Critical Reviews in Oncology/Hematology

Advances in immunotherapy for gynecological malignancies

To date, surgery, chemotherapy and radiotherapy are mainly used to treat or remove gynecological malignancies. However, these approaches have their limitations when facing complicated female diseases such as advanced cervical and endometrial cancer (EC), chemotherapy-resistant gestational trophoblastic neoplasia and platinum-resistant ovarian cancer. Instead, immunotherapy, as an alternative, could significantly improve prognosis of those patients receiving traditional treatments, with better antitumor activities and possibly less cellular toxicities. Its' development is still not fast enough to meet the current clinical needs. More preclinical studies and larger-scale clinical trials are required. This review aims to introduce the landscape and up-to-date status of immunotherapy against gynecological malignancies, with a discussion of the challenges and future direction.

Advanced and recurrent endometrial cancer: State of the art and future perspectives

Patients with primary metastatic/recurrent endometrial cancer have poor prognosis and available therapeutic options are limited. Current treatment is mainly based on platinum-based chemotherapy. Recently, the Food and Drug Administration (FDA) granted approval for the combination of pembrolizumab and lenvatinib for endometrial cancer patients without microsatellite instability (MSS) progressing on a previous line of therapy while European Medicines Agency (EMA) approved the combination for all comers patients failing previous platinum treatment. Anti programmed cell death protein-1 (PD-1) dostarlimab (TSR-042) was approved as monotherapy in patients with advanced, microsatellite instable (MSI) endometrial cancer progressing to platinum treatment. Phase II-III clinical trials in metastatic endometrial cancer are mainly focused on target therapies and immunotherapy as single agents or in combination. Unfortunately, most of these trials are lacking of predictive biomarkers of response to select patients most or at least likely to benefit from those treatments.

Management of ovarian reserve in breast cancer patients seeking pregnancies (MORE BREAKS): A Delphi consensus

Surface-Enhanced Raman Scattering (SERS) combined with machine learning enables accurate diagnosis of cervical cancer: From molecule to cell to tissue level

The rising number of cervical cancer cases is placing a heavy economic strain on the country and its people. Improving survival rates hinges on early detection, precise diagnosis, and thorough treatment. Common screening and diagnostic methods like Pap smears, HPV testing, colposcopy, and histopathological exams are used in clinical practice, but they are often costly, time-consuming, invasive, subjective, and may lack the necessary sensitivity and specificity for accurate diagnosis. Developing a quick, non-invasive, and precise method for cervical cancer screening is crucial. Raman spectroscopy offers structural insights without damaging samples, but its weak signals and interference from biological fluorescence limit its clinical use. Surface-Enhanced Raman Scattering (SERS) overcomes these challenges, and recent advances, especially when combined with machine learning, enhance cervical cancer diagnosis by enabling precise detection of tumor. This paper comprehensively reviews and summarizes the application of SERS in cervical cancer diagnosis, ranging from molecular biomarker detection to live cell level and then to tissue level diagnosis. By integrating with machine learning, it facilitates the development of accurate, non-invasive diagnosis of cervical cancer.

Impact of molecular testing on the surgical management of advanced epithelial ovarian cancer

Ovarian carcinoma remains the most lethal gynaecologic malignancy. Half of all high-grade serous ovarian cancers (HGSOCs) have a homologous recombination deficiency (HRD) with regard to the repair of double-strand DNA breaks and are candidate to receive maintenance treatment with PARP inhibitors. While a wealth of literature exists regarding the therapeutic guidance of patients from a medical standpoint, the influence of the HRD status on the surgical outlook has been comparatively limited. In this review, the clinical and biological features of advanced ovarian cancers with BRCA1/2 mutation and/or HRD status are considered with particular reference to their impact on the surgical management and on the medico-surgical sequence. The modification of the surgical indications according to the results of molecular testing in first-line and recurrent settings are discussed.

Risk factors for developing both primary breast and primary ovarian cancer: A systematic review

Women with breast cancer have an increased risk of primary ovarian cancer (BR→OV), and women with ovarian cancer have an increased risk of primary breast cancer (OV→BR). This systematic review summarizes risk factors for developing BR→OV and OV→BR. We searched PubMed and Embase until June 2022. We identified 23 articles meeting our inclusion criteria. Studies observed a lower risk of BR→OV for Black versus White women, alcohol consumption, radiotherapy and hormone therapy, BRCA2 versus BRCA1, and ER/PR positive versus negative breast tumors, and a higher risk with family history of breast/ovarian cancer, triple negative versus luminal breast cancer, and higher grade breast tumors. There was an increased risk of OV→BR with family history of cancer. Tumor characteristics, and genetic and familial factors are associated with risk of BR→OV and OV→BR. These results could aid clinicians in decision-making for breast and ovarian cancer patients, including risk-reducing strategies.

Prognostic and therapeutic potential of STAT3: Opportunities and challenges in targeting HPV-mediated cervical carcinogenesis

Cervical cancer (CaCx) ranks as the fourth most prevalent cancer among women globally. Persistent infection of high-risk human papillomaviruses (HR-HPVs) is major etiological factor associated with CaCx. Signal Transducer and Activator of Transcription 3 (STAT3), a prominent member of the STAT family, has emerged as independent oncogenic driver. It is a target of many oncogenic viruses including HPV. How STAT3 influences HPV viral gene expression or gets affected by HPV is an area of active investigation. A better understanding of host-virus interaction will provide a prognostic and therapeutic window for CaCx control and management. In this comprehensive review, we delve into carcinogenic role of STAT3 in development of HPV-induced CaCx. With an emphasis on fascinating interplay between STAT3 and HPV genome, the review explores the diverse array of opportunities and challenges associated with this field to harness the prognostic and therapeutic potential of STAT3 in CaCx.

Potential agnostic role of BRCA alterations in patients with several solid tumors: One for all, all for one?

Germline BRCA1/2 alterations in the Homologous Recombination (HR) pathway are considered as main susceptibility biomarkers to Hereditary Breast and Ovarian Cancers (HBOC). The modern molecular biology technologies allowed to characterize germline and somatic BRCA1/2 alterations in several malignancies, broadening the landscape of BRCA1/2-alterated tumors. In the last years, BRCA genetic testing, beyond the preventive value, also assumed a predictive and prognostic significance for patient management. The approval of molecules with agnostic indication is leading to a new clinical model, defined "mutational". Among these drugs, the Poly (ADP)-Ribose Polymerase inhibitors (PARPi) for BRCA1/2-deficient tumors were widely studied leading to increasing therapeutic implications. In this Review we provided an overview of the main clinical studies describing the association between BRCA-mutated tumors and PARPi response, focusing on the controversial evidence about the potential agnostic indication based on BRCA1/2 alterations in several solid tumors.

Systemic treatment of newly diagnosed advanced epithelial ovarian cancer: From chemotherapy to precision medicine

Despite optimal first-line treatment based on debulking surgery and platinum-paclitaxel chemotherapy, most of the patients with advanced ovarian cancer (AOC) will eventually relapse. Over the last decades, different strategies have been assessed to improve AOC patients' outcomes in the front-line treatment. However, first line treatment landscape of AOC had not undergone major changes until the last three years. In the present review, we will navigate through the different therapeutic approaches developed in first-line AOC which range from variations in dose/administration via of conventional carboplatin-based chemotherapy to the incorporation of anti-angiogenic agents and PARP inhibitors.

Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: An updated systematic review and meta-analysis of randomized controlled trials

Poly-ADP-ribose polymerase (PARP) inhibitors have emerged as a novel class of therapeutics for ovarian cancer (OC); however, PARP inhibitors present a class effect adverse-event profile. A comprehensive literature review was performed for phase II or III randomized controlled trials (RCTs) published up to and including January 2020. We analyzed relevant clinical trials reporting the efficacy and toxicity profile of PARP inhibitors in patients with advanced OC. We estimated hazard ratios (HRs), incidences, risk ratios (RRs) and relative 95 % confidence intervals (95 % CI) for progression-free survival (PFS) and selected adverse events, using Stata 12.0 software package. The systematic review process yielded 10 eligible trials comprising 4,241 patients with advanced OC for survival analysis and 4553 patients for evaluation of toxicity profile. The pooled HR (PARP inhibitor vs control group) for PFS was 0.41 (95 % CI, 0.35-0.50) in overall patients, 0.51 (95 % CI, 0.40-0.64) in unselected setting, 0.32 (95 % CI, 0.26-0.39) in BRCA mutation setting, and 0.57 (95 % CI, 0.41-0.78) in wild-type setting. Patients treated with PARP inhibitors exhibited higher risks of all-grade and high-grade haematological toxicities, including anemia, leucopenia, neutropenia, thrombocytopenia (P < 0.05), and also presented higher risks of all-grade gastrointestinal side effects, including constipation, diarrhea, nausea, and vomiting as well as high-grade nausea and vomiting (P < 0.05). This study indicated that the use of PARP inhibitor provided substantial progression-free survival (PFS) benefits, irrespective of BRCA mutation status; however, treatment with PARP inhibitor was associated with increased risks of selected treatment-related adverse events.

BRCA1/2 status and chemotherapy response score to tailor ovarian cancer surgery

In advanced ovarian cancer (AOC) the complete eradication of all macroscopic disease at primary debulking surgery (PDS) is associated with the best outcome. If this cannot be achieved, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) can make complete cytoreduction possible while reducing postoperative morbidity. It is still debated if PDS and NACT- IDS are associated with similar survival and if they provide different outcomes when optimal cytoreduction is achieved. For a tailored surgical planning, accurate prediction of tumor's resectability, assessment of patient's performance status and in-depth knowledge of tumor biology are required. Both BRCA1/2 status and the "chemotherapy response score" are reliable markers of chemosensitivity and may thus improve our way to triage patients to PDS or NACT-IDS; furthermore, they could be used to modulate our surgical approach and define appropriate subgroups of patients for whom new therapies should be tested.

