The Wnt signaling pathway antagonist SFRP1 is frequently silenced by promoter DNA hypermethylation in colorectal cancer (CRC). MBD2, a DNA methylation reader, is known to contribute to SFRP1 epigenetic silencing. Previous work showed that MBD2 critically suppresses SFRP1 expression without altering promoter methylation, though the underlying mechanism remained unclear. Elucidating how DNA methylation silences tumor suppressor genes, such as SFRP1, could reveal novel therapeutic targets with significant clinical potential.

MBD2 was inhibited in CRC models using either siRNA or a small molecule inhibitor (KCC07). The effects on SFRP1 and β-catenin expression, Wnt pathway activity, cell proliferation, and apoptosis were assessed. Tumor growth was also evaluated in vivo. Mechanistic studies investigated the role of MBD2 in mediating MED19 binding to the SFRP1 promoter and its impact on RNA polymerase II CTD-S7 phosphorylation.

The IC50 of KCC07 was 23.25 μM in SW480 cells, 26.83 μM in HCT116 cells, and 39.66 μM in NCM460 cells. Inhibition of MBD2, either genetically or pharmacologically with KCC07, upregulated SFRP1 expression, downregulated β-catenin, and suppressed the Wnt pathway. KCC07 treatment also inhibited CRC cell proliferation, promoted apoptosis, and suppressed tumor growth in vivo. Mechanistically, MBD2 was found to silence SFRP1 by blocking MED19 binding to its promoter, which subsequently reduced RNA polymerase II CTD-S7 phosphorylation and impaired transcription.

This study reveals a novel mechanism whereby DNA methylation suppresses gene expression via MBD2, independent of changes in methylation status, by disrupting MED19 binding and subsequent transcription. Targeting MBD2 represents a promising therapeutic strategy for colorectal cancer.

In Italy, the first women invited for HPV vaccination at 15-16 years reached the age for cervical screening (25 years) in 2018. The real-world vaccination impact was evaluated. Women born in 1993-1996 invited for organised cervical screening in three Italian areas in 2018-2022 were eligible. After informed consent, they were tested for high-risk HPV and genotyped. Positives, triaged by cytology, were immediately referred to colposcopy if ASCUS+ (irrespective of genotyping); otherwise, recalled for cytology after 3 years. We estimated the relative (vaccinated with ≥ 2 doses vs. unvaccinated women) infection prevalence of three groups of genotypes: HPV16/18, HPV31/33/45 and HPV 35, 39, 51, 52, 56, 58, 59, 66, 68 ('non-vaccine preventable') and the relative positive predictive value (PPV) for histology-based CIN2+ detected at immediate colposcopy. Of 14,346 enrolled women, 34% had no vaccination, 66% ≥ 2 doses. The relative infection prevalence was 0.05 (0.03-0.10) for HPV16/18 without non-vaccine genotypes, 1.36 (1.23-1.50) for non-vaccine genotypes without HPV16/18 infections and 0.06 (0.03-0.12) for co-infections by both groups. The relative PPV for CIN2+ was very high (4.09; 1.40-12.01) in vaccinated women co-infected by HPV16/18 and non-vaccine types (4/9 vs. 7/84 cases) but reduced to zero in case of stand-alone HPV16/18 infections (0/12 vs. 15/117 cases). The CIN2+ relative detection in women infected only by non-vaccine types was 1.57 (0.87-2.82). The increase in infections and high-grade CIN from the pool of all non-vaccine genotypes requires further research (including pooling of data) to be confirmed with longer follow-up and on a larger study population.

Sleep health, defined as a multidimensional construct encompassing regularity, duration, efficiency, satisfaction, timing, and daytime alertness, is a neglected pillar of testicular cancer survivorship. In parallel, common sleep disorders, including insomnia disorder and obstructive sleep apnea, remain underrecognized despite their relevance to cardiometabolic and endocrine health. This comment argues for the systematic integration of sleep screening and targeted interventions, such as CBT-I, into multi-disciplinary survivorship care. Recognizing sleep as a fundamental component of recovery offers a high-impact opportunity to optimize long-term clinical outcomes and quality of life for survivors.

