Multiple endocrine neoplasia syndrome type 1 (MEN-1) is a rare, autosomal dominant disorder resulting from inactivating mutations in the MEN1 gene. It demonstrates high penetrance, with the "classic triad" of manifestations comprising primary hyperparathyroidism (PHPT), gastrointestinal neuroendocrine neoplasms (NEN), and pituitary adenomas. Diagnosis relies on clinical, familial, and genetic criteria. However, significant phenotypic variability and the lack of a clear genotype-phenotype correlation complicate early diagnosis.

 To investigate the clinical-epidemiological, laboratory-instrumental, and genetic characteristics of familial MEN-1 in the Russian population.

 We conducted a single-center, single-stage study (2015-2025) at the Endocrinology Research Centre enrolling 102 genetically confirmed MEN-1 patients from 43 families. Participants were stratified by age at PHPT onset (≤18 years, 19-40 years, and >40 years) and MEN1 mutation type/location. We compared groups using calcium-phosphorus metabolism parameters, disease progression patterns, PHPT surgical outcomes, and genotype-phenotype correlations.

 Cohort baseline characteristics (sex, manifestations) were comparable (p>0,05), but we observed significant differences in NEN onset age (p<0,001) and a trend toward higher pituitary adenoma prevalence (p=0,003). Exon 10 mutation were associated with a 7,7-fold increased pituitary adenoma risk (OR=7,7; p=0,006), though mutation type did not predict broader phenotype. Groups did not differ in multiglandular involvement, surgical outcomes, or histopathology (p>0,05).

 MEN-1 exhibits marked clinical heterogeneity in the Russian population, with exon 10 mutations significantly increasing pituitary adenoma risk. Early-onset PHPT predicts earlier NEN and pituitary adenoma development. These findings support proactive genetic screening and risk-stratified monitoring for MEN-1 families.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, largely due to metastasis and therapeutic resistance. Beauvericin, a cyclohexadepsipeptide mycotoxin produced by Beauveria and Cordyceps species, has demonstrated anticancer activity in multiple malignancies; however, its mechanistic effects in CRC have not been fully defined. In this study, we investigated the cellular and molecular effects of beauvericin in HCT116 and SW480 CRC cells using in vitro models. Beauvericin reduced cell viability and clonogenic growth, induced G0/G1 cell-cycle arrest, and activated mitochondria-dependent apoptosis through modulation of Bcl-2 family proteins and caspase activation. At sub-cytotoxic concentrations, beauvericin significantly suppressed migratory and invasive phenotypes and attenuated epithelial-mesenchymal transition (EMT)-associated features, accompanied by reduced activation of integrin α6/FAK/Src/ERK1/2 signaling without altering total protein expression. Conditioned medium from beauvericin-treated CRC cells markedly inhibited endothelial proliferation, invasion, and tube formation, coinciding with reduced VEGF secretion. Network-based target prediction and immunoblot validation further demonstrated that beauvericin treatment was associated with decreased phosphorylation of JAK2, STAT1, and STAT3. Collectively, these findings indicate that beauvericin modulates multiple malignant phenotypes of CRC cells in vitro by inducing mitochondrial apoptosis and attenuating EMT-associated signaling, VEGF-dependent endothelial activation, and JAK/STAT pathway activity. These results provide mechanistic insight into the anti-tumor potential of beauvericin and support further preclinical evaluation.

The ketogenic diet (KD) is an emerging metabolic approach for enhancing the efficacy of cancer therapy, and the KD is characterized by increased production of ketone bodies, including β-hydroxybutyrate (β-HB). Clarifying the direct effects of β-HB on cancer cells is critical for optimizing the therapeutic potential of KD. In this study, we show that β-HB levels were markedly decreased in tumor tissues and serum from patients with breast cancer, particularly in metastatic patients. Additionally, β-HB supplementation demonstrated potent antitumor effects in breast cancer models in vitro and in vivo. P21-activated kinase 5 (PAK5) inhibited β-HB synthesis by interacting with 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), a key enzyme in ketone generation, and inducing phosphorylation at Ser138 and Ser311. PAK5-mediated HMGCS2 Ser138 phosphorylation recruited the E3 ubiquitin ligase BMI1, thereby facilitating HMGCS2 degradation, and phosphorylation at Ser311 reduced the enzymatic activity of HMGCS2 by inhibiting SIRT3-dependent deacetylation. Collectively, phosphorylation at these two sites coordinately suppressed the generation of intracellular β-HB. Elevated PAK5 in breast cancer stimulated lymph node metastasis, whereas the expression of HMGCS2, particularly its nonphosphorylatable mutants, inhibited PAK5-driven breast tumor growth and metastasis. Consistently, KD or β-HB treatment could reverse breast cancer progression induced by PAK5. Low HMGCS2 expression and β-HB synthesis were associated with lymph node metastasis and poor clinical outcomes in patients, and PAK5 protein levels positively correlated with HMGCS2 phosphorylation at Ser311 residue in breast cancer tissues. Together, these findings demonstrated that the PAK5-HMGCS2 pathway drives breast cancer metastasis and can be circumvented using a KD.