Prevalence and prognostic role of PD-L1 in patients with gynecological cancers: A systematic review and meta-analysis

Our study aims to evaluate programmed cell death ligand-1 (PD-L1) expression and its prognostic significance in cervical cancer (CC), endometrial cancer (EC) and ovarian cancer (OC). Several electronic databases were searched. Fixed effects models or random effects models were employed to calculate the pooled prevalence of PD-L1 positivity and pooled hazard ratios (HRs) as appropriate. Heterogeneity and publication bias were also assessed. The pooled prevalence of PD-L1 positivity was 58.1%, 33.8% and 37.5% for CC, EC and OC patients, respectively. There were significant differences in the pooled estimates after stratification by PD-L1-positive assessment criteria and antibody clones. PD-L1 positivity was associated with worse OS in CC and EC patients and poorer progression-free survival (PFS) in CC patients. The prevalence of PD-L1-positive expression was considerably high in CC and modestly high in EC and OC patients. PD-L1 expression has the potential to be a prognostic biomarker for predicting the clinical outcomes of patients with CC and EC but not OC.

The DNA damaging revolution

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in the repair of single-strand DNA damage via the base excision repair pathway. PARP inhibitors have substantial single-agent antitumor activity by inducing synthetic lethality. They have also emerged as promising anticancer targeted therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. PARP inhibition produces single-strand DNA breaks, which may be repaired by homologous recombination, a process partially dependent on BRCA1 and BRCA2. The PARP inhibitors olaparib, veliparib, talazoparib, niraparib, and rucaparib have predominantly been studied in patients with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2. Ongoing clinical trials are evaluating the role of PARP inhibitors alone and in combination with other therapies, including selective inhibitors against key targets involved in the DNA damage response. In this review we summarize the use of PARP inhibitors in various tumor types, as well as possible approaches for overcoming resistance to PARP inhibitors.

First line ovarian cancer treatment: Scanning the horizon

Fertility preservation in women with cervical cancer

Fertility preservation in women with cervical cancer is a demanding but evolving issue. Some remarkable achievements have been reached, in particular the improvement of primary and secondary prevention and the broadening of the indications for conservative surgery up to FIGO 2018 stage IB2. Natural pregnancy rate and the rate of obstetrics complications following conservative approach is satisfactory even if not optimal. On the other hand, the use of classic strategies for fertility preservation such as oocytes or ovarian cortex freezing is extremely limited, being the uterus compromised by treatment in a high proportion of cases. In fact, the availability of uterine surrogacy can play a role in the counseling and the decision-making process. The recent advent of uterus transplantation is fascinating but, at present, cannot be viewed as a realistic solution.

PARP and PD-1/PD-L1 checkpoint inhibition in recurrent or metastatic endometrial cancer

The prognosis of recurrent or metastatic endometrial cancer is poor, with five-year survival of only 10-20 %. First-line therapy consists of either platinum-based chemotherapy or hormonal therapy. No standard subsequent-line therapy has been identified. In recent years, significant progress has been made in the knowledge on underlying molecular biology of endometrial cancer and potential targets for therapy have been identified. Targeted therapies as poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy as PD-1/PD-L1 checkpoint inhibitors have the potential to be effective against specific subtypes of endometrial cancer. Preclinical studies have shown that combining these agents may result in a synergistic effect. In this review, we focus on the molecular basis of checkpoint inhibition and targeted therapy as PARP inhibition in endometrial cancer and summarize available clinical data, and ongoing and planned clinical trials that investigate these agents as mono- or combination therapies in endometrial cancer and where relevant, other gynecological cancers.

Emerging trends and treatment strategies in ovarian cancer: A comprehensive review

Ovarian cancer (OC) is the eighth leading cause of cancer deaths in women globally, mainly originating from epithelial cells. It is further divided into type-I and type-II based on histology, molecular, clinical, and epidemiological characteristics. OC is commonly diagnosed in postmenopausal women, although this varies by ethnicity and genetics. Non-Hispanic white women have higher rates of OC, while African American women, despite lower incidence, are diagnosed at a younger median age. Family history and BReast CAncer gene 1&2 (BRCA1/BRCA2) mutations significantly correlate with a heightened risk of OC. Obesity, particularly from childhood, is associated with a higher risk of OC. Late menopause and smoking, are linked to a higher risk, especially for mucinous and possibly serous OC. Hormone-replacement-therapy, particularly with unopposed estrogen, also increases the risk of OC. Endometriosis raises the risk for specific subtypes like clear cell and endometrioid carcinoma. Women who have never given birth (null-parity) are at higher-risk for endometrioid and clear cell carcinoma. Surgical resection is crucial for reducing primary and local metastatic disease, involving inspection of the peritoneal cavity, cytology, lymph node removal, and biopsies. The success of surgery is limited by the visibility, extent, and tissue infiltration of the disease. The choice between neoadjuvant-chemotherapy and primary debulking surgery depends on patient health and tumor biology. Secondary cytoreductive surgery may be beneficial for platinum-sensitive recurrent OC. The use of PARP inhibitors and targeted therapies adds complexity to surgical decisions. Ongoing trials and new therapeutic strategies are expected to enhance the management and outcomes of OC.

Diagnostic and prognostic significance of circulating HPV cfDNA in cervical cancer: A systematic review and meta-analysis

Human papillomavirus circulating free DNA (HPV cfDNA) is an emerging biomarker with potential utility in the detection and treatment monitoring of cervical cancer. To conduct a systematic review and meta-analysis evaluating the diagnostic and prognostic performance of HPV cfDNA in cervical cancer. A comprehensive literature search was conducted in PubMed, CINAHL, Cochrane Library, Scopus, and Embase through April 2025. Eligible studies reported or allowed calculation of diagnostic performance of HPV cfDNA in HPV-positive cervical cancer patients and/or included serial HPV cfDNA testing during post-treatment follow-up. Meta-analyses were conducted using a random-effects model. Heterogeneity was assessed with the I² statistic. The review followed PRISMA guidelines, and study quality was assessed using QUADAS-2. Of 106 studies screened, 20 met the inclusion criteria. Eleven studies contributed to the diagnostic meta-analysis and six to the prognostic analysis. The pooled sensitivity and specificity of HPV cfDNA for cervical cancer detection were 0.47 (95 % CI, 0.43-0.52) and 0.96 (95 % CI, 0.92-0.98), respectively. Positive and negative likelihood ratios were 10.49 and 0.28, with a diagnostic odds ratio of 71.31. The area under the SROC curve was 0.9825, indicating excellent overall diagnostic performance. Prognostically, HPV cfDNA positivity at 3 months post-treatment was significantly associated with reduced progression-free survival (HR = 8.50; 95 % CI, 4.69-15.41; I² = 0 %). HPV cfDNA shows high specificity and strong prognostic value, supporting its clinical utility in cervical cancer detection and treatment surveillance.

Postoperative treatment of intermediate-risk early stage cervical cancer: results of a survey from the Gynecology Study Group in the AIRO Gyn and MITO Groups

This survey investigated prognostic factors, treatment modalities, references followed and radiation oncologists' opinions to prescribe adjuvant therapy in early intermediate-risk cervical cancer. All but one recommended pelvic radiotherapy ± vaginal boost (45%) with or without chemotherapy (20%). 88% believed other prognostic factors could integrate classic risk criteria. 66% considered chemo-radiation indicated in case of lymphovascular invasion and suboptimal node dissection, high grade, size ≥ 4 cm, non squamous histology and risk factors combination. This wide heterogeneity of treatments reflects the different guideline options due to the lack of defined indications. The need of integrating the classic prognostic factors with others factors was unanimously expressed by radiation oncologists. The best local and systemic therapy should be established through new studies. These results highlighted the need of a position paper to standardize adjuvant treatment in Italy and to design collaborative studies to clarify the controversial aspects.

Novel therapeutic strategies for targeting E6 and E7 oncoproteins in cervical cancer

Cervical cancer is the fourth most common cause of cancer-related mortality among women worldwide. The main aetiological factor for developing cervical cancer is the persistent infection of Human papillomavirus (HPV). The E6 and E7 oncoproteins produced by HPV mainly contribute to the carcinogenic process by inhibiting the function of tumour suppressor genes. The E6 protein causes degradation of p53 leading to impaired cellular stress response. In contrast, the E7 protein impairs the activity of retinoblastoma protein (pRb) resulting in continuous cell cycle propagation. Even though screening programmes and prophylactic vaccination have reduced the incidence of cervical cancer, the disease burden is still high, especially in low socioeconomic countries. Treatment of cervical cancer involves a multimodal strategy incorporating surgery, chemotherapy, and radiotherapy. Most of these management approaches use invasive techniques and are associated with adverse effects. Drug resistance is observed over time with chemotherapeutic agents. Hence there is a crucial need for developing novel targeted treatment strategies for cervical cancer. The E6 and E7 viral oncoproteins are continuously expressed in HPV infected cells making them ideal targets for developing therapies. Therapeutic DNA vaccines, gene therapy involving RNA interference technology, and CRISPR are currently under intensive study. These technologies represent a productive and promising approach for the future treatment of cervical cancer. Moreover, several new compounds demonstrate significant anti-cancer effects against cervical cancer. This review provides an updated account of therapeutic strategies currently under research targeting the E6 and E7 viral oncoproteins.

