Unlocking the potential of Molecular Tumor Boards: from cutting-edge data interpretation to innovative clinical pathways.

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.

Real world data of niraparib in platinum sensitive relapsed ovarian cancer: A multicenter experience of the MITO group.

OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.

Dermatofibrosarcoma Protuberans of the Vulva: A Review of the MITO Rare Cancer Group.

BACKGROUND: Vulvar dermatofibrosarcoma protuberans is an extremely rare disease. Its rarity can hamper the quality of treatment; deeper knowledge is necessary to plan appropriate management. The purpose of this review is to analyse the data reported in the literature to obtain evidence regarding appropriate disease management. METHODS: We made a systematic search of the literature, including the terms "dermatofibrosarcoma protuberans", "vulva", and "vulvar", alone or in combination. We selected articles published in English from two electronic databases, PubMed and MEDLINE, and we analysed their reference lists to include other potentially relevant studies. RESULTS: We selected 39 articles, with a total of 68 cases reported; they were retrospective case reports and case series. Dermatofibrosarcoma protuberans of the vulva tends towards local recurrence; an early and timely pathological diagnosis, together with an appropriate surgical approach, are of utmost importance to ensure free margins and maximise the curative potential. CONCLUSIONS: Even if this is an indolent disease and it generally shows a good prognosis, appropriate management may help in reducing the rate of local recurrences that may hamper patients' quality of life. Management by a multidisciplinary team is highly recommended.

Reproductive outcomes after conservative treatment in early and advanced stage MOGCTs.

BACKGROUND: Malignant ovarian germ cell tumors usually occur in young women. The standard of care is fertility sparing surgery and comprehensive surgical staging followed by adjuvant chemotherapy with BEP (bleomycin, etoposide, cisplatin) if needed. The aim of this study was to analyze the reproductive outcomes after conservative treatment in patients diagnosed, treated and followed up in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. METHODS: A questionnaire concerning gynecological symptoms, reproductive outcomes and fertility treatment was administered to 164 MOGCTs survivors. Data regarding patients deceased were collected from MITO-9 database. There were 114 patients diagnosed at reproductive age between 1983 and 2019 included. RESULTS: 109 patients answered the questionnaire and 5 patients decesased were included (median age 24.9 years). 78.1% were stage I,4.4% stage II, 14.9% stage III and 2.6% stage IV. 57.9% received chemotherapy, the mean number of cycles was 4.1. Median time to menstrual recovery after BEP was of 5.6 months range, only 1 case of premature ovarian failure was reported. Among the 114 patients 38 (33.3%) attempted to become pregnant, 29/38 (76.3%) got pregnant with a total of 44 conceptions. 40.9% received chemotherapy and 22.9% did not (p 0.048). Pregnancy desire was the only predictive factor associated with live births among women who attempted pregnancy after treatment. CONCLUSIONS: As MOGCTs affect women of child-bearing age, fertility preservation represents a major treatment issue. Our results are consistent with the available evidence, confirming that adjuvant chemotherapy for MOGCT does not impact the reproductive function and fertility.

Fertility outcomes following surgery and multiagent chemotherapy in malignant ovarian germ cell tumor survivors: a survey study.

OBJECTIVE: To assess fertility outcomes in long-term survivors of malignant ovarian germ cell tumors treated with fertility-sparing surgery with or without additional chemotherapy. METHODS: Women diagnosed and treated for malignant ovarian germ cell tumors at Charing Cross Hospital or Mount Vernon Cancer Centre between 1977 and 2015 were included. Questionnaires assessing fertility issues were sent to patients treated with fertility-sparing surgery. Fertility outcomes were evaluated according to the treatment received. The effect of the mean total dose of cyclophosphamide and cisplatin was assessed. RESULTS: A total of 146 patients were sent the questionnaire; 77 (56.5%) patients were included in the analysis. A total of 49 (64%) patients received platinum-based chemotherapy after surgery, 39 (79.6%) of these with cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, and etoposide, while 10 (20.4%) with bleomycin, etoposide, and cisplatin. After any treatment, 39/46 patients (85%) became pregnant: the conception rate was not different between those receiving surgery only and those receiving also chemotherapy (85.7% vs 84.4%, p=1.0). Live birth rate was 80.4% (37/46), with no statistically significant difference between the treatment groups (p=0.42). Median age of women achieving conception was 29 years (IQR 26-33). The probability of live birth at 5 years was 48% and 40% for patients in the surgery only and chemotherapy group, respectively (p=0.55). Infertility and miscarriage rates did not differ significantly between the two treatment groups (p=0.30 and p=0.32). The mean doses of cisplatin and cyclophosphamide received by patients failing and achieving conception were not different (p=0.10, p=0.47). CONCLUSIONS: Our results suggest that fertility may not be hampered in patients with malignant ovarian germ cell tumor treated with fertility-sparing surgery or receiving additional chemotherapy.

