Gloucestershire Royal Hospital is an acute District General Hospital on the Great Western Road in Gloucester operated by the Gloucestershire Hospitals NHS Foundation Trust.
Abstract Vulvovaginal mucosal melanomas (VVMMs) affect 1.6 individuals per million per year. Patients frequently present with advanced disease and have poor outcomes. As VVMMs are rare, there is a paucity of high-quality evidence on which to base treatment strategies. This study aimed to describe the clinical course and outcomes for patients diagnosed with VVMM and audit the service provided in our tertiary referral centre. In total, 18 cases of VVMM were identified from 358 records of patients diagnosed with vulvovaginal cancer between January 2015 and September 2025. Treatment course and patient outcomes were compared with standards set out by Melanoma Focus for ano-uro-genital mucosal melanoma. Fifteen patients (83%) were first assessed in a gynaecology urgent suspected cancer clinic, and 15 (83%) underwent a diagnostic biopsy prior to surgical resection. Seventeen (94%) had invasive disease at presentation and 50% had an initial Breslow thickness ≥ 4 mm. Overall, 78% had features of both melanoma in situ and invasive disease. Lateral margins following excision were involved in 53%, predominantly with in situ disease. When next-generation sequencing was performed, KIT mutations were identified in 17% (n = 2). Most patients underwent staging investigations including computed tomography (CT) of the thorax, abdomen and pelvis, and CT of the head (93%). Adjuvant treatments included dacarbazine chemotherapy (n = 1), radiotherapy (n = 3) and immunotherapy (n = 8). Five (28%) of the 18 patients were deceased at the point of data collection. One-quarter of patients (2 of 8, 25%) who received immunotherapy did not survive, compared with 30% (3 of 10) who did not receive immunotherapy; treatment was frequently limited by adverse effects. No patients underwent formal assessment of the impact of VVMM on their quality of life. This study highlights the critical need for further research into optimal management strategies for VVMM, particularly the impact of molecular profiles and relevance of immunotherapy. Studies into the impact of VVMM on quality of life are urgently required. Our team have developed a local standard operating procedure to improve patient management.
Breast cancer is the most common malignancy in women worldwide. A large proportion of breast cancer cases demonstrate human epidermal growth factor receptor 2 (HER2) overexpression. Trastuzumab emtansine (T-DM1) is an established therapy for HER2-positive metastatic breast cancer, though rare but serious adverse effects may occur. We report a 58-year-old woman with HER2-positive metastatic breast cancer who developed progressive exertional dyspnoea while receiving T-DM1. Echocardiography demonstrated right ventricular dilation and dysfunction with elevated pulmonary pressures. Right heart catheterisation confirmed pulmonary arterial hypertension (PAH) with increased pulmonary vascular resistance. Comprehensive evaluation, including computed tomography, pulmonary angiography, and ventilation-perfusion scanning, excluded thromboembolic disease. There was no significant parenchymal lung disease, and left ventricular function was preserved. In the absence of alternative causes and given the temporal relationship with T-DM1 exposure, drug-induced PAH was considered likely. The patient was treated with sildenafil and ambrisentan, resulting in symptomatic and haemodynamic improvement. Concurrent hepatotoxicity also resolved following discontinuation of T-DM1, further supporting a causal association. PAH is a rare complication of HER2-targeted therapies, with limited cases reported. This case highlights the importance of recognising PAH as a potential adverse effect of T-DM1. Clinicians should maintain a high index of suspicion in patients presenting with unexplained dyspnoea or right ventricular dysfunction to enable early diagnosis and appropriate management.
Abstract Background Zinc finger protein 36-like 1 (ZFP36L1) is an AU-rich element-binding RNA-binding protein that regulates post-transcriptional gene expression and has been implicated in tumor progression, cell-cycle regulation, and DNA damage responses. However, its functional role in triple-negative breast cancer (TNBC) remains poorly understood. This study investigated the effects of CRISPR/Cas9-mediated ZFP36L1 knockout on cell proliferation, doxorubicin (DOX) sensitivity, cell-cycle progression, and DNA damage responses in MDA-MB-231 TNBC cells. Methods Wild-type (WT) and CRISPR/Cas9-generated ZFP36L1 knockout (KO) MDA-MB-231 cells were cultured under standard conditions. Cellular proliferation was evaluated by cell counting over three weeks. Cell viability following DOX treatment was determined using the MTT assay, and half-maximal inhibitory concentration (IC 50 ) values were calculated. Cell-cycle distribution was assessed by propidium iodide flow cytometry after 24 h of DOX exposure, while DNA damage was quantified by γ-H2AX flow cytometric analysis. Statistical significance was determined using Student’s t -test with P < 0.05 considered significant. Results ZFP36L1 knockout reduced the proliferative capacity of MDA-MB-231 cells compared with WT cells. Both cell lines exhibited dose-dependent decreases in viability following DOX treatment. KO cells demonstrated a higher mean IC 50 than WT cells (9.64 vs. 8.40 μM), indicating a trend toward reduced DOX sensitivity; however, this difference was not statistically significant ( P = 0.569). Flow cytometric analysis revealed enhanced accumulation of KO cells in the S and G 2 /M phases following DOX treatment, suggesting altered cell-cycle checkpoint regulation. Furthermore, KO cells exhibited elevated basal γ-H2AX expression and greater DOX-induced γ-H2AX accumulation than WT cells, indicating increased DNA damage and impaired maintenance of genomic stability. Conclusions CRISPR/Cas9-mediated loss of ZFP36L1 suppresses proliferation, alters cell-cycle checkpoint dynamics, and enhances DNA damage accumulation in MDA-MB-231 TNBC cells. These findings indicate that ZFP36L1 plays a context-dependent role in regulating genomic stability and cellular responses to genotoxic stress, highlighting its potential as a biomarker and therapeutic target in triple-negative breast cancer.