A new approach to the treatment of ovarian cancer: The application of CAR-T cell therapy

Ovarian cancer poses a significant threat to women's health, and the limitations of current treatments demand the exploration of new therapeutic solutions. Chimeric antigen receptor (CAR) T cell therapy, a novel form of immunotherapy, has demonstrated substantial efficacy in the treatment of hematological malignancies and holds considerable promise for ovarian cancer treatment. This paper provides a comprehensive review of the application of CAR-T cell therapy in ovarian cancer, with a detailed discussion of therapeutic targets such as mesothelin, MUC16, and FOLR1, along with associated clinical trials. Presently, the application of CAR-T cell therapy in ovarian cancer is confronted with challenges including immunosuppression within the tumor microenvironment (TME), tumor heterogeneity, target-related issues, toxic reactions, and limitations in cell efficacy. To address these challenges, strategies such as modulating immunosuppressive cells, employing dual-target strategies, optimizing target selection and CAR structure, enhancing cell performance, and utilizing combination therapies are proposed. Future research directions are likely to focus on the expansion of combination therapies, the application of nanotechnology, the advanced development of personalized medicine, and the exploration of immune cell diversification. Although CAR-T cell therapy remains in its nascent stages for the treatment of ovarian cancer, ongoing research and technological advancements are anticipated to yield significant breakthroughs, potentially offering more effective treatment options for patients with ovarian cancer.

Comprehensive analysis of BRCA1/2 mutations, “BRCAness” and PARP inhibitors in melanoma

Unveiling the Role of JAK2/STAT3 signaling in chemoresistance of gynecological cancers: From mechanisms to therapeutic implications

Exploring the molecular interactions between ferroptosis and the Wnt/β-catenin signaling pathway: Implications for cancer and disease therapy

Outcomes of tumor-infiltrating lymphocyte therapy in solid tumours – A systematic review and meta analysis

Neoadjuvant therapy in ovarian cancer: Emerging paradigms and therapeutic frontiers

The use of neoadjuvant therapy followed by intermittent tumor cytoreduction has emerged as an effective treatment for advanced ovarian cancer patients with high tumor load and poor physical status. Research on specific dosing regimens for neoadjuvant therapy has continued to gain momentum in recent years, involving the optimization of conventional chemotherapy regimens, the introduction of targeted agents and immunotherapies, and single-agent or multi-agent combination strategies. The purpose of this review is to provide a comprehensive review of these recent advances, with the aim of providing valuable references and bases for the clinical treatment of advanced ovarian cancer.

Strategies to overcome chemoresistance in epithelial ovarian cancer: Navigating beyond challenges

Epithelial ovarian cancer (EOC) is the most fetal gynecological malignancy. The main causes of treatment failure are primary and acquired chemoresistance that remains a major therapeutic challenge. The mechanisms underlying chemoresistance in EOC are complex and not fully understood. This review explores novel therapeutic strategies targeting chemoresistant EOC, including advanced drug delivery systems, targeting non-coding RNAs, peptide-based therapies, immunotherapy, and the use of poly-ADP ribose polymerase inhibitors. By summarizing the latest research and potential treatments, this review aims to contribute to the development of more effective therapies for patients with chemoresistant EOC.

Management of early-stage ovarian cancer: Open questions and debated issues

The management of epithelial ovarian cancer (EOC) is linked to the histological subtypes. However, literature did not provide strong evidence to support the best subtype-specific therapeutic strategy. In this review, we aim to summarizethe available evidenceto better guide the surgical and medical management of each specific EOC subtypes. The article cited in this review were obtained quering the pubmed database in the English language between January 2007 and December 2024. Laparotomy remains the standard for surgical management of early-stage EOC. The roleof adjuvant chemotherapy remains an open issue due to outdated studies with small sample size. Laparoscopy for the surgical management of early-staged EOC seems to be associated with equivalent oncologic outcome compared with laparotomy. The benefit of adjuvant chemotherapy is dependent on the histological subtype. Furthermore, targeted agents may replace adjuvant chemotherapy and clinical trials are urgently awaited.

Efficacy and safety of targeted therapy and immunotherapy in advanced vulvar squamous cell carcinoma: A scoping review

Vulvar squamous cell carcinoma (VSCC) is a rare gynecological tumor with limited treatment options for advanced stages. Current chemotherapy, adapted from cervical cancer protocols, often results in poor outcomes. This scoping review evaluates the efficacy and safety of immunotherapy and targeted therapies in advanced VSCC. After extensive assessment, examination, and curation of relevant literature data, eight trials focused on immunotherapy or targeted therapy for advanced, recurrent, or metastatic VSCCs were identified and selected. The findings have been compiled and synthesized into a narrative overview, adhering to the PRISMA-ScR guidelines. The study analyzed four unpublished and four published trials, evaluating the efficacy and safety of immunotherapy or targeted therapy for VSCCs. Pembrolizumab was assessed in the KEYNOTE-028 and KEYNOTE-158 trials, showing objective response rates (ORRs) of 6 % and 10.9 %, respectively, and median overall survival (OS) between 3.8 and 6.2 months. CheckMate 358 reported a 20 % ORR for nivolumab. Combination strategies (ipilimumab plus nivolumab and pembrolizumab plus vorinostat) demonstrated efficacy with median OS of 7.6 and 17.5 months, respectively. Toripalimab showed an ORR of 33.3 %. Safety profiles were generally manageable, with common adverse events like fatigue and gastrointestinal disorders. Serious adverse events included grade 5 immune-related hepatitis and chronic kidney disease. Immunotherapy may be considered an option for VSCCs in the second-line setting. Despite the limited research on targeted therapies for VSCCs, combination approaches with immunotherapy demonstrate promising potential. Prioritizing the identification of biomarkers that predict responses to immune checkpoint inhibitors is essential.

The multiple facets of ovarian high grade serous carcinoma: A review on morphological, immunohistochemical and molecular features

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive subtype of epithelial ovarian cancer and a leading cause of mortality among gynecologic malignancies. This review aims to comprehensively analyze the morphological, immunohistochemical, and molecular features of HGSOC, highlighting its pathogenesis and identifying biomarkers with diagnostic, prognostic, and therapeutic significance. Special emphasis is placed on the role of tumor microenvironment (TME) and genomic instability in shaping the tumor's behavior and therapeutic vulnerabilities. Key advancements, such as the identification of TP53 and BRCA mutations, the classification of homologous recombination repair (HRR) deficiencies, and the clinical implications of biomarkers like folate receptor alpha (FRα) and PD-L1 are discussed. These findings reveal actionable insights into targeted therapies, including immune checkpoint inhibitors and PARP inhibitors, which hold promise for improving outcomes in HGSOC. This synthesis of knowledge aims to bridge gaps in understanding HGSOC's multifaceted biology, enhance clinical decision-making, and foster the development of precision therapies.

Unlocking the intricacies: Exploring the complex interplay between platelets and ovarian cancer

Ovarian cancer, an aggressive malignancy of the female reproductive tract, is frequently linked to an elevated risk of thrombotic events. This association is manifested by a pronounced rise in platelet counts and activation levels. Current research firmly supports the pivotal role of platelets in the oncogenic processes of ovarian cancer, influencing tumor cell proliferation and metastasis. Platelets influence these processes through direct interactions with tumor cells or by secreting cytokines and growth factors that enhance tumor growth, angiogenesis, and metastasis. This review aims to thoroughly dissect the interactions between platelets and ovarian cancer cells, emphasizing their combined role in tumor progression and associated thrombotic events. Additionally, it summarizes therapeutic strategies targeting platelet-cancer interface which show significant promise. Such approaches could not only be effective in managing the primary ovarian tumor but also play a pivotal role in preventing metastasis and attenuating thrombotic complications associated with ovarian cancer.

Polycomb Repressor Complex 1 (PRC1) in ovarian cancer: A scoping literature review

High grade serous carcinoma (HGSC) is the most common and the deadliest histologic subtype of epithelial ovarian cancer. HGSC is a therapeutic challenge, as it recurs in 80 % of patients diagnosed, often as chemoresistant disease. The mechanism of this chemoresistance is not fully elucidated, but it is partly attributed to the ability of HGSC to maintain a stem-like phenotype that enables development of resistance to current therapies. Polycomb Repressor Complexes 1 and 2 (PRC1/2) have been implicated in the maintenance of the stem cell compartment through silencing tumor suppressor genes and regulating stem cells. These complexes are comprised of multiple polycomb group (PcG) proteins that play a role in normal development, and when deregulated contribute to the development of cancer [2]. Proteins included in PRC1 include B lymphoma mouse Moloney leukemia virus insertion region (BMI1), RING1, and chromobox (CBX) proteins. We aimed to review each of the protein components of PRC1 and their mechanistic relationships to promoting chemoresistant recurrences and propagation of ovarian cancer. Where possible, we reviewed therapeutic investigations of these proteins. We utilized a scoping literature review through Covidence to identify 42 articles meeting criteria for inclusion. The authors identified four relevant articles and the Yale MeSH Analysis Grid Generator was used to establish additional keywords and heading terms. A medical librarian used these terms and articles to draft an initial search strategy within each of the following databases: MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection, yielding 439 articles based on title and abstract. Abstracts were independently reviewed by the authors, identifying 77 articles for full text review, of which 35 were ultimately excluded, leaving 42 articles for full review. Our review identified the currently known mechanisms of the subunits of PRC1 that contribute to HGSC development, recurrence, and chemoresistance. By compiling a comprehensive review of available scientific knowledge, we support and direct further investigation into PRC1 that can affect meaningful advances in the treatment of HGSC.

Non-apoptotic cell death programs in cervical cancer with an emphasis on ferroptosis

Cervical cancer, a pernicious gynecological malignancy, causes the mortality of hundreds of thousands of females worldwide. Despite a considerable decline in mortality, the surging incidence rate among younger women has raised serious concerns. Immortality is the most important characteristic of tumor cells, hence the carcinogenesis of cervical cancer cells pivotally requires compromising with cell death mechanisms. The current study comprehensively reviewed the mechanisms of non-apoptotic cell death programs to provide possible disease management strategies. Comprehensive evidence has stated that focusing on necroptosis, pyroptosis, and autophagy for disease management is associated with significant limitations such as insufficient understanding, contradictory functions, dependence on disease stage, and complexity of intracellular pathways. However, ferroptosis represents a predictable role in cervix carcinogenesis, and ferroptosis-related genes demonstrate a remarkable correlation with patient survival and clinical outcomes. Ferroptosis may be an appropriate option for disease management strategies from predicting prognosis to treatment.