PAK5-mediated phosphorylation of HMGCS2 promotes breast cancer growth and metastasis by inhibiting β-hydroxybutyrate production, revealing the role of PAK5 in ketone metabolism and highlighting a potential therapeutic target for breast cancer metastasis.

T-cell lymphomas (TCLs) account for a relatively small fraction of lymphoid malignancies and are characterized by highly aggressive course often refractory to current available therapies. We previously reported potent in vitro and in vivo antitumor activity of a Bispecific T-Cell Engager (UMG1/CD3ε-BTCE) directed against UMG1, a unique CD43 epitope that is abundantly expressed on T-cell acute lymphoblastic leukemia (T-ALL) and diffuse large B-cell lymphoma (DLBCL) cells, while absent in most normal tissues, except thymocytes and a small fraction of peripheral blood T lymphocytes (< 5%). Here, we investigated the in vitro efficacy of UMG1/CD3ε-BTCE against TCLs. IHC analysis of Tissue Micro Arrays (TMAs) revealed high UMG1 expression in 62.3% of TCL samples, including peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and ALK-negative anaplastic large cell lymphoma (ALCL). Notably, all T-PLL primary specimens (27/27) were positive, and 3 of 4 TCL cell lines also expressed UMG1 by flow cytometry. The asymmetric UMG1/CD3ε-BTCE induced robust redirected cytotoxicity against UMG1-expressing TCL cells. Moreover, this activity was strengthened by cell exposure to the HDAC inhibitor SAHA. We observed a dose-dependent engaged T-cell-mediated cytotoxicity and inflammatory cytokine release, resulting in lysis of UMG1-expressing cells, with no significant effect on UMG1-not expressing cells. Our findings suggest that the UMG1/CD3ε-BTCE selectively exerts potent anti-tumor activity against a relevant subset of TCLs. These findings support the development of a precision immunotherapy approach for patients with UMG1-expressing aggressive hematologic malignancies.

To investigate whether neuroendocrine carcinoma of the cervix (NECC) with coexisting non-neuroendocrine tumor components (mixed subtype) is associated with a worse prognosis compared to the pure subtype.

A total of 121 patients diagnosed with NECC at 4 participating hospitals in the Republic of Korea between August 1997 and November 2023 were included. All diagnoses were confirmed through surgical specimens obtained via conization or hysterectomy. Clinical and pathological variables were collected through medical record review. The association between tumor heterogeneity (pure vs. mixed subtype) and progression-free survival (PFS) was analyzed using a Cox proportional hazards model.

The majority of patients was diagnosed at stage I (62%), had small cell histology (63%), and presented with the pure subtype (66%). Most patients (n=106) underwent surgery with or without adjuvant therapy as initial treatment. In univariate analysis, there was no significant difference in PFS between the pure and mixed subtypes (p=0.952). However, after adjusting for covariates, the mixed subtype was significantly associated with worse PFS compared to the pure subtype (adjusted hazard ratio=3.16; 95% confidence interval=1.58-6.35; p=0.001).

NECC with non-neuroendocrine components is associated with significantly worse prognosis than the pure subtype.

Gastric-type endocervical adenocarcinoma (G-EAC) is a distinctive form of adenocarcinoma that is not associated with human papillomavirus. This neoplasm exhibits a low incidence, low screening and biopsy positivity, low preoperative diagnosis, and a high susceptibility to underdiagnosis and misdiagnosis. It is associated with a poor prognosis for patients. Currently, there is an absence of a standardized postoperative adjuvant treatment plan for G-EAC, which constitutes an urgent clinical problem that demands resolution. However, there is still no prospective analysis on the adjuvant treatment of cervicogastric adenocarcinoma. This study is the first randomized phase III trial, which aims to recommend better adjuvant treatment options for G-EAC patients at high risk of recurrence in China, in order to better optimize and personalize patient care and improve progression-free survival (PFS) and overall survival (OS).

