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Epithelial ovarian cancer is the most lethal gynecologic malignancy. In most women, it is diagnosed at an advanced stage, which largely explains the poor prognosis of this malignancy. Germline mutations of the genes BRCA1 and BRCA2 , which encode proteins essential for the repair of double-strand DNA breaks through homologous recombination, lead to increased cancer predisposition. BRCA mutations are present in approximately 14% of epithelial ovarian cancers. Somatic BRCA mutations have also been described. Current first-line treatment of high-grade epithelial ovarian cancer includes debulking surgery followed by combination chemotherapy, usually carboplatin and paclitaxel. Ovarian cancer is highly sensitive to chemotherapy, in particular to platinum drugs. Most patient will achieve remission with initial chemotherapy, but most will eventually experience disease recurrence. Targeted therapies, including the anti-angiogenic agent bevacizumab and oral poly (ADP-ribose) polymerase (PARP) inhibitors, have been recently approved for the treatment of ovarian cancer, based on the results from randomized clinical trials showing significant benefits in terms of progression-free survival, with acceptable tolerability and no detrimental effects on quality of life. Olaparib, the first PARP inhibitor to be granted approval, is currently indicated as maintenance monotherapy in ovarian cancer patients with relapsed disease and mutated BRCA who have achieved a complete or partial response to platinum-based chemotherapy. The analysis of BRCA mutational status has, therefore, also become crucial for therapeutic decisions. Such advances are making personalized treatment of ovarian cancer feasible. Here we briefly review treatments for platinum-sensitive, high-grade serous epithelial ovarian cancer that are currently available in Italy, with a focus on targeted therapies and the relevance of BRCA mutational analysis. Based on the evidence and on current guidelines, we propose strategies for the tailored treatment of patients with relapsed ovarian cancer that take into account BRCA mutational status and the treatment received in the first-line setting.

PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0–1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m2 with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5–20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36–11·02] vs 3·49 months [2·01–5·66]; hazard ratio 0·42 [95% CI 0·25–0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3–4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. National Cancer Institute of Napoli and GlaxoSmithKline.

Cervical cancer (CC) is still characterized by a poor prognosis despite the progress made in its treatment in recent years. Although immunotherapy has improved outcomes for advanced/recurrent disease, there is a significant gap in addressing patients’ needs when they progress after platinum and immunotherapy treatments. In this setting, traditional chemotherapy showed limited effectiveness. In this context, antibody–drug conjugates (ADCs) emerged as a promising tool within targeted cancer therapies. Tisotumab vedotin (TV), an ADC targeting tissue factor, represents the first ADC approved by the US Food and Drug Administration for the treatment of recurrent or metastatic CC with disease progression on or after chemotherapy. In phase I–III published trials, TV has already demonstrated an advantage in terms of objective response rate (17.8%–54.4%) and progression-free survival (3.1–6.9 months) in patients who progressed to the first-line standard therapy. Data concerning the addition of TV to platinum/pembrolizumab first-line chemotherapy are still under analysis and strongly expected. However, several questions are still unresolved: (1) the identification of the most suitable timing for ADCs administration in the treatment sequence of advanced/recurrent CC; (2) the evaluation of combination therapies as a tool to minimize the emergence of resistant clones and to enhance overall effectiveness; and (3) the assessment of tolerability and correct management of special toxicities (e.g. ocular and neurological adverse events). In the near future, an improvement in patient selection via biomarker-driven strategies should be crucial for optimizing both treatment benefits and maintaining an acceptable toxicity profile.

Up to now, a vaginal well-differentiated neuroendocrine tumor (NET) has never been well described in the literature. A 2-cm vaginal nodule morphologically revealed a proliferation of mild to moderately atypical eosinophilic epithelioid cells, without tumor cell necrosis. Immunohistochemistry (IHC) showed positivity for CK (AE1/AE3), chromogranin A, and synaptophysin, focal positivity for CDX2, and negativity for PAX8 and TTF1. Metastatic origin was excluded by imaging and the morphological context with benign mucinous glands as present in the surgical resection specimen. Considering mitotic index and Mib1/Ki67 (8 mitoses/2 mm2; >20%), the case was diagnosed as vaginal NET G2 in the light of the WHO 2020 grading system for the gynecologic neuroendocrine neoplasms (NENs). Ranges of Mib1-Ki67 are not yet standardized. Currently, mitotic index and tumor cell necrosis were taken into consideration for the grading system. Gynecologic NENs still represent a diagnostic challenge. A clinico-radiologic workup and an appropriate diagnostic path ruling out the metastatic nature are mandatory to achieve the diagnosis.