Efficacy and safety of neoadjuvant chemotherapy containing anti-angiogenic drugs, immunotherapy, or PARP inhibitors for ovarian cancer

Ovarian cancer is the most lethal gynecologic malignancy. The standard treatment involves chemotherapy with platinum-paclitaxel following cytoreductive surgery. For patients battling widespread and aggressive tumor spread, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery emerges as an encouraging alternative. However, the effectiveness of this strategy is often limited by advanced-stage diagnosis and high likelihood of recurrence. The high mortality rate necessitates the exploration of targeted therapies. Present results signal promising efficacy and acceptable toxicities of anti-angiogenic drugs, immunotherapy, or PARP inhibitors used in chemotherapy. However, the potential integration of these drugs into NACT raises questions about response rates, surgical outcomes, and adverse events. This review delves into the findings from all published articles and ongoing studies, aiming to summarize the clinical use of anti-angiogenic drugs, immunotherapy, or PARP inhibitors in NACT, highlight the positive and negative aspects, and outline future perspectives.

Stereotactic body radiotherapy as an alternative to brachytherapy in cervical cancer (SCORE): A systematic review and meta-analysis

This study evaluates the efficacy and safety of Stereotactic Body Radiotherapy (SBRT) as an alternative to brachytherapy (BCT) for patients with locally advanced cervical cancer (CC) who face barriers such as resource constraints, anatomical challenges, or comorbidities precluding standard treatment. A systematic review and meta-analysis, registered with PROSPERO and adhered to PRISMA standards, was conducted to evaluate SBRT in place of BCT for CC treatment. Eligible studies were systematically sourced from PubMed, Embase, and Cochrane databases. A random-effects model was applied to address study heterogeneity. The analysis focused on outcomes including local control (LC), late gastrointestinal (GI) and genitourinary (GU) toxicity, and overall survival (OS) rates with meta-regression exploring correlations between treatment variables and outcomes. The review analyzed thirteen studies from 2012 to 2024 across diverse regions, with participant ages ranging from 52 to 80 years and sample sizes from 6 to 55 patients. The combined LC rate was 94 % (95 % CI: 91-97 %), and the OS rate was 56 % (95 % CI: 48-63 %), showing no heterogeneity. Late grade ≥ 3 GI and GU toxicity were both 2 %. Meta-regression analysis found no significant associations between treatment parameters and the analyzed outcomes. SBRT is a viable boost therapy for CC patients unable to undergo BCT. It demonstrates strong LC and low levels of severe late toxicity. Further prospective randomized trials are necessary to refine SBRT protocols and confirm long-term outcomes.

Clinical and molecular features of platinum resistance in ovarian cancer

Ovarian cancer is the most lethal of all the gynecological tumors despite remarkable advances in our understanding of its molecular biology. The cornerstone treatment remains cytoreductive surgery followed by platinum-based chemotherapy. Recently, the addition of targeted therapies, such as PARP inhibitors, as first-line maintenance has led to outstanding improvements, mainly in BRCA mutated and homologous recombination deficient tumors. However, a significant proportion of patients will experience recurrence, primarily due to platinum resistance, which ultimately result in fatality. Among these patients, primary platinum-resistant have a particularly dismal prognosis due to their low response to current available therapies, historical exclusion from clinical trials, and the absence of validated biomarkers. In this review, we discuss the concept of platinum resistance in ovarian cancer, the clinical and molecular characteristics of this resistance, and the current and new treatment options for these patients.

Gut microbiota and its influence on ovarian cancer carcinogenesis, anticancer therapy and surgical treatment: A literature review

Ovarian cancer (OC) is the most lethal gynecological malignancy and very little is known about the underlying tumorigenesis mechanisms. For other tumors, like colorectal cancer, a relationship between several opportunistic pathogens and cancer development and progression has been proven. Recent researches also underline a possible correlation between gut microbiota dysbiosis and cancer treatment efficacy and adverse effects. Several studies have also demonstrated a link between abdominal surgery and gut microbiota modifications. In this paper, we aim to review the available evidences of this issue in OC to understand if there is a relationship between gut microbiota modifications and efficacy and adverse effects of cancer therapies, either surgical and medical treatments. Well-designed clinical studies, with a robust translational component, are required to better understand the modulation of gut microbiota during OC treatment. The microbiota/microbiome composition analysis, in the near future, could represent a novel instrument to personalize anticancer therapies.

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.

Molecular landscape of recurrent cervical cancer

Cervical cancer (CC) is a major gynecological problem in developing and underdeveloped countries. Despite the significant advancement in early detection and treatment modalities, several patients recur. Moreover, the molecular mechanisms responsible for CC recurrence remains obscure. The patients with CC recurrence often show poor prognosis and significantly high mortality rates. The clinical management of recurrent CC depends on treatment history, site, and extent of the recurrence. Owing to poor prognosis and limited treatment options, recurrent CC often presents a challenge to the clinicians. Several in vitro, in vivo, and patient studies have led to the identification of the critical molecular changes responsible for CC recurrence. Both aberrant genetic and epigenetic modifications leading to altered cell signaling pathways have been reported to impact CC recurrence. Researchers are currently trying to dissect the molecular pathways in CC and translate these findings for better management of disease. This article attempts to review the existing knowledge of disease relapse, accompanying challenges, and associated molecular players in CC.

A diagnostic and prognostic value of blood-based circulating long non-coding RNAs in thyroid, pancreatic and ovarian cancer

Several studies have demonstrated the potential of circulating long non-coding RNAs (lncRNAs) as promising cancer biomarkers. Herein, we addressed the regulatory role of circulating lncRNAs and their potential value as diagnostic/prognostic markers for thyroid, pancreatic and ovarian cancers. Furthermore, we analyzed and measured the clinical implications and association of lncRNAs with sensitivity, specificity, and area under the ROC curve (AUC). Based on our meta-analysis, we found that GAS8-AS1 could discriminate thyroid cancer from non-cancer and other cancers with higher accuracy (AUC = 0.746; sensitivity = 61.70 %, and specificity = 90.00 %). Similarly, for ovarian cancer, lncRNA RP5-837J1.2 was found to have ideal diagnostic potential with critical clinical specifications of AUC = 0.996; sensitivity = 97.30 % and specificity = 94.60 %. Whereas we could not find any lncRNA having high diagnostic/prognostic efficiency in pancreatic cancer. We believe that lncRNAs mentioned above may explore clinical settings for the diagnosis and prognosis of cancer patients.

Radiomics in cervical cancer: Current applications and future potential

Cervical cancer is the most commonly diagnosed cancer among women. Early diagnosis and prediction will greatly improve the treatment outcome. Many clinical parameters have been used as diagnostic and prognostic factors for cervical cancer patients, including tumor stage, histological type, lymph node status, but with limitations in prediction accuracy. The development of noninvasive biomarker with the potential to provide more specific tumor characterization before treatment begins or during therapy is urgent needed, which may permit clinicians to administer a more individualized anti-cancer treatment. Radiomics is a mathematical-statistical procedure extracting information from medial images, which has the potential for prediction of staging, histological type, node status, relapse and survival in patients with cervical cancer. In this manuscript, we reviewed recent clinical studies and future potential for the application of radiomics in the treatment of patients with cervical cancer, and discussed the current challenges and limitations of radiomics for oncology.

Cervical cancer patterns of care in Italy: A radiation oncology survey of MITO and AIRO GYN groups

Large heterogeneity in therapeutic approaches to cervical cancer (CC) patients has been registered worldwide; a national survey exploring practice settings and equipments in CC treatment was distributed to radiation oncologists. Questionnaires were compiled in 90 of 194 Centers (compliance: 46.3 %). Most of respondents reported the presence of multidisciplinary tumor board, and modern equipments/techniques; 55.5 % of centers reported >1 brachytherapy (BT) equipment, thus implying the need to refer their patients outside for the remaining centers. Post-surgery radiotherapy was performed in 96.7 % of early CC (ECC) cases with pathological high risk factors. Exclusive chemoradiation with concomitant platinum schedules was referred to be used by 84.4 % of centers in locally advanced CC. Alternative options were reported with a range between 4.4 and 28.9 %. The present survey reports a broad spectrum of therapeutic options for CC in Italy. Availability and use of modern techniques is quite diffuse, but the distribution of BT resources and skills remains a challenge.

HER2 in gynecological malignancies: Bridging the gap between standardized pathological assessment and precision therapy

WEE1 inhibition in cancer therapy: Mechanisms, synergies, preclinical insights, and clinical trials

Advancements in tumor-infiltrating lymphocytes: Historical insights, contemporary milestones, and future directions in oncology therapy

Dostarlimab: Review on success story and clinical trials

The impact of PARP inhibitors in the whole scenario of ovarian cancer management: A systematic review and network meta-analysis

Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes. We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered. A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals. This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy. Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI).

Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints

Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.

Artificial intelligence applications in ovarian cancer detection: A systematic literature review of deep learning approaches and clinical translation challenges

This systematic literature review examines artificial intelligence applications in ovarian cancer detection through analysis of 61 studies published between 2020 and 2025. The investigation reveals advancing methodological sophistication alongside persistent limitations constraining clinical translation. Convolutional neural network architectures dominate current research, with ResNet variants achieving accuracy rates between 92 % and 99.7 %. Vision transformer integration demonstrates competitive performance while providing attention-based interpretability mechanisms. Ensemble methodologies produce superior diagnostic accuracy, reaching 98.96 % through multi-model integration strategies. Dataset heterogeneity presents barriers to model generalizability, with sample sizes ranging from hundreds to thousands of images and private institutional datasets limiting external validation opportunities. Hyperparameter optimization receives minimal attention across reviewed studies, with twelve investigations implementing systematic parameter tuning. Explainable AI implementation occurs in seven studies despite growing regulatory requirements for transparent medical AI systems. Object detection applications demonstrate limited adoption compared to classification approaches, with U-Net variants comprising the primary segmentation methodology. Bibliometric analysis indicates increasing research activity, with publication counts rising from 5 papers in 2020-2021, 34 papers in 2023-2024. Future research directions should prioritize standardization initiatives for data collection and evaluation metrics, prospective clinical trials for validation, and regulatory pathway development for medical AI system approval.

