model was fitted. No formal risk-of-bias or certainty-of-evidence assessment was performed. Results: In the 122 published patients, sex was available for 121 patients and 71/121 (58.7%) were female. Primary tumors most frequently arose in the parotid gland (92/122, 75.4%), followed by the submandibular gland (15/122, 12.3%) and palate/soft palate (10/122, 8.2%). The median interval between primary pleomorphic adenoma and MPA was 12 years (IQR 7-21; range 0-69; n = 118). Metastatic site was reported in 120 patients and was non-mutually exclusive: bone/skeleton and lymph nodes/neck were each reported in 42/120 patients (35.0%), followed by lung/pulmonary metastases in 31/120 (25.8%). Treatment information was available for 98/122 patients. MPA-directed surgery was performed in 86/98 patients with available treatment information (87.75%). The non-surgical cohort received radiotherapy, chemotherapy, palliative treatment, treatment refusal, observation, or other non-surgical strategies. A total of 72 patients had complete covariate data for the reported Cox analyses, including 16 deaths. Estimated 1- and 5-year overall survival were 89.97% and 66.2%, respectively. Surgery was associated with improved overall survival in exploratory Kaplan-Meier comparison (log-rank p = 0.008) and univariable Cox analysis (HR 0.119, 95% CI 0.018-0.810, p = 0.030), but this association should not be interpreted as causal. Conclusions: MPA remains difficult to predict and the available evidence is limited by case-report design, missing data, publication bias, and heterogeneous follow-up. Surgical management may be considered in selected patients when technically feasible and clinically appropriate, but the observed survival association is exploratory and may be influenced by selection bias and disease characteristics. Multicenter registries, standardized reporting, centralized pathology review, molecular characterization, and longer follow-up are needed.

Pancreatic acinar cell carcinoma (PACC) is a rare exocrine pancreatic malignancy accounting for approximately 1-2% of adult pancreatic neoplasms. Although historically grouped with pancreatic ductal adenocarcinoma (PDAC), accumulating evidence demonstrates that PACC represents a biologically distinct entity with unique clinical, pathologic, and molecular characteristics. Compared with PDAC, PACC more commonly presents as a large pancreatic mass, is less frequently associated with obstructive jaundice, and exhibits lower rates of KRAS mutations. Recent genomic studies have identified recurrent alterations involving DNA damage repair pathways, WNT/β-catenin signaling, and actionable kinase fusions, including BRAF and RAF1 rearrangements. In advanced disease, fluoropyrimidine- and platinum-based regimens appear to demonstrate greater activity than traditional gemcitabine-based approaches, although prospective comparative data are lacking. This review summarizes the current understanding of the epidemiology, clinical presentation, pathology, molecular landscape, treatment approaches, and prognostic factors associated with PACC. We highlight emerging opportunities for precision oncology and discuss ongoing challenges in the management of this uncommon pancreatic malignancy.

Molecular testing for myeloproliferative neoplasms (MPNs) without defined clinical criteria can lead to inefficient laboratory utilization without proportional diagnostic benefit.

We evaluated the impact of implementing clinical acceptance criteria, including unexplained abnormal blood counts, unusual-site thrombosis, unexplained hepatosplenomegaly, and/or leukoerythroblastic blood film for gene (JAK2, CALR, MPL and/or BCR::ABL1) testing of patients with suspected MPNs in Hamilton, Canada and surrounding areas. The impact of testing criteria on ordering practices and diagnostic yields was assessed by retrospective examination of 3590 MPNs test requests submitted between 1 January and 31 December 2025; including 5.5 months of permissive testing (pre-implementation period), 2 months with a transition in testing criteria (grace period) and 4.5 months with restricted testing (post-implementation period). During the post-implementation period, the Laboratory also transitioned from sequential single-gene PCR-based assays to an MPN next-generation sequencing (NGS) panel for DNA-based MPN testing.

Our results show that test volumes decreased significantly from 1835 in the pre-implementation period to 1050 post-implementation, while the positivity rate increased from 12% to 17% (χ² = 12.26, p = 0.001). Patients with elevated platelet counts (237 of 1050 tested) demonstrated the highest positivity rate of 35% (n = 83/237). JAK2 V617F represented the highest proportion of all detected mutations at 73% (n = 127/174).

These findings show that implementing appropriate pre-test clinical criteria significantly improved MPN test utilization and diagnostic yield.

Objective: Current therapeutic regimens for pancreatic neuroendocrine neoplasms (pNENs) remain limited and fail to yield notable improvements in overall survival. Therefore, the development of novel agents is of paramount importance. Bruton's tyrosine kinase inhibitors (BTKis) have demonstrated promising therapeutic potential in solid tumors; however, ibrutinib, a classic BTKi, exhibits unsatisfactory clinical efficacy against pNENs. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and aimed to investigate its inhibitory effects on pNEN cell proliferation both in vitro and vivo and identify the core signaling pathways mediating its suppressive effects on pNENs. Methods: CCK-8, EdU, and colony formation assays were conducted to assess the effect of QY21 on pNENs in vitro. Transcriptome sequencing, quantitative real-time PCR, Western blotting, and flow cytometry were employed to explore the mechanisms. A xenograft tumor model in nude mice was established for in vivo validation. Results: QY21 significantly suppressed pNENs proliferation in vitro. Compared with the control and ibrutinib groups, QY21 exhibited stronger tumor growth inhibition in vivo. Histopathological analysis revealed a decreased Ki-67 index in the QY21 group, with no significant organ-toxic lesions observed. Transcriptome sequencing identified ATF3 as the core mediator responsible for the anti-proliferative effect of QY21. ATF3 was poorly expressed in pNENs, while QY21 markedly upregulated ATF3 expression. Mechanistically, QY21 induced ferroptosis by elevating ATF3 levels. The knockdown of ATF3 or administration of ferrostatin-1 significantly attenuated the anti-proliferative capacity of QY21, accompanied by reduced accumulation of reactive oxygen species and lipid peroxidation. Conclusions: This study demonstrates that the novel BTKi QY21 suppresses pNENs proliferation by triggering ATF3-mediated ferroptosis, providing a potential preclinical strategy for pNENs.

