Jean Calleja-Agius

Incidence and survival of rare female genital tract cancers in Europe: The EUROCARE-6 study

Cancers of female genital tract (FGTC) account in Europe for 14 % of all female malignancies, and many of them are rare. FGTC epidemiological indicators are usually reported by anatomical site, but they are a heterogeneous group of diseases in terms of morphological characteristics and clinical management. We show incidence and survival population-based estimates and time trends in the European population for FGTC, defined combining topography and morphology codes. We analyzed data of females aged 15 years or more diagnosed with 25 FGTC of which 23 rare. Data were provided by 100 European population-based cancer registries to the EUROCARE-6 project. Incidence was estimated for the period of diagnosis 2001-2013 in terms of both crude and age-adjusted rates. Observed and relative survival was estimated with the complete approach for the period of diagnosis 2008-2013 and with the period approach for trends, considering years of follow-up from 2001 to 2014. Over a total of 793,715 considered diagnoses of FGTC, 279,667 were classified as rare entities. Their crude incidence rate per 100,000 largely varied from almost zero for adenoid cystic carcinoma of corpus uteri to 5.9 for squamous cell carcinoma of cervix uteri. During the period 2001-13, a significant increment was reported for clear cell adenocarcinoma, Mullerian mixed tumor and serous/papillary carcinoma of corpus uteri, for the Mullerian mixed tumor, adenocarcinoma of fallopian tube, and primary peritoneal serous/papillary carcinoma, and malignant/immature teratoma of ovary. Incidence rates significantly reduced for squamous cell carcinoma of cervix uteri, mucinous adenocarcinoma and sex cord tumor of ovary. Five-year relative survival was >84 % for all the non-epithelial tumors of ovary and for choriocarcinoma of placenta. Survival under 40 % was estimated for Mullerian mixed tumors and undifferentiated carcinomas of all the considered sites. Major survival improvements were observed for placenta choriocarcinoma, sex cord tumor, malignant/immature teratoma and mucinous adenocarcinoma of ovary, in adenocarcinoma of fallopian tube and in serous/papillary carcinoma of corpus uteri. Relative survival significantly reduced in squamous cell carcinoma of corpus uteri. The increasing incidence and survival of many rare FGTC can be in part attributed to better diagnostic ability and to a better organisation of care of patients with rare tumors. The epidemiological indicators here provided can be taken as a starting point to evaluate the effectiveness of the future activities of the European Rare Cancers Networks.

Evaluating the role of robotic surgery in gynecological cancer treatment

Robotic surgery has emerged as a transformative force in the field of gynecologic oncology, offering a minimally invasive yet versatile approach to managing a wide range of gynecologic cancers. Robotic platforms, with their enhanced precision, magnified visualization, and ergonomic advantages, have been translated into tangible benefits for patients, including reduced blood loss, shorter hospital stays, and faster recovery times. In the context of endometrial cancer, robotic-assisted hysterectomy has become an increasingly preferred approach for early-stage disease, demonstrating comparable, if not superior, surgical and oncologic outcomes compared to traditional open or laparoscopic methods across various histopathological subtypes. Similarly, robotic surgery has gained traction in the treatment of early-stage cervical cancer, with robotic-assisted radical hysterectomy offering a minimally invasive alternative with favorable early results. However, recent studies highlighting the importance of long-term survival data underscores the need for ongoing research and careful patient selection. While the role of robotic surgery in advanced ovarian cancer remains less definitive compared to endometrial and cervical cancers, ongoing research is exploring its potential benefits in specific scenarios, such as interval debulking surgery and patients with limited disease burden. Despite its demonstrable advantages, robotic surgery in gynecologic oncology is not without its challenges, including the high initial cost, the need for specialized surgical training, and the inherent limitations of robotic platforms. However, as technology continues to advance and surgical expertise grows, robotic surgery holds immense promise for further refining the surgical management of gynecologic cancers, ultimately striving to provide all women facing these diseases with the most effective, safest, and compassionate care possible.

The role of microRNA-9 in ovarian and cervical cancers: An updated overview

Ovarian and cervical cancers are the two most frequent kind of gynaecological cancers (GCs). In spite of advances in prevention, screening and treatment, cervical cancer still leads to an increased morbidity and mortality worldwide. Ovarian cancer is often detected at a late stage, which significantly reduces the effectiveness of available treatments. Therefore, novel methods are desperately needed to improve the clinical care of GC patients. MicroRNAs, also known as short noncoding RNAs (miRNAs/miRs), are a diverse group of RNAs with a length of 22 nucleotides. These typically cause translational repression and mRNA degradation by interacting with target mRNAs' 3' untranslated region (3'-UTR), together with other regions and gene promoters. Under certain conditions, they are also able to activate translation or regulate transcription. It has been demonstrated that miRNAs are crucial to several biological processes leading to tumorigenesis, including GCs. Recent research has shown that miR-9 affects carcinogenesis. In this review, we will provide an overview of current research on the potential utility of miR-9 in the diagnosis, prognosis, and therapy of ovarian and cervical malignancies.