Adjuvant treatment of endometrial cancer in molecular era: Are we ready to move on?

For many decades, the Bokhman dualist vision was used to stratify endometrial cancer (EC) in good or bad tumors. Nowadays, a more robust and reliable molecular stratification is taking place with the The Cancer Genome Atlas Research Network (TCGA) classification bringing new and important information in the field. Collaborative groups are replicating TCGA using accessible tools with immunohistochemistry. It's time to move on and include this information along with pathology features to better delineate adjuvant treatment in EC.

Prediction models for endometrial cancer for the general population or symptomatic women

Consolidation or maintenance systemic therapy for newly diagnosed stage II, III, or IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review

To systematically review the effectiveness and harm of consolidation or maintenance therapy in patients with newly diagnosed stage II-IV EOC. MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO databases, and four relevant conferences were systematically searched. We adhered to PRISMA guidelines, and used the GRADE approach to aggregate data. Among 12,675 citations, 28 comprising 16,310 patients were analyzed. The certainty of aggregated study evidence ranged from high to low. The existing evidence does not find overall survival benefit for consolidation therapy with chemotherapy. For maintenance therapy, comparing with placebo, olaparib, niraparib, veliparib, and bevacizumab are effective as maintenance therapy for certain patients with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma respectively without reducing quality of life. Longer follow-up with more mature results of overall survival will better define the effect of these agents.

Neoadjuvant and adjuvant systemic therapy for newly diagnosed stage II- IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review

To systematically review neoadjuvant and adjuvant therapy options for women with newly diagnosed stage II-IV ovarian cancer. Phase III trials were searched using MEDLINE, EMBASE, and Cochrane Library. Maintenance therapies were excluded. Thirty-three trials were included. For women with high-risk profiles that would contraindicate upfront cytoreductive surgery, neoadjuvant chemotherapy can be an option. In the post-surgical adjuvant setting, the three-weekly regimen consisting of paclitaxel and carboplatin remains the standard of care. Docetaxel may be offered to those who are unable to tolerate paclitaxel. Intraperitoneal cisplatin and paclitaxel increased OS for stage III optimally debulked women (GOG 172). The intraperitoneal regimens in GOG 252 offered no survival benefit and some harms in terms of toxicity and quality of life. There is no evidence to support adding a third agent to the standard carboplatin and paclitaxel. Results of the iPocc study will clarify the role of intraperitoneal chemotherapy.

Non-coding RNAs and liquid biopsies: Emerging biomarkers for cervical cancer

Cervical cancer (CC) is the fourth most common malignancy among women worldwide, highlighting the urgent need for improved predictive, diagnostic and prognostic biomarkers to enhance disease management and patient outcomes. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs), perform various functions in transcriptional, translational and post-translational regulation. Aberrant expression of ncRNAs in CC has been closely associated with disease initiation and progression, underscoring their potential as key regulators of cervical tumorigenesis. Several lncRNAs, such as HOTAIR and PVT1, contribute to cervical tumorigenesis by promoting cell proliferation, migration and invasion. Likewise, circRNAs, such as circ_0018289, act as miRNA sponges, leading to the dysregulation of key target genes. Moreover, specific miRNAs, such as miR-20a and miR-21, promote CC progression (oncogenic miRNAs), whereas others, including miR-214 and miR-218, exhibit a tumor suppressor role. Importantly, many ncRNAs are detectable in body fluids, representing stable and minimally invasive biomarkers suitable for liquid biopsy. Thus, in this comprehensive narrative review, we map the range of candidate ncRNAs reported in the literature and discuss their predictive, diagnostic, prognostic and therapeutic value, including their potential as circulating biomarkers in CC. We also highlight, as a future perspective, how integrated profiling approaches could guide research and support the development of non-invasive strategies for diagnosis, prognostic assessment, and therapy monitoring in CC.

Recent update on the development of HPV16 inhibitors for cervical cancer

Persistent infection with human papillomavirus (HPV) can lead to cervical cancer (CC), which is the fourth most commonly diagnosed cancer in women globally. In this review, we have explained the HPV genome and the development of CC. Additionally, we summarized recently discovered small molecules that act as inhibitors of HPV-16. These molecules were identified through experimental and in-silico studies aimed at preventing or treating CC. HPV-16 and HPV-18 are the most common subtypes of HPV that cause CC globally. E6 oncoprotein of HPV-16 is considered the primary cause of CC progression. Therefore, E6 is the most focused targeted protein for developing specific and novel therapeutic inhibitors to treat HPV-related cancers. In recent years, various HPV inhibitors have been identified by means of experimental and in-silico studies. In addition, artificial intelligence-based medical diagnostic tools have grown more popular as they are capable of screening and diagnosing HPV-related cancer.

Meta-analysis of clinical trial on the comparative efficacy and safety profiles of immunotherapeutic strategies in cervical cancer

Over the years, there have been significant advancements in the field of cervical cancer research in developing new treatment approaches. One of the significant breakthroughs in cancer treatment is the emergence of immunotherapy that can be used as a standalone treatment or in combination with other cancer therapies. Immunotherapy has shown promising results in clinical trials and has become a viable strategy for treating cancer and improves the quality of life for cancer patients and overall survival rate. Here in the systematic review we are focusing towards the effectiveness and safety of immunotherapy in cervical cancer or HPV infections CIN with clinical trial data. The data extracted had from those studies were analyzed through certain statistical methods and subgroup analysis for validating and concluding our objective. PubMed and Science direct database were used for searching the studies with applied screening and filtering and 49 main reports were included for the studies. The immunotherapies subdivided to immune checkpoint inhibitors, cellular therapy and Vaccine were separately analysed through meta-analysis for the conclusion. The Pembrolizumab (immune checkpoint inhibitor), T cell therapy and Bivalent (Ecoli expressed) vaccine were analysed to be higher effective. Thus for future exploration on immunotherapy in cervical cancer, it was described in our studies of a combination of Ecoli rec HPV bivalent vaccine followed by Pembrolizumab or T cell therapy thus improving the immune mediated action against the cancer. Apart from that, a hypothetical model of multiepitope production on ecoli for vaccine generation has also been explained.

Current management of cervical cancer in women living with HIV

Cervical cancer is a significant global health issue, particularly in low- and middle-income countries. Women living with HIV (WLWH) are not only at higher risk of cervical cancer due to their increased susceptibility to high-risk human papillomavirus (HPV) infection and compromised immune status, but also higher mortality rates have been reported. Therefore, prevention, optimal screening, use of highly active antiretroviral therapy (HAART), and early access to treatment are of utmost importance in this population. While international guidelines for cervical cancer state no treatment differences should be made for WLWH, there is evidence that this population of patients represents a challenge in decision-making for medical oncologists, radiation oncologists, and surgical oncologists. This review summarizes the available evidence on the different treatment strategies for WLWH and invasive cervical cancer and highlights the need for special considerations in screening andprevention of cervical cancer in WLWH.

Tertiary prevention strategies for micrometastatic lymph node cervical cancer: A systematic review and a prototype of an adapted model of care

We found a need for balancing the application of clinical guidelines and tailored approaches to follow-up of cervical cancer (CC) patients in the lymph node micrometastatic (MICs) setting. This review aimed to determine the current knowledge of management of MIC-positive CC cases. We addressed prognostic and risk of recurrence monitoring impacts associated with MIC+ cases. The electronic databases for literature and relevant articles were analysed. Fifteen studies, (4882 patients), were included in our systematic review. While the results show that MICs significantly worsen prognosis in early CC. A tertiary prevention algorithm for low volume lymph node disease may stratify follow-up according to the burden of nodal disease and provide data that helps improve follow-up performance. MICs worsen prognosis and should be managed as suggested by the algorithm. However, this algorithm must be externally validated. The clinical impact of isolated tumor cells (ITC) remains unclear.

Primary neuroendocrine neoplasms of the vulva: A review of the MITO rare cancer group

Gynecological neuroendocrine neoplasms are rare entities and can be divided into two groups: carcinoids and neuroendocrine carcinomas. Due to their rarity their management is not standardized. The aim of this work is to summarize and discuss the current literature evidence on this pathology. A scoping literature review was performed in multiple databases. Thirty-one studies were included: 30 case reports and one case series. Patients' age ranged between 28 and 92 years. Surgery was the most used treatment and the surgical approach included local excision (N = 16/31; 51.6%) with (N = 5/16; 31.25%) or without (N = 11/16; 68.75%) inguinal lymphadenectomy. Adjuvant radiotherapy was delivered in 12 (38.7%) cases; instead, platinum-based therapies were frequently used when chemotherapy was chosen for adjuvant treatment. The overall survival ranged between 20 days to 4 years. However, further research is needed; currently, multimodal approach including surgery, chemotherapy and radiotherapy appeared safe and feasible for the treatment of these rare and aggressive diseases.