This trial is a prospective, multicenter study led by the Department of Radiotherapy, Women's Hospital of Zhejiang University. Recruitment will begin in March 2025, and it is expected that 238 patients with postoperative G-EAC with high risk of recurrence will be recruited from 16 clinical centers in China. Patients will be randomly assigned to the experimental group or the control group in a 1:1 ratio. The experimental group will receive paclitaxel combined with platinum-based concurrent chemoradiotherapy (CCRT) and short-term adjuvant chemotherapy, and the control group will receive the current standard treatment regimen, i.e., platinum-based CCRT, without adjuvant chemotherapy. The primary endpoint of the study is the 2-year PFS rate, and the secondary endpoints are disease treatment failure pattern, OS rate, acute/chronic toxicity incidence, and quality of life assessment.

ClinicalTrials.gov Identifier: NCT06870565.

Pediatric gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are extremely rare and clinically heterogeneous. Management has largely been extrapolated from adult practice. This European Standard Clinical Practice Guideline (ESCP), developed by the EXPeRT network in collaboration with adult NEN experts, provides (adult) evidence-informed and consensus-driven recommendations. Using a literature review and GRADE methodology, we address clinical evaluation, imaging pathology, genetics, surgical and systemic therapies, and long-term surveillance. Surgical resection is the cornerstone in localized disease. Systemic treatments are largely adapted from adult data, including somatostatin analogues, radiopharmaceutical therapy, and targeted agents. Multidisciplinary care, genetic counseling, and lifelong follow-up are essential to optimize outcomes.

In colorectal cancer (CRC), circulating tumour cells (CTCs) employ genetic alterations to dodge the body's immune system. These alterations occur in specific "driver" genes, including KRAS, BRAF, p53, MYC, APC and PTEN. Changes in these genes can control how the tumour interacts with the immune system and influence the expression of immune checkpoint molecules such as PD-1, PD-L1, PD-L2, CTLA-4 and CD47. These molecules help suppress the immune system's response against the tumour, thus promoting tumour growth. However, the precise relationship between driver gene mutations and the expression of immune checkpoint molecules in CTCs, along with their clinical significance, remains incompletely understood. By studying these genetic changes and how they affect the behaviour of CTCs, researchers can gain critical insights into the development and progression of CRC, especially the roles of CTCs, which could improve CTCs' implications in liquid biopsy. Moreover, understanding these alterations can also highlight potential therapeutic targets. This may pave the way for more effective, targeted therapies to delay or prevent CRC progression. Therefore, investigating the genetic alterations in CTCs and their role in immune escape mechanisms is a significant area of study in CRC research.

Cutaneous squamous cell carcinoma (cSCC) is a common neoplasm in fair-skinned individuals. Its clinical management requires appropriate histological diagnosis, risk stratification, and an individualized selection of imaging studies. This review summarizes the key aspects of cSCC staging and the selective indication for sentinel lymph node biopsy, integrating the most relevant classification systems (AJCC-8, BWH, UICC-8) and the main prognostic factors. Current recommendations on the use of imaging and the criteria for considering a cSCC as locally advanced or high-risk are also reviewed. The evidence is based on national and international guidelines published between 2015 and 2025.

Melanoma progression is driven by both oncogenic signaling and metabolic reprogramming; however, the roles of G-protein-coupled receptors (GPCRs) in these processes remain unclear. Here, we identified GPR161 as an oncogenic GPCR that is significantly upregulated in melanoma and associated with poor survival in advanced-stage melanoma. Functional studies revealed that GPR161 promotes melanoma cell proliferation and migration, whereas its suppression attenuates these malignant phenotypes. Using promoter analysis and chromatin immunoprecipitation-quantitative polymerase chain reaction, we demonstrated that signal transducer and activator of transcription 3 (STAT3) binds directly to and transcriptionally activates GPR161. Inhibition or silencing of STAT3 reduced GPR161 expression and impaired melanoma cell growth. Transcriptomic profiling further identified thioredoxin-interacting protein (TXNIP) as a key downstream target negatively regulated by GPR161. GPR161 depletion increased TXNIP expression, leading to reduced glycolytic capacity and proliferation under both physiological and high-glucose conditions. STAT3 knockdown recapitulated these effects by establishing a STAT3-GPR161-TXNIP regulatory axis. Analysis of the cancer genome atlas datasets confirmed an inverse correlation between GPR161 and TXNIP expression and showed that low TXNIP levels predicted poor overall survival. Together, our findings revealed that GPR161 promotes melanoma malignancy by linking STAT3 activation to TXNIP suppression and metabolic enhancement. This study identified GPR161 as a potential biomarker and therapeutic target in melanoma.