Vincenzo Canzonieri

Unlocking the potential of organopalladium complexes for high-grade serous ovarian cancer therapy

High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations.

Palladium(II)-Indenyl Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models

In this study, we synthesized novel Pd(II)-indenyl complexes using various

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

Overview of Tumor Heterogeneity in High-Grade Serous Ovarian Cancers

Ovarian cancers encompass a group of neoplasms originating from germinal tissues and exhibiting distinct clinical, pathological, and molecular features. Among these, epithelial ovarian cancers (EOCs) are the most prevalent, comprising five distinct tumor histotypes. Notably, high-grade serous ovarian cancers (HGSOCs) represent the majority, accounting for over 70% of EOC cases. Due to their silent and asymptomatic behavior, HGSOCs are generally diagnosed in advanced stages with an evolved and complex genomic state, characterized by high intratumor heterogeneity (ITH) due to chromosomal instability that distinguishes HGSOCs. Histologically, these cancers exhibit significant morphological diversity both within and between tumors. The histologic patterns associated with solid, endometrioid, and transitional (SET) and classic subtypes of HGSOCs offer prognostic insights and may indicate specific molecular profiles. The evolution of HGSOC from primary to metastasis is typically characterized by clonal ITH, involving shared or divergent mutations in neoplastic sub-clones within primary and metastatic sites. Disease progression and therapy resistance are also influenced by non-clonal ITH, related to interactions with the tumor microenvironment and further genomic changes. Notably, significant alterations occur in nonmalignant cells, including cancer-associated fibroblast and immune cells, during tumor progression. This review provides an overview of the complex nature of HGSOC, encompassing its various aspects of intratumor heterogeneity, histological patterns, and its dynamic evolution during progression and therapy resistance.

Exceptional Response to Trastuzumab Deruxtecan (T-DXd) in HER2-Positive Metastatic Endometrial Cancer

Objectives: Endometrial cancer is the most common gynaecologic malignancy, and its mortality rate is rising. Advanced or recurrent disease remains challenging because historically there have been limited therapeutic options. We aim to describe a complete and durable response to the HER2-directed antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in a heavily pretreated patient with HER2-positive, mismatch-repair-deficient metastatic serous endometrial cancer. Methods: A 72-year-old woman underwent hysterectomy, bilateral salpingo-oophorectomy, and staging procedures for FIGO stage IIIA, high-grade serous papillary endometrial carcinoma. Tumour profiling revealed dMMR, a p53 abnormal pattern, and HER2 overexpression (IHC 3+). She received carboplatin/paclitaxel plus avelumab, followed by pegylated liposomal doxorubicin and weekly paclitaxel. After progression on paclitaxel, off-label T-DXd was initiated. Molecular data (FoundationOne CDx) were collected, along with and serial imaging and CA125 assessments. Results: The patient developed cough after two cycles of T-DXd; interstitial lung disease was excluded, and treatment resumed with steroid cover. By December 2024, PET/CT demonstrated complete metabolic response, with resolution of vaginal-vault and para-aortic lesions and normalisation of CA125. Real-world progression-free survival exceeded eight months, with ongoing symptom improvement. Treatment was generally well tolerated; the principal adverse event was grade 3 neutropenia requiring dose reduction. No cardiotoxicity or interstitial lung disease occurred. Conclusions: This case illustrates that T-DXd can induce deep and durable remission in HER2-positive, dMMR metastatic serous endometrial cancer after multiple lines of therapy. It adds real-world evidence supporting further investigation of HER2-directed antibody–drug conjugates in gynaecologic malignancies, and underscores the need for confirmatory trials and refined biomarker-driven patient selection.

Iron nitroprusside as a chemodynamic agent and inducer of ferroptosis for ovarian cancer therapy

A schematic representation of FeNP-induced ROS production and its involvement in ferroptosis.

Recurrence patterns and prognostic factors in vulvar extramammary Paget’s disease: a 10-year single institution experience

Extramammary Paget's disease of the vulva is a rare intra-epithelial malignancy with a high propensity for multiple local recurrences. Surgical excision remains the treatment of choice in most of the cases. However, due to its rarity, treatment modalities and prognostic indicators are still debated. We aimed to evaluate the recurrence patterns and to identify clinical factors associated with risk of recurrence in women with this disease. Retrospective analysis of women treated for vulvar Paget's disease at a single institution from January 2014 to December 2024. Clinical-pathological features, treatment modalities, and factors potentially related to disease recurrence were analyzed. An additional analysis was conducted to identify factors potentially associated with the development of multiple subsequent recurrences over time. A total of 69 patients fulfilling the study inclusion criteria were considered. A wide vulvo-perineal-peri-anal involvement was observed in 39.1% of cases, with multifocal disease observed in 37.7% of cases. In total, 34 women (49.3%) developed recurrent disease, with a median disease-free survival of 59.6 months (95% CI 33.3 to 95.9). Multifocal disease at initial diagnosis was the only factor significantly associated with an increased risk of recurrence (OR 2.89, 95% CI 1.05 to 7.96, p = .04). In 32.4% of cases, the recurrence occurred in a vulvo-perineal or peri-anal area distinct from the original site. Multiple recurrences over time were observed in 33.3% of patients. Vulvar Paget's disease is associated with a substantial risk of recurrence, particularly in patients with multifocal disease. Recurrences often arise at new anatomical sites, which may be more appropriately defined as "second field" Paget's disease. Although surgery remains a feasible and safe approach even in the setting of recurrent disease, individualized therapeutic strategies are advisable to improve long-term outcomes in this challenging patient population.

