Camelia Alexandra Coadă

Correspondence on ‘MicroRNA expression as a diagnostic parameter in early endometrial cancer’ by Blagojević et al

Combined robotic surgery for concomitant treatment of endometrial cancer and obesity

Endometrial Cancer (EC) is strongly linked to obesity. Bariatric surgery is recognized as a long-term solution for weight loss in severely obese patients. This pilot study investigates the feasibility, intraoperative and 30-day morbidity outcomes of integrating gynecological surgical staging and bariatric robotic surgery in class II and III obese patients affected by early EC or Endometrial Intraepithelial Neoplasia (EIN). Patients aged over 18 years old with early EC or EIN and class II and III obesity (Body mass index (BMI) ≥ 35 kg/m Of the 13 patients who met the inclusion criteria, 5 (38.46%) opted for combined surgery. The groups showed a significant difference in preoperative BMI (49.68 kg/m Integrating robotic EC staging with SG in obese women with early EC increased the operative time without increasing intraoperative risks, early and 30 days post-surgery complication and offering a promising approach to simultaneously treating both conditions.

An Analysis of Clinical, Surgical, Pathological and Molecular Characteristics of Endometrial Cancer According to Mismatch Repair Status. A Multidisciplinary Approach

Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in which case genetic testing is performed if negative for promoter hypermethylation. The primary aim of this study was to investigate the ability of our algorithm to identify Lynch syndrome (LS). The Secondary aims were to investigate the relationship between MMR status and clinicopathological features and prognosis of primary endometrial cancer (EC). From January 2016 to December 2018, 239 patients with EC were retrospectively analyzed and subdivided according to MMR status. Patients were divided in three groups: MMR proficient, LS and Lynch-like cancer (LLC). LS was characterized by a lower age and BMI, more use of contraceptive and less use of hormonal replacement therapy, nulliparity and a trend versus a better prognosis. LLC appeared more related to MMR proficient than LS and exhibited a more aggressive behavior. Our multidisciplinary approach permitted a correct diagnosis of germline mutation in patients with newly diagnosis EC and it confirmed clinicopathologic and prognostic characteristics of LS.

Mitochondrial chaperonin DNAJC15 promotes vulnerability to ferroptosis of chemoresistant ovarian cancer cells

DNAJC15 is a mitochondrial TIMM23-related co-chaperonin known for its role in regulating oxidative phosphorylation efficiency, oxidative stress response and lipid metabolism. Recently, it has been proposed that the loss of DNAJC15 correlates with cisplatin (CDDP)-resistance onset in ovarian cancer (OC), suggesting this protein as a potential prognostic factor during OC progression. However, the molecular mechanisms through which DNAJC15 contributes to CDDP response remains poorly investigated. Here, we show that high levels of DNAJC15 are associated with accumulation of lipid droplets, decreased tumorigenic features and increased sensitivity to CDDP in OC cells. When overexpressed, DNAJC15 induced a phenotype displaying increased lipid peroxidation and subsequent ferroptosis induction. To prove a role for DNAJC15-induced ferroptosis in promoting sensitivity to CDDP, we reduced lipid peroxidation upon Ferrostatin 1 treatment, which decreased cells’ vulnerability to ferroptosis ultimately recovering their CDDP-resistant phenotype. In conclusion, our study uncovers the role of DNAJC15 in modulating ferroptosis activation and in the onset of CDDP resistance in OC cells.

Electrochemotherapy with intravenous bleomycin for heavily pre-treated vulvar cancer patients

The management of vulvar cancer recurrences is complicated by patients' advanced age and comorbidities. Bleomycin-based electrochemotherapy is a potential treatment option in this setting. However, no data on long-term outcomes are available. Therefore, a multicenter observational study was designed to evaluate the 5-year results in these patients. Data about patients and tumor characteristics, electrochemotherapy cycles, clinical response, and follow-up were recorded. Treatment procedures were performed according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines. Response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Fifty-one patients (mean age 82.31±7.28 years) with squamous cell vulvar cancer underwent electrochemotherapy (median number of sessions 1; range 1-4). 20 patients had complete response and 32% of these were disease-free after 2 years (median progression-free survival 16.8 months). In 13 patients with partial response the median progression-free survival was 15.36 months, while patients with stable or progressive disease showed tumor relapse after 6.95 and 3.26 months, respectively (p<0.001). Median overall survival was 18.77, 13.07, 6.73, and 11.13 months in patients with complete response, partial response, stable disease, and progressive disease, respectively (p=0.001). Long-term follow-up of vulvar cancer patients showed reasonable tumor control after electrochemotherapy and improved progression-free survival and overall survival in responder subjects compared with non-responders. Further studies aimed at improving local response after electrochemotherapy are warranted. Thus, this approach represents a potential alternative for these patients.

Endometrial carcinoma and immune escape: prognostic relevance of HLA class I loss in NSMP subtype

Aims This study aims to define and characterize human leukocyte antigen class I (HLA‐I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer–immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results HLA‐I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE ‐mutated, MMR‐deficient (MMRd), p53‐abnormal (p53abn) and NSMP subtypes. Loss of HLA‐I was identified in 31% of cases and was associated with adverse features including high‐grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an ‘excluded’ immune phenotype. While HLA‐I loss showed no significant prognostic impact in POLE , MMRd or p53abn tumours, it significantly correlated with worse disease‐free survival in NSMP tumours ( P  &lt; 0.001). Multivariate analysis confirmed HLA‐I loss as an independent prognostic factor in early‐stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer–immune phenotypes. Integration of HLA‐I status improved the performance of predictive models over time. Conclusions HLA‐I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA‐I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.

miRNA levels are associated with body mass index in endometrial cancer and may have implications for therapy

AbstractEndometrial cancer (EC) is the most prevalent gynecological cancer in high‐income countries. Its incidence is skyrocketing due to the increase in risk factors such as obesity, which represents a true pandemic. This study aimed to evaluate microRNA (miRNA) expression in obesity‐related EC to identify potential associations between this specific cancer type and obesity. miRNA levels were analyzed in 84 EC patients stratified based on body mass index (BMI; ≥30 or &lt;30) and nine noncancer women with obesity. The data were further tested in The Cancer Genome Atlas (TCGA) cohort, including 384 EC patients, 235 with BMI ≥30 and 149 with BMI &lt;30. Prediction of miRNA targets and analysis of their expression were also performed to identify the potential epigenetic networks involved in obesity modulation. In the EC cohort, BMI ≥30 was significantly associated with 11 deregulated miRNAs. The topmost deregulated miRNAs were first analyzed in 84 EC samples by single miRNA assay and then tested in the TCGA dataset. This independent validation provided further confirmation about the significant difference of three miRNAs (miR‐199a‐5p, miR‐449a, miR‐449b‐5p) in normal‐weight EC patients versus EC patients with obesity, resulting significantly higher expressed in the latter. Moreover, the three miRNAs were significantly correlated with grade, histological type, and overall survival. Analysis of their target genes revealed that these miRNAs may regulate obesity‐related pathways. In conclusion, we identified specific miRNAs associated with BMI that are potentially involved in modulating obesity‐related pathways and that may provide novel implications for the clinical management of obese EC patients.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival

Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. PROSPERO Identifier: CRD42022334959.