Exploring the impact of exercise on women with ovarian cancer: A call for more methodologically standardized RCTs to enable a realistic systematic review

Ovarian cancer remains a leading cause of mortality among gynecological malignancies, often diagnosed at advanced stages due to nonspecific symptoms and limited screening tools. Standard treatment, including cytoreductive surgery and chemotherapy, can cause fatigue, physical dysfunction, and psychological distress, impacting quality of life. Exercise interventions have shown potential to mitigate these effects, but inconsistent methodologies in randomized controlled trials (RCTs) limit reliable conclusions and clinical integration. A systematic review was conducted following PRISMA guidelines. RCTs assessing physical exercise effects on women with ovarian cancer were included, excluding pilot trials, reviews, and combined therapies. Data extraction and GRADE assessments were performed by two independent reviewers, and a narrative synthesis was conducted due to study heterogeneity. Eleven RCTs were analyzed, covering aerobic, resistance, and yoga interventions. Findings indicated improvements in physical function, fatigue, and psychological outcomes, such as reduced depressive symptoms and cognitive enhancements. Patients adhering to ≥150 min of moderate-intensity exercise per week experienced the most consistent benefits. Preoperative walking expedited recovery, though significant heterogeneity in study protocols precluded meta-analysis. Evidence supports the feasibility and benefits of exercise across ovarian cancer stages. However, inconsistency in exercise intensity, duration, and reporting hinders the development of standardized protocols. Compared to cardiological rehabilitation, ovarian cancer exercise guidelines remain underdeveloped, emphasizing the need for tailored, evidence-based interventions. Exercise interventions can improve physical and mental health in ovarian cancer patients. Standardized RCTs are urgently needed to establish robust exercise protocols and enable clinical implementation, enhancing survivorship outcomes and quality of life.

Ovarian cancer in children and adolescents: A unique clinical challenge

Ovarian cancer in children and adolescents is rare, presenting unique diagnostic and management challenges distinct from adult cases. This paper provides a comprehensive overview of this disease, focusing on the importance of a multidisciplinary approach to care. We discuss the common presentation of ovarian malignant masses in young patients, highlighting the role of imaging and tumor markers in diagnosis. The paper delves into the surgical management of these tumors, emphasizing the importance of fertility-sparing techniques whenever possible. We explore the role of adjuvant chemotherapy, considering histological subtypes and disease stage. Furthermore, we address the good prognosis associated with early diagnosis and treatment, with survival rates exceeding 90 % in many cases. Finally, the need for long-term follow-up to monitor for potential recurrence is underscored and the long-term treatment-related effects are addressed. This review aims to guide clinicians in providing optimal care for this unique patient population, emphasizing the importance of balancing oncological control with the preservation of future fertility and quality of life.

Sarcopenia in gynaecological cancers

Sentinel lymph node biopsy in gynecological malignancies: A modern approach to surgical staging – A narrative review

Sentinel lymph node biopsy (SLNB) has emerged as a valuable alternative to traditional lymphadenectomy in the surgical management of gynecological cancers. This narrative review delves into the advantages, practical applications, and future research directions of SLNB in this context. Compared to the more extensive lymphadenectomy, SLNB offers a minimally invasive approach to lymph node staging, leading to reduced surgical morbidity, faster recovery times, and improved quality of life for the patients involved. This narrative review highlights the high detection rates and accuracy of SLNB in predicting lymph node metastasis, particularly in early-stage endometrial, cervical and vulvar cancers. By accurately assessing lymph node status, SLNB provides crucial information for treatment planning, potentially guiding decisions regarding adjuvant therapies and assessing the need for further lymph node dissection. From clinical practice guidelines, prospective studies, and relevant research articles, this review provides a thorough understanding the evolving role of SLNB in managing gynecological malignancies. The findings presented underscore the potential of SLNB to improve patient outcomes by providing accurate staging while minimizing surgical complications.

