Long-term outcomes of PARP inhibitors in ovarian cancer: survival, adverse events, and post-progression insights.

Poly-ADP-ribose polymerase inhibitors (PARPis) have revolutionized the management of BRCA-mutated (BRCA) and homologous recombination deficiency (HRD)-positive ovarian cancer (OC). While long-term analyses clearly support the use of PARPi as maintenance therapy after first-line chemotherapy, recent data have raised concerns on detrimental overall survival (OS) in non-BRCA OC, a greater incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and unfavorable outcomes following subsequent platinum-based chemotherapy in pretreated OC patients. In this report we discuss the long-term follow-up results from phase III trials in pretreated OC patients, which led to the Food and Drug Administration's withdrawal of PARPi indications in this setting.

Crosstalk of T cells within the ovarian cancer microenvironment.

Ovarian cancer (OC) represents ecosystems of highly diverse tumor microenvironments (TMEs). The presence of tumor-infiltrating lymphocytes (TILs) is linked to enhanced immune responses and long-term survival. In this review we present emerging evidence suggesting that cellular crosstalk tightly regulates the distribution of TILs within the TME, underscoring the need to better understand key cellular networks that promote or impede T cell infiltration in OC.

Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma.

Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8 cells that preferentially infiltrated tumors post-ACT.

The Impact of Neoadjuvant Chemotherapy on Ovarian Cancer Tumor Microenvironment: A Systematic Review of the Literature.

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies.

PGE inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses.

Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8 T-myeloid cell networks in melanoma.

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden.

Retrospective Analysis of the Correlation of MSI-h/dMMR Status and Response to Therapy for Endometrial Cancer: RAME Study, a Multicenter Experience.

Background: There is poor evidence regarding sensitivity to chemotherapy in endometrial cancer (EC) based on microsatellite instability (MSI)/mismatch repair (MMR) status.

Methodology: The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h)/deficient (d) MMR and MSI-low (l)/proficient (p) MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study.

Introduction: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms.

Time trends in health-related quality of life assessment and reporting within publications of oncology randomised phase III trials: a meta-research study.

Objective: To assess time trends in the inclusion of health-related quality of life (QoL) among study endpoints and in the reporting of QoL results in study publications, randomised phase III oncology trials published between 2017 and 2021 were compared with the trials published in the previous 5 years.

Methods And Analysis: All issues published between 2012 and 2021 by 11 major journals were handsearched for primary publications of phase III trials in adult patients with solid tumours. Trials published in 2017-2021 were compared with trials published in 2012-2016 for three endpoints: (1) proportion of publications including QoL among endpoints out of all the eligible publications; (2) proportion of publications presenting QoL results out of those including QoL among endpoints and (3) proportion of publications presenting QoL data out of all the eligible publications.

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study.

Background: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC).

Methods: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers.

Patient-reported outcomes in adoptive cell-therapy trials: mind the gap.

Adoptive cell therapies (ACT) have demonstrated promise in the treatment of patients with cancer, leading to long-lasting responses and, in some cases, even cure. Technological advances have brought these individualized therapies closer to reality, establishing them as credible therapeutic option. However, to date, few efforts have been made to understand patients' experience during ACT trials.

Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1) tumors are thus T cell inflamed at baseline.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

Background: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts.

Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete.

Methods: To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019.

Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience.

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting.

Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically.

Validation of Androgen Receptor loss as a risk factor for the development of brain metastases from ovarian cancers.

Background: Central nervous system (CNS) spreading from epithelial ovarian carcinoma (EOC) is an uncommon but increasing phenomenon. We previously reported in a small series of 11 patients a correlation between Androgen Receptor (AR) loss and localization to CNS. Aims of this study were: to confirm a predictive role of AR loss in an independent validation cohort; to evaluate if AR status impacts on EOC survival.

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer.

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients.

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives.

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC.

Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs.

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

Background: In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials.

Methods: We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals.

Results: Out of the 67 publications identified, in 41 (61.

Role of Mediterranean diet in preventing platinum based gastrointestinal toxicity in gynecolocological malignancies: A single Institution experience.

Background: Gynecological malignancies represent a major cause of death in women and are often treated with platinum-based regimens. Patients undergoing chemotherapy suffer from alterations in nutritional status which may worsen gastrointestinal (GI) toxicities, quality of life and affect the overall prognosis. Indeed, assuring a good nutritional status and limiting toxicities during treatment are still major goals for clinicians.

Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications.

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature cancer cells, represent a potential field of expansion for drug development.