Intracholecystic papillary-tubular neoplasms (ICPNs) are infrequent preinvasive gallbladder lesions. The literature lacks standard reporting criteria and is limited to single-center series and case reports. This systematic review and meta-analysis aimed to synthesize the available evidence on their epidemiology, pathology, and possible association between high-grade dysplasia and invasive carcinoma.

MEDLINE, Scopus, and Web of Science were searched on the June 9, 2025, for "intracholecystic papillary neoplasm" OR "intracholecystic papillary-tubular neoplasm" OR "ICPN" (PROSPERO ID: CRD420250636493). Human studies reporting histologically confirmed ICPNs were included, and case reports, reviews, and animal studies were excluded. Pooled proportions were calculated using generalized linear mixed models with random effects and restricted maximum likelihood.

A total of 17 retrospective series, including 15,018 cholecystectomies and 620 ICPN cases, met the criteria. In four studies (13,559 cholecystectomies), the pooled incidence of ICPNs was 1.5% (95% confidence interval [CI] 0.8-2.8). The patients were mainly female (56%), with a mean age of 65 years. Papillary architecture and biliary or gastric phenotypes were also predominant. High-grade dysplasia was observed in the 35.4% of the lesions (six studies) and concomitant gallbladder adenocarcinoma in 26.9% (nine studies). Lymph node metastases were present in 18% of invasive cases, and the 5-year overall survival ranged from 46.7% to 89.7%.

ICPNs are uncommon but clinically relevant preinvasive gallbladder neoplasms that frequently harbor high-grade dysplasia or invasive carcinoma. Future research should aim to improve the preoperative diagnostic accuracy, define possible pathological-clinical correlations, and optimize the surgical management.

Hyalinizing clear cell carcinoma (HCCC) is a rare tumor. Most lesions arise in the salivary gland; however, other primary sites include the nasal and oral cavities, and rarely lung. Lesions are characterized by tumor lobules with pale or clear cytoplasm, arranged in nests or cords, surrounded by a mixed hyalinized and fibrocellular stroma. EWSR1-ATF1 gene fusion is often reported in these lesions. Typically, HCCC bears a good prognosis. We report a unique case of primary lung HCCC (PLHCCC) with cutaneous metastasis and aggressive clinical course. To the best of our knowledge, cutaneous metastasis by PLHCCC has not been previously observed and may signal an aggressive clinical course with poor prognosis.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with brain metastasis being one of the most common complications in advanced-stage disease. The development of noninvasive and efficient early diagnostic methods is therefore of critical clinical importance. In this study, untargeted liquid chromatography-mass spectrometry (LC-MS) was employed to perform metabolomic profiling of 66 serum samples from patients with lung cancer brain metastasis, early-stage lung cancer, and healthy controls. A total of 719 metabolites were identified with high data reliability. Comparative analysis revealed 20 significantly upregulated and 12 significantly downregulated metabolites in the lung cancer brain metastasis group. These differentially expressed metabolites were primarily enriched in amino acid and energy metabolism pathways. This specific metabolic signature was highly associated with the brain metastatic state. Although not yet validated for clinical application, this profile demonstrated robust discriminatory power within the current cohort and serves as a potential set of risk-stratification biomarkers. These findings identify a distinct metabolic phenotype associated with brain metastasis, laying the critical groundwork for future research into noninvasive diagnostic strategies. Nevertheless, further validation within independent, longitudinal cohorts is required.

Primary tumors of the pulmonary artery are rare and often mimic thromboembolic disease, leading to delayed diagnosis with potentially serious consequences.

A middle-aged woman with reduced exercise tolerance was found to have a progressive left hilar mass causing near-complete obstruction of the left pulmonary artery. Given high procedural risk, an intracardiac echocardiography (ICE)-guided endovascular biopsy was performed. Tissue sampling was successful and complication free. Histopathology and molecular analysis demonstrated a malignant pleomorphic neoplasm with MDM2 amplification, consistent with pulmonary artery intimal sarcoma.

ICE-guided biopsy enables safe, real-time tissue acquisition from central pulmonary artery lesions. This technique enables timely histological and molecular diagnosis, especially when conventional biopsy approaches are deemed too risky.

Pulmonary artery intimal sarcoma should be differentiated from thromboembolic disease using imaging and clinical progression. ICE-guided biopsy represents a safe diagnostic option in high-risk cases and supports multidisciplinary decision-making.