Immunotherapy is an effective treatment option for gynecological malignancies. Radiologists dealing with gynecological patients undergoing treatment with immune checkpoint inhibitors should be aware of unconventional immune-related imaging features for the evaluation of tumor response and immune-related adverse events. In this paper, immune checkpoint inhibitors used for gynecological malignancies and their mechanisms of action are briefly presented. In the second part, patterns of pseudoprogression are illustrated, and different forms of immune-related adverse events are discussed.

Endometrial carcinoma is the most frequent cancer of the reproductive female organs. Most endometrial cancers are diagnosed at early stage (75%). Treatment options depend on pathogenetic, histopathologic and clinical characteristic at the diagnosis. To improve patient management in the near future, recent research has focused on new molecular features; evidence has shown that these give a better definition of patient prognosis and can help in tailoring adjuvant treatments by identifying specific subgroups of patients whose tumors may benefit from specific therapeutic approaches. In this review, we will focus on current knowledge of adjuvant treatment of endometrial carcinoma, using a prognostic-risk group stratification based on pathogenetic, clinical and molecular features, and will take a look at the ongoing trials that will further change the therapeutic approach in coming years.

Although ovarian cancer often presents as a widespread disease, metastases to the breast and/or axillary lymph nodes are a very rare event, accounting for only 0.03–0.6% of all breast cancers. Its early recognition and accurate distinction from primary breast cancer are of crucial importance to choose an adequate systemic therapy over unnecessary surgeries. We presented the case of a 53-year-old woman who was diagnosed with breast metastases 2 years after the diagnosis of advanced primary serous ovarian cancer. The patient underwent primary cytoreductive surgery and platinum-based chemotherapy in combination with bevacizumab, followed by bevacizumab maintenance for 18 months. After 2 years of negative follow-ups, the disease unexpectedly spread to the left breast and axillary lymph nodes. No axillary lymph node dissection or breast surgery was performed. The patient received axillary radiotherapy and multiple chemotherapy lines: gemcitabine/cisplatin, liposomal doxorubicin, topotecan, olaparib/cediranib, paclitaxel, and cisplatin. Unfortunately, none of these treatments improved her prognosis and she died 3 years after the disease recurrence. Ovarian cancer metastasis to the breast reveals a disseminated disease with a poor prognosis. Currently, no valid treatment options are available as the disease shows multidrug chemoresistance. In the era of precision medicine, the characterization of genetic and molecular markers may play a role in offering new promising targeted therapies.

Background and Aims: Ovarian clear cell carcinoma (CCC) has a poorer prognosis than other subtypes of ovarian cancer. In this study, we evaluated the responsiveness to second-line chemotherapy in recurrent ovarian CCC. Methods: The MITO-9 project investigated a cohort of patients observed between 1991 and 2007 in 20 centers. We identified 72 out of 240 patients with recurrent disease (28% stage I-II and 72% stage III-IV at diagnosis). Results: In 56% of patients, the clear cell histology was pure. Twenty-five patients were platinum-resistant, 18 were platinum-sensitive with a platinum-free interval (PFI) of 6-12 months, and 29 had a PFI >12 months. Upon recurrence, 47% of patients were treated with platinum chemotherapy according to the PFI. The overall response rate (RR) to platinum was 80%, with 55, 100, and 80% RR in patients with PFI of 6-12, >12, and >24 months. The RR to nonplatinum agents in resistant patients was 33%. Among the nonplatinum agents used in primary and secondary resistant cases, gemcitabine, administered in 12 cases, had a higher activity (RR = 66%) compared to topotecan or liposomal doxorubicin (n = 31; RR = 33 and 10%, respectively). Conclusions: This study showed that the treatment of recurrent ovarian CCC should be based on the PFI as in the other subtypes. Data in platinum-resistant patients suggest gemcitabine as the drug with the highest activity. We recommend that gemcitabine be studied prospectively in a phase 2 trial.