Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as "immune cold" and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology.

The recently proposed revised Dynamic International Prognostic Scoring System (DIPSS-R) excludes age and constitutional symptoms and relies exclusively on disease-related variables. We aimed to externally validate the DIPSS-R and to characterize how it reclassifies patients relative to the DIPSS.

We retrospectively studied 285 patients with primary or secondary myelofibrosis from seven centers. Both scores were calculable in 270 patients (148 deaths). The two systems were compared for discrimination, reclassification, calibration, and robustness across pre-specified subgroups and landmarks.

During a median follow-up of 90.3 months, median overall survival (OS) was 66.1 months (5-year OS 52.7%). The two systems showed similar discrimination (C-index 0.691 vs. 0.697; difference -0.006, 95% CI -0.046 to +0.030; p = 0.77) with no significant difference across any subgroup, fibrosis grade, driver mutation, age or sex. The DIPSS-R assigned more patients to higher-risk categories (59.3% vs. 46.3%; p < 0.001). Reclassification was discordant in 57 patients (21.1%); the DIPSS-R up-stratified 46 patients (17.0%) classified as lower-risk by the DIPSS, and these patients had significantly worse survival than concordantly lower-risk patients (5-year OS 57.7% vs. 81.7%; p < 0.001). Among transplant-eligible patients aged ≤65 years, the DIPSS-R up-stratified 26 (22.6%). The reclassification was driven by the DIPSS-R-specific variables (monocytosis, leukocytosis and thrombocytopenia). In multivariable analysis the DIPSS-R remained independently prognostic of the Charlson comorbidity index (CCI), with both retaining independent value (DIPSS-R: HR 1.96 per category, 95% CI 1.58-2.44, p < 0.001; CCI: HR 1.18 per point, 95% CI 1.06-1.32, p = 0.003). In secondary myelofibrosis the DIPSS-R discriminated comparably to the disease-specific MYSEC-PM (C-index 0.659 vs. 0.698; p = 0.44).

The DIPSS-R matches the DIPSS in discrimination while identifying additional adverse-risk patients, most relevantly transplant-eligible younger patients, who would otherwise be considered lower-risk by the age-containing DIPSS; in secondary myelofibrosis it performs comparably to the disease-specific MYSEC-PM.

Objective: We aimed to investigate the effects of traditional acupuncture combined with auricular acupressure on quality of life in patients with head and neck squamous cell carcinoma undergoing radiotherapy. Study Design: This is a two-arm, parallel, randomized clinical trial with blinded outcome assessment. The study population comprised 107 patients (55 without intervention and 52 with intervention). Data were collected at Dilson Godinho Hospital in Brazil from March 2017 to June 2018, and all patients provided informed consent and were registered under the UTN U1111-1204-8410/RBR-10v5gcdk. Patients in the intervention group received traditional and auricular acupressure in weekly sessions during their radiotherapy treatment, and patients in the control group received no acupuncture. In addition, quality-of-life assessment data were collected using the WHOQOL-BREF instrument. Results: Analysis of the scores obtained in the WHOQOL-BREF before and after radiotherapy demonstrated that the use of traditional and auricular acupressure had a positive impact on physical, psychological, social, environmental, and overall quality of life. Conclusions: Our findings suggest benefits and provide a context for patients and physicians to decide if acupuncture is a desirable treatment option. However, further studies are required to understand the therapy's effectiveness better.

Pituitary carcinoma (PC) is a rare, aggressive endocrine neoplasm characterized by metastasis and challenging clinical management. The transformation from pituitary adenoma (PA) to PC is poorly understood, and predictors of metastasis remain elusive. This study evaluates the clinical course, surgical outcomes, and molecular characteristics of PC.

We retrospectively reviewed patients with PC treated at the M. D. Anderson Cancer Center between 1993 and 2023. Primary outcomes included metastasis-free survival and overall survival (OS). Clinical features, radiographic findings, surgical strategies and outcomes, immunohistochemical profiles, and MIB-1 were analyzed.