Adenomatoid tumor is a rare benign neoplasm of mesothelial origin occurring in various anatomical locations, including the uterus. In this article, we describe an adenomatoid tumor of the uterus exhibiting severe nuclear atypia in the clinical context of long-term hormone therapy. The patient was a 51-year-old woman who underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy for uterine leiomyomas. Gross evaluation of the uterus revealed multiple intramural and subserosal unencapsulated nodules that were both well and poorly circumscribed and measured from 4 to 25 mm. Microscopically, one of the nodules consisted of hyperplastic leiomyocytes intermixed with irregular vascular-like and tubular spaces lined by flattened cells that occasionally showed moderate to severe nuclear atypia (enlargement, hyperchromasia, and multinucleation). Bizarre pleomorphic cells were also present. Mitotic activity was minimal. The tumor cells showed diffuse positivity for calretinin, keratin AE1/AE3, L1 cell adhesion molecule, and podoplanin, while CD31, CD34, epithelial membrane antigen, HMB45, MDM2, and S100 protein stains were negative. Expression of BRCA1-associated deubiquitinase 1 and methylthioadenosine phosphorylase was retained. This immunophenotype supported a mesothelial origin of the neoplastic cells, leading to the final diagnosis of adenomatoid tumor with marked nuclear atypia. Unusual histopathological findings in adenomatoid tumors, such as marked nuclear atypia and pleomorphism, may pose significant diagnostic challenges and result in misdiagnosis. Despite these unusual features, the tumor in our study showed no evidence of aggressive behavior or malignant transformation. Although we hypothesize that these changes may be related to prolonged hormone therapy, their pathogenesis and clinical significance remain unclear, underscoring the need for further investigation.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoma with a poor prognosis. The human T-lymphotropic virus 1 (HTLV-1) is associated with immunodeficiency and increased extranodal involvement in patients with diffuse large B-cell lymphoma (DLBCL). We report on a 47-year-old woman with spastic paraparesis and hepatitis B who was diagnosed with the acute form of ATLL. The clinical picture reveals peripheral generalized lymphadenopathy and splenomegaly. Findings on a hematologic exam indicated leukocytosis with lymphocytosis. A bone marrow biopsy/aspiration confirmed 50% T-cell lymphoid infiltration. Biochemistry results revealed hypercalcemia and a high lactate dehydrogenase value. Results of a CT scan indicated abdominal and thoracic adenopathy as well as moderate splenomegaly. A supraclavicular lymph node biopsy established a DLBCL diagnosis. The final diagnosis was composite lymphoma, DLBCL, and ATLL. The CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], and prednisone) regimen was chosen due to the patient's ECOG performance status. Multiple infectious complications were diagnosed during chemotherapy-induced secondary aplasia. A complete remission, confirmed via PET-CT imaging, was obtained. After 1 month, a skin tumor on the upper right thigh was discovered and biopsied, and the histopathological exam and immunochemistry findings indicated Epstein-Barr virus-DLBCL lymphoma. The association of 2 aggressive lymphomas in a single HTLV-1 carrier is a rare report, and the evolution was severe, complicated by opportunistic infections, and unfavorable.

Synovial sarcoma (SS) is a genetically defined soft tissue sarcoma driven by the pathognomonic SS18::SSX fusion and is generally characterized by a low burden of secondary genomic alterations. We report a 42-year-old man with metastatic SS harboring both the SS18::SSX1 rearrangement and the BRAF V600E mutation. The patient developed metastatic disease following standard multimodal therapy. Comprehensive genomic profiling using DNA and RNA based next-generation sequencing identified the SS18::SSX1 fusion and the activating BRAF V600E mutation. The SS18 rearrangement was further confirmed by fluorescence in situ hybridization (FISH), and immunohistochemistry supported the histologic diagnosis. Treatment with combined BRAF and MEK inhibition (dabrafenib and trametinib) resulted in a clinical response. In addition to this index case, a literature review identified multiple additional SS harboring BRAF V600E, supporting its role as a recurrent, potentially targetable alteration in a small subset of SS. These findings highlight the value of comprehensive genomic profiling in SS, particularly in advanced or refractory cases, to identify rare but actionable molecular events that may expand therapeutic options.