Epigenetic mechanisms of PARP inhibitor resistance in ovarian cancer: A systematic review with bioinformatic analysis of clinically actionable genes

PARP inhibitors (PARPi) improve ovarian cancer (OC) outcomes, but resistance remains a major challenge without reliable prognostic biomarkers. This study identified epigenetic hallmarks of PARPi resistance by integrating 27 studies (22 preclinical, 5 clinical) from the past 15 years, and validating candidate genes using web-based bioinformatics tools and public microarray/RNA-seq datasets from non-relapsed, primary OC tissues. We hypothesised that early aberrant expression of these epigenetically altered, PARPi resistance-related genes in tumours may be linked to disease progression (PFS) and could serve as early biomarkers to be associated with PARPi resistance during first-line treatment. We confirmed epigenetic involvement in PARPi resistance across 36 genes linked to epigenetic modifications. Of these, 10 genes (n = 614-1435)-including RNASEH2B (HR=1.41), VHL (HR=1.26), ATM (HR=1.22), XRCC1 (HR=1.20), NRP1 (HR=1.16), KAT2B (HR=1.16), EZH2 (HR=1.15), CREBBP (HR=1.14), FZD10 (HR=0.87), and CARM1 (HR=0.86)-showed significant prognostic value for PFS (all: p < 0.05). This 10-gene signature remained collectively significant (HR 1.27, p = 0.014). RNA-seq validation showed differential expression of these genes, with highest fold-change overexpression in tumours for FZD10 (4.20), EZH2 (3.56), and CARM1 (1.61), and lowest in ATM (0.22), KAT2B (0.33), and NRP1 (0.44). GO and KEGG analyses revealed these genes are enriched in key resistance pathways, including impaired DNA repair, reduced replication stress, immune evasion, and stemness maintenance. This review with bioinformatic validation identified a 10-gene epigenetic signature associated with PARPi resistance and disease progression. These clinically actionable genes, aberrantly expressed before treatment, may serve as early biomarkers for risk stratification. Further validation in PARPi-sensitive and -resistant ovarian cancer cohorts is needed.

First-line treatments for advanced or recurrent endometrial cancer: Systematic literature review of clinical evidence

Novel therapies are driving meaningful changes to the management of endometrial cancer (EC). Herein, a systematic literature review was conducted to evaluate the efficacy and safety of first-line treatments for advanced/recurrent EC. Searches were conducted using multiple databases through October 26, 2023. In total, 108 records of 57 unique trials (48 of first-line therapies) met the inclusion criteria. Baseline characteristics varied by study, and sample sizes ranged from 28 to 1328. Median progression-free survival was reported in 28 trials (range, 1.9-18.8 months), median overall survival in 26 trials with mature data (range, 6.9-41 months), and safety in 21 trials evaluating first-line systemic therapy ± maintenance. The potentially high risk of adverse events may outweigh the suboptimal efficacy benefits reported for conventional chemotherapy or hormonal therapies. The safety and efficacy of immunotherapies identified within are expected to contribute to a paradigm shift in the management of primary advanced/recurrent EC.

The epigenetic correlation among ovarian cancer, endometriosis and PCOS: A review

Ovarian cancer is a frequent malignancy that affects a large percentage of women. Endometriosis is a chronic condition, where there is a production of benign lesions were observed in the uterine environment. PCOS is a metabolic disorder characterized by the presence of numerous cysts in the ovaries. The relation between ovarian malignancies and PCOS, by an increased ratio of ovarian stromal tissues in PCOS patients. The direct correlation is not yet confirmed among the three disorders, but it is often noted that they share risk factors, such as obesity, hormonal imbalances. Epigenetic factors have shown to be an important reason for cancer progression. Our findings at the epigenetic level includes a comparative analysis, point mutations in genes, overactivation of signaling pathways. This review paper, highlight the possible correlation between the three disorders in terms of genetic and epigenetic factors and how it could together trigger the cancer progression and metastasis.

A systematic review and meta-analysis of adjuvant chemotherapy after chemoradiation for locally advanced cervical cancer

We investigated whether the addition of adjuvant chemotherapy to chemoradiation improves overall survival (OS) and progression-free survival (PFS) by conducting a systematic review and meta-analysis. Systematic searches in the databases of PubMed, Embase and Web of Science yielded 881 articles. Two reviewer authors independently selected 31 articles for full text review and deemed eight studies eligible for inclusion. Two were randomised controlled trials (RCT), one was a large (n = 609) matched-case study and the remaining were small retrospective cohort studies; in total 2150 patients. Risk of bias assessment showed that the RCTs were at low risk and all other studies were at high risk of bias. Pooled hazard ratios for OS and PFS were 0.78 (95%CI 0.45-1.33, p = 0.36) and 0.85 (95%CI 0.65-1.10, p = 0.22), respectively. Analysis stratified by study design and sensitivity analysis showed similar results. Funnel plots showed significant publication bias due to a lack of small studies with negative outcomes.

Cyclin E1 as a driver of oncogenesis; high grade serous ovarian cancer as an exemplar

Cyclin E1 is a critical mediator of cell cycle dynamics, controlling G1/S phase transition in complex with CDK2. Overexpression of cyclin E1 can lead to replication stress, DNA damage, and heightened genomic instability. This is associated with oncogenesis, and is frequently observed pan-cancer; but is particularly common in high grade serous ovarian cancer (HGSOC). HGSOC exhibits a genomic landscape dominated by structural variation and instability, with high cyclin E1 expression in up to 58 % and CCNE1 amplification in up to 30 % of cases. HGSOC therefore represents an exemplar setting for investigating cyclin E dysregulation in cancer. HGSOC patients with high tumour expression of cyclin E1, in combination with copy number amplification, experience particularly poor survival. Agents targeting CDK2, WEE1, and PYMKT1, and other cell cycle associated targets have shown strong preclinical activity in models of high cyclin E expression and CCNE1 amplification. Recent clinical trials have explored the efficacy and tolerability of these agents, particularly in biomarker selected cohorts. The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53 % and 33 % respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.

Elucidating the mechanistic role of ovarian cancer biomarkers: Lessons learnt from affinity-proteomics

A salient feature of ovarian carcinoma (OC) is its unique tumor microenvironment (TME) enabling early onset of transcoelomic dissemination via the malignant ascites, with the omentum as a preferred site of tumor metastasis. These traits together with typical late diagnosis and high incidence of chemoresistance render OC the most lethal gynecological malignancy. Deciphering the mechanisms allowing tumor progression and metastasis represents an important aim in OC research. Also, there is a high medical need to identify biomarkers that could serve as diagnostic tools for detection of early and recurrent disease. Due to the easy access, one overarching goal is to define clinically relevant blood biomarkers reflecting the pro-tumorigenic features of the TME. For its part, the ascites better reflects the tumor secretome by holding large amounts of stromal, immune and tumor cells, as well as soluble secreted factors and extracellular vesicles, which justifies a more detailed analysis of the ascites proteome. Despite previous efforts based on mass-spectrometry analyses, biomarkers derived from these studies have so far not been integrated into clinical practice. Novel approaches applying affinity-based proteomics have more recently revolutionized biomarker research by providing systematic high-throughput analysis and highly sensitive detection. In the following, we discuss key findings in OC research applying these approaches to unravel intercellular crosstalk within the TME while identifying novel biomarkers. Understanding the origin, function and clinical impact of putative biomarkers is crucial, not only to depict the intercellular communication in the OC TME, but also to develop targeted therapies and improved diagnostic tools.

Genetic and epigenetic alterations in DNA repair genes and treatment outcome of chemoradiotherapy in cervical cancer

Cervical cancer (CaCx) is the deadliest malignancy among women which is caused by human papillomavirus (HPV) and anthro-demographical/clinicopathological factors. HPV oncoproteins E6 and E7 target p53 and RB (retinoblastoma) protein degradation, Ataxia telangiectasia mutated (ATM), ATM-RAD3-related (ATR) inactivation and subsequent impairment of non-homologous end joining (NHEJ), homologous recombination, and base excision repair pathways. There is also an accumulation of genetic and epigenetic alterations in Tumor Growth Suppressors (TGS), oncogenes, and DNA repair genes leading to increased genome instability and CaCx development. These alterations might be responsible for differential clinical response to Cisplatin-based chemoradiotherapy (CRT) in patients. This review explores HPV-mediated DNA damage as a risk factor in CaCx development, the mechanistic role of genetic and epigenetic alterations in DNA repair genes and their association with CRT and outcome, It also explores new possibilities for the development of genetic and epigenetic-based biomarkers for diagnostic, prognostic, and molecular therapeutic interventions.

Ethnicity as modifier of risk for Vitamin D receptors polymorphisms: Comprehensive meta-analysis of all cancer sites

Vitamin D receptors polymorphisms are found to be associated with several cancers. Since their prevalence vary across ethnicities and ethnicity itself seems to influence the cancer risk, a comprehensive meta-analysis was performed to investigate the role of VDR Fok1, Bsm1, Taq1, Apa1, Cdx2 and cancer risk at specific organ sites. Odds ratios, calculated with random-effects models, summarized one-hundred-ninety-two independent studies for twenty-two cancer sites. Evidence was provided that Fok1, Bsm1, Cdx2, Apa1 and Taq1 are linked to cancer susceptibility for colorectal, lung, ovarian, skin, multiple myeloma and brain cancer. Stratifying by ethnicity, some differences were found, partially explained by minor allele frequency (MAF), for colorectal cancer, ovarian and prostate cancer in Caucasian and prostate cancer in Asian populations. In summary, ethnicity may be a modifier of cancer risk, in particular for hormone dependent cancers and it should be considered evaluating the effect of VDR on cancer risk.