The cohort (n = 20) had a median age at PA and PC diagnosis of 33.9 and 43.3 years, respectively. The median metastasis-free interval was 7.4 years. GH- and ACTH-secreting tumors showed shorter times to PC diagnosis, while nonfunctioning PAs had longer metastasis-free survival. PAs with MIB-1 > 10% had shorter survival. Dura was the most common site of metastasis within the CNS, and bone was the most common outside the CNS. Leptomeningeal disease was seen in six patients. PAs became aggressive > five years after initial surgical resection (n = 13) or metastasized early within the first five years (n = 7). Median OS from PA diagnosis was 13.7 years, and 8.6 years from PC diagnosis. A total of 102 neurosurgical procedures were performed, with a median of five per patient; the median was similar in patients surviving longer than five years vs. those whose survival was shorter (5.0 vs. 4.5 procedures, p = 0.661). Most surgical interventions post-PC diagnosis were for optic decompression or metastasectomy. All long-term survivors (at least five years after PC diagnosis) received temozolomide-based therapy, with most also receiving radiotherapy.

PC shows a variable clinical course, with some PAs progressing to PC after years, while others transform rapidly. All long-term survivors received temozolomide-based therapy, most in combination with radiotherapy and repeated surgical intervention, suggesting that aggressive multimodal management may be associated with prolonged survival. Future research will focus on identifying reliable predictors of metastasis at different time points in the complex clinical evolution of these tumors.

Background: Para-aortic lymph node involvement is present in approximately 17-24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of Gynecology and Obstetrics (FIGO) and European Society of Gynecologic Oncology (ESGO) endorse imaging-based staging as the primary method to define radiation fields, whereas the National Comprehensive Cancer Network (NCCN) lists pre-treatment minimally invasive para-aortic lymphadenectomy as a Category 2B recommendation. Objective: We aimed to review and critically appraise the available evidence on the oncologic impact (progression-free and overall survival) of pre-treatment surgical para-aortic staging compared with clinical imaging-based staging in women with LACC. Methods: We searched MEDLINE (Ovid), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus from inception to January 2026, complemented by manually searching the reference lists for relevant articles and prior reviews. The review focused on comparative studies of women with LACC of squamous, adenocarcinoma, or adenosquamous histology-operationally defined as FIGO 2009 stages IB2-IVA with pelvic nodal involvement or FIGO 2018 stages IB3-IVA who received definitive-intent radiotherapy with or without concurrent chemotherapy and brachytherapy, and for whom comparative survival outcomes between a surgical-staging arm and an imaging-staging arm were reported. For this manuscript, a narrative review style was planned and reported in line with SANRA (Scale for the Assessment of Narrative Review Articles) quality criteria. Results: Twelve studies were included: two randomized controlled trials and ten observational studies (nine retrospective cohorts and one population-based analysis). Surgical staging consistently increased detection of occult para-aortic disease and led to more frequent use of extended-field radiotherapy (18-44%), but it did not yield a reproducible advantage in terms of progression-free or overall survival over imaging-guided chemoradiation. Conclusions: In LACC, pre-treatment surgical para-aortic staging improves anatomic and prognostic information but has not shown a consistent survival advantage over imaging-based staging combined with contemporary chemoradiation. Current comparative evidence does not support routine surgical staging, and its use still warrants further prospective evaluation in large clinical trials. Until results from ongoing phase III trials are available, surgical staging should be considered an individualized option in highly selected cases within multidisciplinary decision-making at experienced clinical centers.

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn.

In-transit melanoma (ITM) is a unique presentation of metastatic cutaneous melanoma associated with therapeutic challenges. Despite its clinical importance, the molecular drivers of ITM remain poorly defined. We aimed to characterize the mutational landscape of ITM and identify genetic alterations distinguishing it from other melanoma metastases. Tumor samples from 528 patients in the MSK-IMPACT dataset, comprised of over 300 cancer-related genes, were analyzed. Samples were classified as primary, in-transit, regional lymph node, or distant metastases. Driver mutation frequencies were compared across groups, and mutual information (MI) and principal component analysis (PCA) were used to identify ITM-associated genes and mutation patterns. NRAS Q61 mutations were enriched in ITM compared with other melanoma sites, while NF1 mutations were less common. Exploratory MI, PCA, and pairwise analyses identified recurrent NRAS^MUT/wild-type gene patterns that may distinguish ITM from other melanoma samples. Genes retained in the wild-type state alongside NRAS^MUT were associated with PI3K/AKT/mTOR, TGF-β, and E2F-related pathways. Collectively, these findings suggest that ITM is enriched for NRAS Q61 mutations and may have a comparatively lower co-mutation burden, providing a basis for future studies of ITM biology and clinical behavior.