Epithelial ovarian cancer is infiltrated by activated effector T cells co-expressing CD39, PD-1, TIM-3, CD137 and interacting with cancer cells and myeloid cells.

Introduction: Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity. Methods: In this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs). Results: Activated T cells showing features of partial exhaustion with a CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ signature. Conclusion: These data demonstrate that EOC is enriched in CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

Radiation Therapy for Gestational Trophoblastic Neoplasia: Forward-Looking Lessons Learnt.

Gestational trophoblastic neoplasia (GTN) includes several rare malignant diseases occurring after pregnancy: invasive moles, choriocarcinoma, placental site trophoblastic tumours, and epithelioid trophoblastic tumours. Multidisciplinary protocols including multi-agent chemotherapy, surgery, and occasionally radiotherapy achieve good outcomes for some high-risk metastatic patients. In this narrative review of the published studies on the topic, we have tried to identify the role of radiotherapy. The available studies are mainly small, old, and retrospective, with incomplete data regarding radiotherapy protocols delivering low doses (which can make this disease appear radioresistant in some cases despite high response rates with palliative doses) to wide fields (whole-brain, whole-liver, etc.), which can increase toxicity. Studies considering modern techniques are needed to overcome these limitations and determine the full potential of radiotherapy beyond its antihemorrhagic and palliative roles.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer.

PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

Endometriosis-Related Ovarian Cancers: Evidence for a Dichotomy in the Histogenesis of the Two Associated Histotypes.

Evidence indicates that different pathways of malignant degeneration underlie the development of endometriosis-associated ovarian tumors of endometrioid and clear cell histotypes. The aim of this study was to compare data from patients affected by these two histotypes to investigate the hypothesis of a dichotomy in the histogenesis of these tumors. Clinical data and tumor characteristics of 48 patients who were diagnosed with either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer arising from endometriosis (ECC, n = 22) or endometriosis-associated endometrioid ovarian cancer (EAEOC, n = 26) were compared. A previous diagnosis of endometriosis was detected more frequently in the ECC group (32% vs. 4%, p = 0.01). The incidence of bilaterality was significantly higher in the EAOEC group (35% vs. 5%, p = 0.01) as well as a solid/cystic rate at gross pathology (57.7 ± 7.9% vs. 30.9 ± 7.5%, p = 0.02). Patients with ECC had a more advanced disease stage (41% vs. 15%; p = 0.04). A synchronous endometrial carcinoma was detected in 38% of EAEOC patients. A comparison of the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis showed a significantly decreasing trend for ECC compared to EAEOC (p = 0.02). These findings support the hypothesis that the origin, clinical behavior and relationship with endometriosis might be different for these histotypes. ECC, unlike EAEOC, seems to develop within an endometriotic cyst, thus representing a window of possibility for ultrasound-based early diagnosis.

Outcomes of High-Grade Cervical Dysplasia with Positive Margins and HPV Persistence after Cervical Conization.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Role of Machine Learning (ML)-Based Classification Using Conventional 18F-FDG PET Parameters in Predicting Postsurgical Features of Endometrial Cancer Aggressiveness.

PURPOSE: to investigate the preoperative role of ML-based classification using conventional 18F-FDG PET parameters and clinical data in predicting features of EC aggressiveness. METHODS: retrospective study, including 123 EC patients who underwent 18F-FDG PET (2009-2021) for preoperative staging. Maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were computed on the primary tumour. Age and BMI were collected. Histotype, myometrial invasion (MI), risk group, lymph-nodal involvement (LN), and p53 expression were retrieved from histology. The population was split into a train and a validation set (80-20%). The train set was used to select relevant parameters (Mann-Whitney U test; ROC analysis) and implement ML models, while the validation set was used to test prediction abilities. RESULTS: on the validation set, the best accuracies obtained with individual parameters and ML were: 61% (TLG) and 87% (ML) for MI; 71% (SUVmax) and 79% (ML) for risk groups; 72% (TLG) and 83% (ML) for LN; 45% (SUVmax; SUVmean) and 73% (ML) for p53 expression. CONCLUSIONS: ML-based classification using conventional 18F-FDG PET parameters and clinical data demonstrated ability to characterize the investigated features of EC aggressiveness, providing a non-invasive way to support preoperative stratification of EC patients.

CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.

BACKGROUND: To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded. METHODS: In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products. RESULTS: CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy. CONCLUSIONS: Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.

Granulosa cell tumors (GCTs) of the ovary: What is the role of radiotherapy?

Granulosa cell tumors of the ovary have an indolent behavior and a good prognosis, but a high incidence of local recurrence after surgery. The best treatment in the recurrent setting is unclear and randomized clinical trials on the management in the recurrent setting are lacking. The role of radiotherapy is controversial in adjuvant settings and unknown in case of relapse after surgery. This review aims to summarize the level of evidence of the role of radiation treatments for granulosa cell tumors of the ovary.