Oncologic and pregnancy outcomes of fertility-sparing treatment with medroxyprogesterone acetate in women with premalignant and malignant endometrial lesions: A case series

Current trends of delaying childbearing and the increasing incidence of endometrial cancer in nulliparous woman necessitate research and development of fertility sparing treatments. Hormonal therapy with progestins offers an alternative to surgical treatment for a select group of patients of reproductive-age, who wish to preserve their reproductive potential. The study evaluates the effectiveness of medroxyprogesterone acetate therapy in patients with early-stage endometrial cancer, atypical endometrial hyperplasia or atypical polypoid adenomyoma, seeking to preserve fertility. This prospective case series encompasses nine patients (6 with endometrial cancer, 2 with atypical endometrial hyperplasia and 1 with atypical polypoid adenomyoma) treated in the period between 2015 and 2022 with high-dose medroxyprogesterone acetate therapy. Treatment and monitoring were conducted at the University Clinic for Gynecology and Obstetrics in Skopje, R. Macedonia, with clinical assessments carried out every three to six months via hysteroscopy with endometrial biopsy or exploratory curettage. Primary response was achieved in 4 patients (44.4 %). Secondary response was achieved in the remaining 5 cases (55.6 %). Therefore, all 9 patients (100 %) showed complete response to progestin treatment in the time interval 3-9 months. Recurrence occurred in 3 cases (33.3 %) after follow-up of 15, 33 and 84 months, respectively. During the study period, 2 patients (22.2 %) underwent definitive surgery with hysterectomy because of disease recurrence (both with endometrial cancer, stage IA). Fertility was achieved in 1 patient (11.1 %), who had a full-term delivery with caesarean section. Conservative treatment approach to patients with endometrial cancer aiming to preserve fertility can be safe and have acceptable outcomes in terms of oncologic response as well as pregnancy results, with high-dose medroxyprogesterone acetate therapy being an effective option. The selection of endometrial cancer patients, for whom fertility-sparing progestin therapy is appropriate, is of great importance to achieve the best outcomes. Continuous and careful monitoring of patients undergoing conservative treatment is essential, due to the risk of disease recurrence and progression.

Exploring the protein signature of endometrial cancer: A comprehensive review through diverse samples and mass spectrometry-based proteomics

Endometrial cancer (EC) is increasing incidence among women, and it constitutes a health problem for women globally. An important aspect of EC management involves the use of protein biomarkers for early detection and monitoring. Protein biomarkers allow the identification of high-risk patients, the detection of the disease in its early stages, and the assessment of treatment responses. Mass spectrometry (MS)-based proteomics offers robust analytical techniques and a comprehensive understanding of proteins. Proteomics methods allow scientists to investigate both the quantities and functions of proteins. Thus, it provides valuable insights into how proteins are altered under different conditions. This review summarizes recent advances in MS-based proteomic biomarker discovery for EC, focusing on different sample types and MS-based techniques used in clinical studies. The review emphasized in detail the most commonly used key sources such as blood, urine, vaginal fluids and tissue. Furthermore, MS-based proteomics techniques such as untargeted, targeted, sequential window acquisition of all theoretical mass spectra (SWATH-MS) and mass spectrometry imaging used in the discovery and validation/validation phases were evaluated. This review highlights the importance of biomarker discovery and clinical translation to improve diagnostic and therapeutic outcomes in EC. It aims to provide a comprehensive overview of MS-based proteomics in EC, guiding future research and clinical applications.

Advancements in uterine sarcoma management: A review

Uterine sarcomas are rare, accounting for 3-7% of uterine malignancies. This review aims to summarize advancements in diagnostics and treatment over the last decade, focusing on innovative imaging techniques, molecular diagnostics, and treatment modalities. Recent diagnostic advancements include enhanced imaging techniques such as MRI and AI-driven algorithms, improving accuracy in differentiating between benign and malignant uterine tumors. Biomarkers like lactate dehydrogenase (LDH) and microRNAs have shown potential in preoperative identification. Treatment strategies continue to evolve, with surgical resection being the cornerstone. The role of lymphadenectomy and adnexectomy varies by histopathological subtype, emphasizing personalized approaches. Adjuvant therapies remain controversial, tailored to patient risk factors and tumor characteristics. Fertility-sparing options are viable for selected patients, though not recommended for high-grade tumors. Significant progress in diagnostic techniques and personalized treatment approaches has improved the management of uterine sarcomas. Future guidelines from major oncology groups are expected to standardize care. Continued research is essential for refining treatment protocols and enhancing patient outcomes.