Despite major advances in antiretroviral therapy (ART), HIV-associated malignancies remain a significant cause of morbidity and mortality in low- and middle-income countries. In Tunisia, data on AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) among people living with HIV (PLWH) remain scarce.

We conducted a descriptive retrospective cohort study over a 30-year period (1994-2024) at Farhat Hached University Hospital, Sousse, Tunisia. All PLWH who developed at least one malignant neoplasm were included. Epidemiological, clinical, immunovirological, pathological, and outcome data were retrospectively collected and analyzed.

Among 655 PLWH followed during the study period, 25 patients with a median age of 36 years developed malignancies, representing 3.8% of all PLWH. 27 malignancies were identified with 2 patients developing 2 distinct malignancies: a Kaposi sarcoma (KS) and a Non-AIDS-defining cancer (NADC). AIDS-defining cancers (ADC) predominated (81.5%), mainly KS (44.4%) and non-Hodgkin lymphoma (33.3%), while NADCs accounted for 18.5%. Cancer and HIV diagnoses were concomitant in 56% of patients (n = 14) and 92% of malignancies occurred within the first year following HIV diagnosis. Most patients presented with advanced immunodeficiency, with median CD4 counts at tumor diagnosis of 73 cells/mm³ for ADCs and 57 cells/mm³ for NADCs. Median overall survival was 1.9 years for ADCs and 3.7 years for NADCs.

In this North African cohort, HIV-associated malignancies were predominantly AIDS-defining and affected young adults with advanced immunosuppression, reflecting late HIV diagnosis for PLWH developing malignancies. Beyond strengthening early HIV testing and timely ART initiation, targeted patient education focusing on high-risk behaviors, along with efforts to reduce HIV-related stigma, are essential components to improve cancer prevention, early diagnosis, and outcomes among PLWH in resource-limited settings.

Cancer cells counteract oxidative stress through upregulation of antioxidant networks. Peroxiredoxin 3 (PRX3), a mitochondrial antioxidant enzyme, regulates reactive oxygen species homeostasis and promotes tumor cell survival. The natural compound thiostrepton (TS) covalently inhibits PRX3, disrupting redox balance and selectively induces tumor cell death. Mesothelioma, an aggressive malignancy, has limited therapeutic options, particularly in relapsed or refractory settings. Here, we demonstrate genetic deletion of PRX3 impairs mitochondrial bioenergetics and suppresses mesothelioma growth, while pharmacological inhibition of PRX3 with TS induces apoptosis in patient-derived mesothelioma explants. In a phase 1 trial treating patients with relapsed pleural mesothelioma and malignant pleural effusion (NCT05278975), weekly local intrapleural treatment with the TS formulated drug product RSO-021 at 90 mg is well tolerated leading to disease control in 67% of patients at 12 weeks and is associated with tumor reductions. Primary endpoints of safety, tolerability and dose finding were met, and secondary endpoints of pharmacokinetics, objective response rate, disease control rate, and progression free survival are explored. Genomic screening identified Solute Carrier Family 7 member 11 (SLC7A11) as a mediator of TS resistance, suggesting combined targeting may further enhance the pro-oxidant activity of RSO-021.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive and lethal malignancy originating from the epithelial cells lining the pancreatic ducts. To date, no robust biomarkers have been established to reliably predict PAAD prognosis. To identify potential transcriptional biomarkers, we analyzed transcription factor expression in PAAD patients from The Cancer Genome Atlas (TCGA) and identified ZNF821 as a novel prognostic marker. Higher ZNF821 expression was significantly associated with improved patient survival and was positively correlated with increased immune infiltration and cytotoxic activity within the tumor microenvironment. Additionally, elevated ZNF821 levels predicted a favorable response to immunotherapy. We further discovered that tumors downregulate ZNF821 through DNA methylation, facilitating immune evasion during tumor progression. To investigate its functional mechanisms, we analyzed proteins regulated by or interacting with ZNF821. Moreover, we identified existing drugs that may target ZNF821, suggesting potential therapeutic applications for PAAD. Experimental validation using RT-PCR confirmed ZNF821 downregulation in pancreatic cancer cell lines. Furthermore, tumor growth comparisons between ZNF821-overexpressing and ZNF821-null models demonstrated that ZNF821 enhances anti-tumor immunity, contributing to tumor suppression. In summary, our study identified ZNF821 as a novel prognostic biomarker in PAAD, offering new insights into tumor immune evasion and potential therapeutic strategies.