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)-Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors-A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study.

OBJECTIVE: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment. METHODOLOGY: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group. RESULTS: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10-12) in the control group vs. 8 months (95% IC 6-9) in the case group (p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28-5.06) for the case group (p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand-foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented. CONCLUSION: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers.

INTRODUCTION: Fallopian tube carcinoma (FC) as a single entity is a rare disease. Although its diagnosis is increasing thanks to the widespread use of prophylactic salpingectomy, there are no clinical trials exclusively designed for FC. AREAS COVERED: This review aims at identifying the most promising trials and future therapeutic pathways in the setting of FC. EXPERT OPINION: Hot topics in FC treatment include the consequences of using PARP inhibitors (PARPi) as first-line therapy, ways to overcome platinum resistance, and the role of immunotherapy. Patient selection is a key point for future development of target therapies. Next-generation sequencing (NGS) is one of the most investigated technologies both for drug discovery and identification of reverse mutations, involved in resistance to PARPi and platinum. New, promising molecular targets are emerging. Notwithstanding the disappointing outcomes when used by itself, immunotherapy in FC treatment could still have a role in combination with other agents, exploiting synergistic effects at the molecular level. The development of cancer vaccines is currently hampered by the high variability of tumor neoantigens in FC. Genomic profiling could be a solution, allowing the synthesis of individualized vaccines.

Efficacy and safety of trabectedin for the treatment of advanced uterine or ovarian carcinosarcoma: Results of a phase II multicenter clinical trial (MITO-26).

OBJECTIVE: This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC). METHODS: Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations. RESULTS: Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity. CONCLUSION: Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug.

A prospective, observational study of chemotherapy-induced ovarian damage on follicular reserve and maturation.

BACKGROUND: Chemotherapy negatively affects gonadal function, often resulting in premature ovarian failure (POF) due to ovarian reserve depletion. Mechanisms of gonadotoxicity, such as primordial follicle overactivation and "burnout", remain to be established. Ovarian tissue cryopreservation (OTC) before treatment plays an important role in safeguarding fertility. METHODS: This is a prospective observational study that aims to evaluate the feasibility of OTC after chemotherapeutic treatment initiation. Patients were divided into 2 groups depending on whether they received chemotherapy before the harvesting procedure (Group 1) or not (Group 2). The main outcomes of this study are serum anti-Mullerian hormone (AMH) levels and histological follicular counts on ovarian tissue biopsies. RESULTS: Between 2012 and 2020, 79 patients underwent OTC at our Hospital. Follicular counts from the ovarian biopsies of 30 post-pubertal patients and respective serum AMH levels were included in the analysis. AMH levels did not significantly differ between the 2 groups (P = 0.70) as well as the number of primordial follicles (P = 0.73). Ovarian biopsies of patients from Group 1 showed a higher number of primary follicles (P = 0.04) and atretic follicles (P = 0.05) with respect to Group 2. CONCLUSIONS: In conclusion, OTC appears to be feasible even after the start of chemotherapeutic treatment, since in treated patients, the main ovarian reserve indicators (number of primordial follicles and serum AMH levels) were not significantly reduced compared to untreated patients. The "burnout" theory of chemotherapeutic damage to the ovary seems to be supported by the higher number of primary follicles found in the ovaries of patients who received chemotherapy before OTC.

Current Evidence on Immunotherapy for Gestational Trophoblastic Neoplasia (GTN).

BACKGROUND: Gestational trophoblastic disease includes a rare group of benign and malignant tumors derived from abnormal trophoblastic proliferation. Malignant forms are called gestational trophoblastic neoplasia (GTN) and include invasive mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor. Standard treatment of GTN is chemotherapy. The regimen of choice mainly depends on the FIGO prognostic score. Low-risk and high-risk GTN is treated with single-agent or multiagent chemotherapy, respectively. In the case of chemoresistance, immunotherapy may represent a new therapeutic strategy. METHODS: Literature obtained from searches on PubMed concerning GTN and immunotherapy was reviewed. RESULTS: Programmed cell death 1 (PD-1) and its ligands (PD-L1/2) are expressed in GTN. Published data on PD-1/PD-L1 inhibitors alone in GTN were available for 51 patients. Pembrolizumab is an anti-PD-1 inhibitor used in chemoresistant forms of GTN. In the TROPHIMMUN trial, Avelumab, a monoclonal antibody inhibiting PD-L1, showed promising results only in patients with GTN resistant to monochemotherapy. Conversely, in patients with resistance to multiagent chemotherapy, treatment with Avelumab was discontinued due to severe toxicity and disease progression. The association of Camrelizumab and Apatinib could represent a different treatment for forms of GTN refractory to polychemotherapy or for relapses. CONCLUSIONS: Anti-PD-1 or anti-PD-L1 might represent an important new treatment strategy for the management of chemoresistant/refractory GTN.