Systematic review of cost-effectiveness studies on cervical cancer screening across Europe

Cervical cancer (CC) is a type of cancer with poor prognosis when diagnosed in advanced stage with a big socioeconomic burden. The incidence rates have wide variations among European countries depending on the implementation or not of screening, vaccination programs and the human development index (HDI). Most studies on cost-effectiveness of CC screening programs are carried out in countries with a high HDI, however more recent reviews of screening approaches are coming from countries with lower HDI aiming to identify the best screening strategies. Our study aims to identify which are the currently applied and most cost-effective strategies of CC screening in Europe. This is a systematic review conducted in three different databases (PubMed, Scopus and ScienceDirect) and reported following the PRISMA guidelines. General key terms for all databases were the following: cost-effectiveness, cervical cancer, screening, Europe. We included studies in English, Italian, Spanish and Bulgarian, published in the last 25 years, reporting data on cost-effectiveness of CC screening, costs and outcome measures. The methodological quality of the articles was evaluated with a standardized tool. A total of 262 studies were identified and 22 studies were included in the final analysis. In 90.1 % of the economic studies, the new screening strategy was shown to be more cost-effective compared to the current one or compared to no screening. The optimal strategy mostly involved primary HPV testing, combined with cytology or as stand-alone screening technique. Several scenarios differing on starting age and periodicities for CC screening, combination of techniques and triage, were found to be cost-effective and below the willingness to pay (WTP) threshold. The methodology of all included studies was assessed from 10 to 11 on the JBI standardized tool and Drummond 11-point checklist. Numerous cost-effective options for CC screening in different European countries were identified in this systematic review. HPV testing, with or without cytology, mainly starting at 30 years of age and repeated every 5 years or more was the most cost-effective technique. Future studies should focus on the most appropriate CC screening approach for each context and setting, also considering HPV vaccination in Europe.

Trophoblastic disease and choriocarcinoma

Gestational trophoblastic disease (GTD) is a group of diseases associated with pregnancies that demonstrate abnormal development of trophoblastic cells. GTD includes hydatidiform moles (HM) that may continue to further develop into gestational trophoblastic neoplasms (GTN), such as choriocarcinoma (CC). Gestational CC is a malignant mass development that may arise from HM, from other (normal) pregnancies or from other gestational events (such as ectopic pregnancies). The aim of this review is to outline current understating of the genetics and epigenetics of GTD and gestational CC and the link between the two diseases.

Biobanking and gynecologic oncology - Special considerations, challenges and opportunities

Biobanks of gynecological tissues occupy a critical niche in oncologic research. They are essential components of contemporary research strategies on gynecologic malignancy by integrating clinical, molecular and longitudinal biospecimen data. They also implement protocols for quality control, regulate sample and data sharing, provide ethical and regulatory oversight, and establish governance mechanisms to regulate their function. Gynecologic tissue biobanks also face some unique challenges. The broad heterogeneity of disease entities encompassed under this domain include common and rare malignancies, each with unique molecular subtypes that must be integrated into biobank information systems. Specimen acquisition extends beyond conventional tissues to include cervicovaginal microbiomes and ascitic fluid. Thus, gynecologic tissue biobanks should develop tailored collection strategies and the establishment of dedicated gynecologic tissue repositories that enable the aggregation of rare specimens through collaborative networks. This article emphasizes the need for high-quality annotation of biospecimens, the incorporation of multi-omics approaches to enhance the translational approaches, challenges associated with integration of high dimensional datasets, the role of biobank networks, and various ethical and cultural considerations concerning gynecologic biobanks. Emerging technologies that integrate multi omics, spatial biology and liquid biopsies now offer enhanced opportunities that augment classical specimen collection and should be integrated into standardized protocols.

Gynecological cancers: Bridging the gap between research and cure

Approximately 1.5 million women suffer from gynecological malignancies every year. Around 60 % of these cancers are classified as rare in the European population. Because of their rarity, the management of these tumors requires specific approaches by the cancer community and national health systems. Effective international collaborations in the area of gynecological cancer are underway, thanks to various initiatives such as GYNOCARE and other Collaboration in Science and Technology (COST) Actions. This special issue of EJSO collects expert opinions on the ongoing research and treatment options in various types of gynecological malignancy.