Efficacy and safety of mirvetuximab soravtansine in recurrent ovarian cancer with FRa positive expression: A systematic review and meta-analysis

To evaluate the efficacy and safety of mirvetuximab soravtansine in treating recurrent ovarian cancer with folate receptor alpha (FRa) expression. A comprehensive search was conducted on online databases, including PubMed, Cochrane Library, and EMBASE, to identify relevant literature about the efficacy and safety of mirvetuximab soravtansine in recurrent ovarian cancer with FRa-positive expression. The keywords were the following: recurrent ovarian cancer, mirvetuximab soravtansine, FRa, and antibody-drug conjugate. Furthermore, studies that satisfied the necessary qualifications were carefully evaluated for further meta-analysis. This meta-analysis involved the examination of seven trials with a total of 631 patients. According to the pooled data, the objective response rate (ORR) was 36% (95%CI: 27%-45%). Similarly, the disease control rate (DCR) was 88% (95% CI: 84-91%). Furthermore, the median progression-free survival (PFS) was determined to be 6.1 months (95% CI: 4.27-7.47). The overall response rate and PFS for platinum-resistant ovarian cancer were found to be 29% (95% CI: 25-32%) and 6.26 months (95% CI: 4.67-7.85), respectively. The most often observed adverse events (AEs) in patients with recurrent ovarian cancer (OC) receiving mirvetuximab soravtansine were blurred vision (all grades: 45%, Grade III: 2%), nausea (all grades: 42%, Grade III: 1%), and diarrhea (all grades: 42%, Grade III: 2%). These AEs were specifically associated with the safety profile of mirvetuximab soravtansine in this patient population. The efficacy of mirvetuximab soravtansine in treating recurrent ovarian cancer with FRa-positive expression is satisfactory, and the safety is tolerable.

Magnitude of benefit of the addition of poly ADP-ribose polymerase (PARP) inhibitors to therapy for malignant tumor: A meta-analysis

The purpose of this study was to analyze the efficacy of PARP inhibitor on solid tumors. For this study, the following databases were searched for articles published from its inception until July 2019: PubMed, Web of Science, EBSCO, and Cochrane library, of which the main conclusion was the overall survival (OS) and progression-free survival (PFS). We conducted a meta-analysis and the results showed that PARP inhibitor increased the patients' PFS (HR: 0.51, p < 0.001), PFS with BRCA1/2 mutations (HR: 0.32, p < 0.001), OS (HR: 0.74, p < 0.001), OS with BRCA1/2 mutations (HR: 0.78, p = 0.03), complete response (CR) (RR: 1.89, p = 0.10), partial response (PR) (RR: 1.34, p = 0.01), overall response rate (ORR) (RR: 1.42, p = 0.001) respectively. The main adverse events (AEs) observed were decreased appetite. PARP inhibitors may prolong survival. PARP inhibitors were more favorable for BRCA1/2 mutations in ovarian cancer patients. Additionally, the overall safety factor was controllable.

Therapeutic potential of p53 reactivation in cervical cancer

Cervical cancer (CC) is one of most common malignancies affecting women worldwide. To date, surgical resection is the only effective radical remedy for CC at its early stages, while the prognosis of metastatic or recurrent CC is very poor. Dysfunction of the tumor suppressor p53 due to aberrant expression, post-translational modification, mutations, SNPs, and LOH as well as sequestration by viral antigens and MDM2/HDM2-mediated degradation is closely associated with the therapeutic insensitivity and relapse of many malignancies, including CC. Accumulating studies have demonstrated that restoration of p53 activity can induce cell cycle arrest and apoptosis, eliminate radio- and chemotherapy resistance, and inhibit tumor growth in CC cells. Therefore, activation of wild-type p53 as well as restoration of p53 function seems appealing as a therapeutic strategy. In this review, we focus on the potential roles of p53 reactivation in CC treatment and their underlying molecular mechanisms towards the development of novel therapies.

Integrating hereditary breast and ovarian cancer genetic counselling and testing into mainstream clinical practice: Legal and ethical challenges

Health professionals not specialized in genetics are expected to take an increasing role in genetic services delivery. This article aims to identify legal and ethical challenges related to a collaborative oncogenetics service model, where non-genetic health professionals provide genetic services to patients. Through a scoping literature review, we identified issues to the provision of hereditary breast and ovarian cancer, or other hereditary adult cancers, genetic testing under this model. Concerns that arose in the literature were informed consent, lack of adherence to best practice guidelines, lack of education of non-genetic health professionals on the provision of genetic services, psychological impacts of genetic testing, continuity of care, the complexity of genetic test results, confidentiality, risks of medical mismanagement, and the associated medical responsibility liabilities. Despite these challenges, there is a growing consensus towards the feasibility of cancer genetic testing being undertaken by non-genetic healthcare professionals in a collaborative oncogenetics service model.

Guidelines for the prevention and diagnosis of vaginal and vulvar cancers: A systematic review

Variation in care is known to exist for those diagnosed with vaginal and vulvar cancers. Guidelines are integral to providing a consistent, quality standard of care. To provide an evidence-based background for vaginal and vulvar cancers, a systematic review was conducted to identify available guidelines relevant to prevention and early detection; presentation, initial investigations and referral; and diagnosis. We conducted a systematic search of databases (CINAHL, Cochrane Library, Embase, PubMed, Scopus, Web of Science) and targeted websites (n = 23) to identify guidelines published in English within the past 10 years (from 2013 onwards) relevant to either vaginal or vulvar cancers and pertaining to the first three steps of the cancer care continuum. We screened the guidelines, extracted recommendations and statements, and assessed their quality using standard forms. A total of 45 guidelines were included in this review (33 evidence-based, 12 consensus-based). Guidelines were developed by a range of professional organisations and across countries. Guidelines covered multiple topics including prevention and early detection (n = 37; 82 %), presentation, initial investigations and referral (n = 24; 53 %), and diagnosis (n = 23; 51 %). Common and consistent guideline recommendations and statements were identified. Example recommendation topics included risk factors, management of precursor conditions, signs and symptoms, initial tests and referral, and diagnostic workup. Few timeframes were specified. This review has collated relevant and current guidelines available to health professionals from prevention to diagnosis of vaginal and vulvar cancers. Our synthesis demonstrates consistency but a lack of specificity in the available recommendations/statements.

BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: Looking for the hidden meaning

Hereditary breast and ovarian cancer syndrome is caused by germline mutations in BRCA1/2 genes. These genes are very large and their mutations are heterogeneous and scattered throughout the coding sequence. In addition to the above-mentioned mutations, variants of uncertain/unknown significance (VUSs) have been identified in BRCA genes, which make more difficult the clinical management of the patient and risk assessment. In the last decades, several laboratories have developed different databases that contain more than 2000 variants for the two genes and integrated strategies which include multifactorial prediction models based on direct and indirect genetic evidence, to classify the VUSs and attribute them a clinical significance associated with a deleterious, high/low or neutral risk. This review provides a comprehensive overview of literature studies concerning the VUSs, in order to assess their impact on the population and provide new insight useful for the appropriate patient management in clinical practice.

The role of PARP inhibitors in gastrointestinal cancers

The use of BReast CAncer (BRCA) mutations as biomarkers for sensitivity to DNA damage response (DDR) targeted drugs and platinum agents is well documented in breast and gynaecological cancers. More recently the successful use DDR targeted therapies including poly (ADP-ribose) polymerases (PARP) inhibitors has been shown to extend to other germline and somatic deficiencies within the homologous recombination (HR) pathway (Farmer et al., 2005; Turner et al., 2019; Li and Heyer, 2008). Gastrointestinal (GI) cancers are lagging behind other tumour types when it comes to personalising treatment with targeted therapies. Current methods of identifying PARP-inhibitor sensitivity in gastrointestinal cancers are based on analogies from other cancer types despite there being a lack of uniformity in determining HR status between tumour types. There is an urgent clinical need to better understand the treatment implications of DDR alterations in gastrointestinal cancers. We have reviewed PARP-inhibitor use in pancreatic, gastroesophageal, hepatobiliary and colorectal cancers and explored HRD as a biomarker for sensitivity to PARP-inhibitors.

Long noncoding RNAs (lncRNAs) in cervical carcinogenesis: New molecular targets, current prospects

Aberrant expression of lncRNAs has been seen as a key factor in a wide range of diseases including cancer. The role of lncRNAs in cervical cancer has not been clearly explained, and has been the subject of recent studies. In this review, we have compiled an updated list of previously reported lncRNAs and established a general profile of these transcripts in accordance with the role they play in cervical carcinogenesis. Thus, information here includes the influence of lncRNAs on cervical tumorigenic process through a disturbance of cellular activities. Additionally, we described recent discoveries about how HPV contributes to lncRNAs expression in cervical cancer and we summarized exploratory studies of strategies adopted to modulate the expression levels of lncRNAs to treat cervical neoplasia, by drawing attention to radio and chemo-resistance. Finally, this paper provides a broad overview that sets out new research directions about the role of lncRNAs in cervical cancer.

Chimeric antigen receptor T cell immunotherapy for gynecological malignancies

Gynecologic malignancies pose a serious threat to women's health worldwide. Although immunotherapy has significantly revolutionized cancer treatment strategies, effective therapeutic options for recurrent or advanced gynecologic malignancies are still deficient, posing significant challenges to clinical therapy. Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable efficacy in treating hematologic malignancies, marking a significant change in the oncology treatment paradigm. However, despite the gradual increase in CAR T cell therapy used in treating solid tumors in recent years, its efficacy in treating gynecologic malignancies still needs further validation. This review will thoroughly examine CAR-T cell engineering and its mechanism of action on specific antigens associated with gynecologic malignancies, systematically assess the current application of CAR T cell therapy in gynecologic tumors and the advancements in clinical trials, and discuss the significant challenges and corresponding strategies, thereby offering a scientific foundation and guidance for future research in this area.