Accurate pre-operative identification of high-risk intraductal papillary mucinous neoplasms (IPMNs) remains a major clinical challenge, particularly for branch-duct (BD) lesions where guideline-based criteria incompletely capture biologic aggressiveness. We investigated whether tumoral mucin expression identifies high-risk IPMN pathology (i.e., high-grade dysplasia or invasive carcinoma) and whether computed tomography (CT)-derived radiomic features can serve as non-invasive biomarkers to enhance pre-operative risk assessment beyond international consensus guidelines (ICG) criteria.

Multiplex immunofluorescence quantified MUC1, MUC2, MUC5AC, and MUC6 expression in tissue microarrays from 101 surgically resected IPMNs classified as low-risk (low-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma). Associations were evaluated using Wilcoxon rank-sum tests, and their discriminatory capability evaluated using receiver operating characteristic curves. For mucins predictive of high-risk pathology, a CT-based 'radiomic' signature was developed. Incremental value beyond ICG criteria was evaluated using discrimination metrics and decision curve analysis.

Reduced MUC6 expression was significantly associated with high-risk pathology (p = 0.001) and had the highest discriminatory performance (AUC = 0.72). A CT-derived radiomic signature predictive of low MUC6 expression achieved an AUC of 0.75 and, when integrated with ICG high-risk stigmata (HRS), demonstrated improved discrimination and favorable decision-curve characteristics compared with HRS alone, including among BD-IPMNs.

Loss of tumoral MUC6 expression is associated with high-risk IPMN pathology and may be approximated using CT-derived radiomic features, supporting the feasibility of non-invasive molecular phenotyping. These findings suggest that integration of molecular and imaging biomarkers with guideline-based criteria may enhance pre-operative IPMN risk stratification; however, prospective external validation in broader surveillance populations and multi-institutional cohorts is warranted prior to clinical implementation.

Inflammation is a hallmark of cancer and contributes to tumour initiation, progression, and therapeutic resistance. Among inflammatory mediators, interleukin-1β (IL-1β) and interleukin-6 (IL-6) are central cytokines linking innate immune responses with oncogenic signalling networks. This narrative review summarizes current experimental and clinical evidence regarding the role of IL-1β and IL-6 in carcinogenesis, with particular emphasis on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We discuss the molecular pathways associated with these cytokines, their interactions within the tumour microenvironment, and their contribution to tumour proliferation, angiogenesis, immune modulation, metastatic dissemination, and resistance to anticancer therapies. Particular attention is given to GEP-NENs, in which chronic inflammation and cytokine dysregulation may influence tumour behaviour, systemic inflammatory activity, and clinical outcomes. Accumulating evidence suggests that IL-6 may represent a promising exploratory biomarker associated with tumour burden, histological grade, disease progression, and systemic inflammation, whereas IL-1β appears to be more closely linked to local inflammatory signalling, microenvironmental remodelling, and potential susceptibility mechanisms. However, current evidence in GEP-NENs remains limited by small study cohorts, heterogeneous patient populations, variable analytical methodologies, and the lack of prospective validation. Further translational and clinical investigations are warranted to determine whether cytokine-based biomarkers and therapeutic modulation of inflammatory pathways may expand current diagnostic, prognostic, and therapeutic approaches in GEP-NENs.

Background/Objectives: Penile malignant tumors are rare neoplasms, and both clinicopathologic features and prognoses remain unclear in Japanese patients. Here, we investigated the prognoses of penile malignant tumors in Japan using the nationwide hospital-based cancer registry (HBCR) database. Methods: The 2015 HBCR database cohort was queried to identify patients with penile malignant tumors. Moreover, we investigated age, pathology, tumor-node-metastases classification, first-course treatment, and overall survival in these patients. Results: A total of 269 patients were analyzed from the 2015 cohort (149 squamous cell carcinoma [SCC] patients and 56 extramammary Paget disease [EMPD] patients). The median ages at diagnosis in both SCC and EMPD patients were 76.0 and 76.5 years. The median observation period was 53 months in the present study. The 5-year overall survival (OS) rates of SCC and EMPD were 56.8% and 78.5%. The 5-year OS rates of clinical stages 0-I, II, III, and IV were (respectively) 68.0%, 70.1%, 38.5%, and 11.9% in SCC patients and (respectively) 83.7%, 83.3%, not evaluated, and 0% in patients with EMPD. Conclusions: We revealed the OS of Japanese patients with penile SCC and EMPD in a large population-based study for the first time. Patients with clinical stage IV penile SCC and EMPD had extremely poor prognoses, highlighting a need for improved disease management in these patients.