Extramammary Paget’s Disease of the Vulva and Concomitant Premalignant/Malignant Vulvar Lesions: A Potential Challenge in Diagnosis and Treatment

The aim of the present study was to evaluate the incidence of concomitant vulvar cancers or premalignant lesions in women surgically treated for extramammary Paget’s disease of the vulva (EMPDV) through a multicenter case series. The medical records of all women diagnosed with and treated for EMPDV from January 2010 to December 2020 were retrospectively analyzed. Women with EMPDV and synchronous vulvar cancer, vulvar intraepithelial neoplasia (VIN) and/or lichen sclerosus (LS) at the histology report were included in the study. A total of 69 women eligible for the present study were considered. Concomitant vulvar lesions occurred in 22 cases (31.9%). A total of 11 cases of synchronous VIN (50%) and 14 cases (63.6%) of concomitant LS were observed. One patient (4.5%) had synchronous vulvar SCC (FIGO stage 1B). Women with EMPDV and concomitant premalignant/malignant vulvar lesions had a significantly higher rate of invasive EMPDV and wider lesions with an extravulvar involvement. The specific meaning of the association between EMPDV, VIN, SCC and LS remains unclear. The potential overlapping features between different vulvar lesions highlight the importance of dedicated gynecologists and pathologists in referral centers.

The future of gynecologic oncologic surgery: a narrative review of current surgical trials

Recent advances in gynecologic oncology have driven a paradigm shift toward less invasive, more personalized surgical approaches. This narrative review critically examines key ongoing international trials investigating innovative surgical strategies across vulvar, cervical, ovarian, and endometrial cancers, with a focus on improving oncologic outcomes while minimizing morbidity. In vulvar cancer, trials are exploring the use of neoadjuvant chemotherapy and the replacement of inguinofemoral lymphadenectomy with chemoradiation in selected patients. For cervical cancer, large multicenter randomized trials are evaluating the oncologic safety of minimally invasive hysterectomy, surgical staging for para-aortic disease, and robotic-assisted surgery. In the contest of ovarian cancer, randomized trials are assessing the role of lymphadenectomy in early-stage disease, the optimal timing of cytoreductive surgery (primary versus interval), and the potential benefits of hyperthermic intraperitoneal chemotherapy, even in cases of platinum-resistant recurrence. For endometrial cancer, both observational and interventional studies are investigating sentinel lymph nodes mapping and robotic-assisted hysterectomy as alternatives to traditional staging procedures. Collectively, these trials underscore the growing importance of individualized treatment strategies guided by disease stage, histologic subtype, response to neoadjuvant therapy, and patient-specific factors. While minimally invasive techniques and surgical de-escalation appear promising for selected patient populations, critical questions remain regarding long-term oncologic safety, cost-effectiveness, and the consistency of practice across institutions. This narrative review synthesizes current evidence and outlines how the outcomes of these pivotal studies are expected to influence future guidelines in gynecologic cancer surgery.

Probe-based confocal laser endomicroscopy intra-operative evaluation in ovarian cancer: definition of in vivo architectural patterns to determine resection strategies.

Probe-based confocal laser endomicroscopy (pCLE) is a novel real-time imaging technique that is potentially useful for accurately distinguishing between normal and cancerous tissues. The aim of this study was to describe the pCLE patterns of areas suggestive of tumors and evaluate the ability of the method to differentiate between normal and cancerous tissue during cytoreductive surgery for epithelial ovarian cancer. In vivo pCLE images and subsequent biopsies were acquired from various anatomical sites including the parietal and visceral peritoneum, ovaries, and omentum. Each endomicroscopic sequence was analyzed by highly experienced investigators using pCLE imaging for cancer diagnosis. Each pCLE sequence was compared with the histology of the corresponding specimens. We enrolled 18 women with International Federation of Gynecology and Obstetrics stage III/IV high-grade serous epithelial ovarian cancer referred for primary or interval debulking surgery. A total of 112 biopsies were obtained for histologic analysis. The pCLE images of normal tissue showed a regular distribution of stromal fibers and consistent cellular architecture, regardless of the anatomical region, with vascularized areas characterized by regular vessels. Conversely, the extravasation of fluorescein, used as a contrast agent, was a distinguishing feature of malignant nodules, which were easily recognized by leakage and are typical of tumor-associated vessels. The leakage often surrounded the dark clusters of neoplastic cells. A substantial agreement between pCLE and histology emerged (k = 0.66), whereas only a fair concordance between the surgeon's intra-operative assessment and histology was found (k = 0.30). Our results suggest that pCLE is a promising intra-operative technique to assist surgeons in accurately detecting peritoneal metastases in patients with advanced epithelial ovarian cancer, enhancing surgical radicality while avoiding unnecessary resection.

USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.