The role of HER2 pathway in vulvar paget’s disease

Vulvar Paget's disease (VPD) is an orphan neoaplasm accounting 1-2 % of vulvar malignancies. Advanced VPD is currently laking effective treatment options. Since HER2 is overexpressed in 30-40 % of VPD cases, this scoping review explores its prognostic significance and the effectiveness of HER2-targeted therapies. A literature review was conducted using the PubMed and Scopus databases. The search was restricted to articles in English and human studies, incorporating the terms "extramammary Paget disease", "vulva", "HER2", "anti-Her2 therapy" and "trastuzumab". Two reviewers screened abstracts and full-text article while recording relevant data. Seventeen small retrospective studies on HER2 expression in VPD were evaluated. All studies assessed HER2 using IHC, while only 9 studies also employed FISH to detect gene amplification. A total of 270 patients are reported, of which 121 patients (45 %) had a 3 + or 2 + score. HER2/neu amplification was reported in 40 % of invasive tumours vs 17.5 % of non-invasive tumor. Eleven case-reports and series suggested a possible benefit of HER2-targeted therapies. To be mentioned, 4 articles reported trastuzumab combined with chemotherapy as the first-line treatment option, while trastuzumab monotherapy resulted in excellent objective response in two case reports. Although HER2 expression in VPD represents a potential therapeutic target, current evidence is largely derived from case reports and lacks substantial clinical trial data. There is an urgent need for targeted clinical trials and expanded genomic profiling to enhance understanding of the underlying molecular mechanisms and optimize treatment strategies.

Precursor lesions of vulvar squamous cell carcinoma – histology and biomarkers: A systematic review

The precursor lesion of vulvar squamous cell carcinoma (VSCC), namely vulvar intraepithelial neoplasia (VIN), is classified as: human papillomavirus (HPV)-related high grade squamous intraepithelial lesion (HSIL), and HPV-independent differentiated VIN (dVIN). Traditionally, histology and immunohistochemistry (IHC) have been the basis of diagnosis and classification of VIN. HSIL shows conspicuous histological atypia, and positivity on p16-IHC, whereas dVIN shows less obvious histological atypia, and overexpression or null-pattern on p53-IHC. For both types of VIN, other diagnostic immunohistochemical markers have also been evaluated. Molecular characterization of VIN has been attempted in few recent studies, and novel genotypic subtypes of HPV-independent VSCC and VIN have been identified. This systematic review appraises the VSCC precursors identified so far, focusing on histology and biomarkers (immunohistochemical and molecular). To gain further insights into the carcinogenesis and to identify additional potential biomarkers, gene expression omnibus (GEO) datasets on VSCC were analyzed; the results are presented.

Comment on “The risk of breast cancer and gynecologic malignancies after ovarian stimulation: Meta-analysis of cohort study”

The role of liquid biopsy in epithelial ovarian cancer: State of the art

The clinical implementation of liquid biopsy has dramatically modified the analytical paradigm for several solid tumors. To date, however, only circulating free DNA (cfDNA) has been approved in clinical practice to select targeted treatments for patients with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and breast cancer (BC). Interestingly, emerging liquid biopsy analytes in peripheral blood, including circulating tumor cells (CTC), miRNA, and extracellular vesicles (EVs), have been shown to play a crucial role in the clinical management of solid tumor patients. Here, we review how these blood-based biomarkers may positively impact early diagnosis, prognosis, and treatment response in ovarian cancer (OC) patients.

Immune evasion in endometrial cancer: Unraveling the latest mechanisms and future directions

Endometrial cancer (EC) is a common gynecological malignancy, and its incidence has been increasing in recent years. The deepening understanding of the interaction between the tumor microenvironment and immune system has drawn increasing research attention to immunotherapy. In 2013, the Cancer Genome Atlas project performed molecular classification of EC, which revealed the genomic alterations of different molecular subtypes. Especially the discovery of microsatellite instability high /mismatch repair deficiency subtypes has made the application of immunotherapy in EC possible. However, immune evasion allows EC to survive after encountering the host immune system. Recently, researchers have continuously identified new mechanisms of immune evasion, such as the alteration of MHC-I molecules, the abnormal expression of immune checkpoint molecules, and the role of immunosuppressive cells. In this review, we will discuss the progress in understanding the basis of immune evasion in EC and summarize various combinations of immune checkpoint inhibitors that have been developed or are being studied. In the future, with a deeper understanding of the immune evasion mechanism, immunotherapy is expected to improve outcomes in patients with EC.

Endometrial cancer in the elderly: Characteristics, prognostic and risk factors, and treatment options

Endometrial cancer incidence and related mortality are on the rise due to aging demographics. This population often presents with unfavorable features, such as myometrial invasion, non-endometrioid histology, high-grade tumors, worse prognosis, etc. The role of age as an independent prognostic factor is still debated, and screening tools addressing frailty emerge as pivotal in guiding treatment decisions; however, they are still underutilized. Treatment disparities are evident in the case of older patients with endometrial cancer, who frequently receive suboptimal care, hindering their survival. Radiotherapy and minimally invasive surgical approaches could be performed in older patients. Data on chemotherapy and immunotherapy are scarce, but their potential remains promising and data are being gathered by recent trials, contingent on optimal patient selection through geriatric assessments. Overall, we recommend personalized, screening tool-guided approaches, adherence to guideline-recommended treatments, and inclusion of older people in clinical trials to help identify the best course of treatment.

Stereotactic body radiotherapy boost as an alternative to brachytherapy for cervical cancer: A scoping review

This scoping review aims to evaluate the evidence for stereotactic body radiotherapy (SBRT) boost as a potential alternative for brachytherapy (BCT) in treating cervical cancer. A comprehensive literature search was conducted across multiple databases. Studies investigating SBRT boost in cervical cancer patients who were either contraindicated for or refused BCT were included. The review examined SBRT efficacy and safety. Sixteen studies were included, encompassing prospective (n = 4) and retrospective cohort studies (n = 8), as well as phase I and II trials (n = 4). The most common SBRT boost dose was 25 Gray(Gy)/5 fractions (ranging from 18 to 40 Gy/3-5 fractions). Local control rates at 1-year, 3-year, and 5-year ranged from 86 % to 100 %, 78-92 %, and 81-92 %, respectively. Overall survival (OS) rates at 1-year, 3-year, and 5-year rates ranged from 49 % to 95 %, 50-77 %, and 50-69 %, respectively. Two studies reported a pathological complete response rate of 93 % and 94 % three months after the SBRT boost. Most studies reported low rates of late grade 3 or higher genitourinary (0-14 %) and gastrointestinal (0-26 %) toxicities. The overall incidence of rectovaginal fistulas ranged from 0 % to 13 %. This scoping review suggests SBRT boost as a promising alternative to selected cervical cancer patients who cannot receive BCT. The results indicate a high local control with acceptable toxicity profiles. However, further research is needed to define optimal SBRT boost parameters, identify patient selection criteria, and address knowledge gaps regarding long-term outcomes and cost-effectiveness.

Mechanistic role of HPV-associated early proteins in cervical cancer: Molecular pathways and targeted therapeutic strategies

Cervical cancer (CC), one of the major causes of death of women throughout the world is primarily caused due to Human Papilloma Virus (HPV) 16 and 18. The early region (E) oncoproteins of HPV are associated with the etiopathogenesis and contribute to the progression of cancer. The present article comprehensively discussed the structural organization and biological functions of all E proteins of HPV and their contribution to progression of CC with an intent to decipher the pathological hallmarks and their relationship. Additionally, the role of E proteins in reference to therapeutics will also be presented. A systematic search has been carried out for articles published in PubMed database by using combinations of different keywords with Boolean operators (AND, OR, NOT) including cervical cancer, HPV, E proteins, and signaling. From the analysis of literature review, its apparent that E proteins are the major contributor to disease progression. E1, E2, and E4 forms are mainly associated with viral integration, replication, and transcription whereas E6 and E7 act as an oncoprotein and are associated with the progression of cancer. E5 regulates cell proliferation, apoptosis, and facilitates the activity of E6 and E7. Additionally, E proteins were observed associated with numerous cell signaling pathways including PI3K/AKT, Wnt, Notch and reasonably contribute to the initiation of malignancy, cell proliferation, metastasis, and drug resistance. Knowing the role and interplay of each protein in initiation to progression of CC, their therapeutic significance has been elucidated. The present study observations demonstrate that E6 and E7 are the major cause of HPV-mediated CC progression. E1, E2, and E5 also act as a backbone for E6 and E7 and most of the current approaches have targeted E6 and E7 mediated action only. The present review illustrates the structural organization as well as function and regulation of all early proteins of HPV and their association with several cellular signaling pathways. The observations provide clue on the regulatory aspect of these proteins in initiation to progression and reasonably represent that targeting these proteins could be a novel therapeutic strategy for CC. In particular, its seemingly appears that inhibition of the activity of E6 and E7 oncoproteins may be a better selective target to delay the progression of CC. The review reaffirms the role of E proteins and encourages future studies on developing diagnostics, and most importantly therapeutics strategies targeting E6 and E7 oncoproteins to tackle CC related morbidity and mortality.

Hydrogel-based drug delivery systems for localised treatment of peritoneal metastasis: A systematic and ideal framework review

Immune checkpoint inhibitors in endometrial cancer

The incidence of endometrial cancer (EC) is increasing worldwide. The prognosis for patients diagnosed with early-stage remains good, whereas for patients with recurrent or metastatic disease, the prognosis is poor and treatment options, until recently, were limited. In 2017, pembrolizumab was approved by the US Food and Drug Administration (FDA) for those patients with mistmach repair deficiency (MMRd) or high microsatellite instability (MSI-H) tumors. However, only 20-30 % of EC have MSI, and just over half of these patients benefit from treatment. In 2019, the FDA granted breakthrough therapy designation to lenvatinib in combination with pembrolizumab for the potential treatment of patients with advanced microsatellite stable EC that has progressed after treatment with at least one previous systemic therapy. It appears clear that immune check-point inhibitors will have a definite place in the management of EC, both as single agent or in combination with other targeted agents. In this review, we summarize the current evidence of immune check point blockade and the identification of potential biomarkers, beyond MSI-H or MMRd, that could help to predict response to this agents in correlation with the genomic EC subtypes.