Analysis of the molecular profile of endometrial cancer depending on microsatelite instability

The absence of precise classification and effective predictive biomarkers in endometrial cancer (EC) leads to suboptimal treatment decisions and outcomes, underscoring the urgent need for improved diagnostic and therapeutic approaches. Endometrial cancer represents 4.8 % of the cases of malignant tumors, being in the sixth place worldwide in terms of incidence of malignant tumors in women. The treatment of endometrial cancer, especially stage I, which affects 70-75 % of patients, remains a subject of debate. According to the current European Society of Medical Oncology (ESMO) recommendations, for the management of patients with endometrial cancer, the treatment strategy is influenced by the results of risk stratification. Regarding endometrial cancer, a large number of prognostic factors are described, which create certain difficulties in their application in clinical practice. Most factors are morphological, and information about them is obtained after surgery on the basis of a standard histological examination. Of particular interest is the study of risk factors in the case of individual endometrial cancer variants. The molecular classification of endometrial tumors has the potential to become an indispensable element of histopathological classification, which would contribute to determining the prognosis and treatment strategies of the disease. In addition, it can lead to the development of a new targeted therapy, as well as to the implementation of molecular diagnostic tests for the detection of endometrial cancer in the early stages, when the prognosis is much more favorable. Despite the large amount of research which focuses on the study of the biological and molecular aspects of endometrial cancer, currently none of the tumor markers is recommended for widespread clinical use in endometrial cancer because there is insufficient information concerning their application into clinical practice.

Rare gynaecological cancers in Malta – An analysis of incidence between 2010 and 2021

Whilst about 18 % of all cancers in females are gynaecological cancers, more than 50 % of these can be classified as rare tumours (defined as an annual incidence of <6 per 100,000). Such cancers represent an important challenge for small countries like Malta where the small caseload may limit the expertise of clinicians in the diagnosis and treatment of such cancers. The study uses data from the Maltese population-based cancer registry to examine trends in incidence rate of the rare gynaecological cancers for the 12-year period between 2010 and 2021. It employs the RARECAREnet list to identify the rare gynaecological cancers by major rare gynaecological cancer categories and histological types and analyses the number of cases and incidence rates in Malta to monitor trends and provide an insight of the burden of such cancers. A total of 709 new cases of rare gynaecological cancers were discovered during the 12-year period. Globally, these rare gynae cancers, constituted 42.6 % of all the gynae cancers that occurred during this period. Most of these rare cancers were ovarian (399 cases, 56.3 %), followed by rare cancers of the vulva and vagina (122 cases, 17.21 %), rare cancers of the corpus uteri (93 cases, 13.12 %) and rare cancers of the cervix uteri (73 cases, 10.3 %). Other rare gynaecological cancers (10 cases, 1.41 %) and cancers of the placenta (2 cases, 0.04 %) were much rarer. The outcomes in terms of 5-year survival was worse for the rare cancers compared with the commoner types of gynae cancers with an overall 5-year survival of 45.10 % and 45.48 % for rare gynae cancers for the 2010-2014 and 2015-2019 cohorts respectively and an overall 5-year survival of 69.94 % and 73.44 % for the common gynae cancers for the 2010-2014 and 2015-2019 cohorts respectively. The study shows that globally rare gynaecological cancers in a small state like Malta are in fact not so rare - with a total of 709 rare gynaecological cancers in 12 years for Malta. These cases are however few when considering that they are divided into over 30 different histopathological groups. Numbers are also small when it comes to accumulating statistical power for analysis. The caseload for the individual sub-categories is small and will often be shared amongst the different individual gynaecologists and/or their clinical team. Thus, it might be difficult for these specialists to gather enough technical expertise that is crucial for early diagnosis and the treatment of these rare cancers. This study provides a rationale for international collaboration where there is scope for joint research and sharing of expertise. Establishment of common databases for the various types of rare gynaecological tumours will provide statistical power, enabling analysis of outcomes for these rare cancers and establishment of guidelines.

Trials of interventions for ovarian and testicular germ cell tumors registered in ClinicalTrials.gov: A cross-sectional study

There is unmet need in the treatment of ovarian and testicular germ cell tumors (GCTs). This study analyzed registered trials of interventions for GCTs. We included trials of interventions for GCTs registered on ClinicalTrials.gov by July 29, 2022. We analyzed their interventions, outcome measures and study design. We included 142 trials registrations; 42 (30 %) for ovarian GCTs, 50 (35 %) for testicular GCTs, and 50 (35 %) trials for both. The majority of the trials were completed (56 %) and did not have results available (75 %). Most trials were in Phase 2. Information about the study design were not reported for many analyzed trials. Most trials had a single-group assignment (44 %) and were open-label (68 %). The median planned number of enrolled participants was 43. Most registrations used medicine(s) (87 %), either as a single type of intervention or in combination. The most commonly used type of medicine was chemotherapy (54 %). Primary outcome was not reported in 23 % of registrations, and secondary outcomes were not reported in 35 % of registrations. Overall survival was used in 6 % of registrations as a primary outcome and in 31 % of registrations as a secondary outcome. Few trials on GCTs were registered on ClinicalTrials.gov, and their number was declining in recent times. Most registrations did not report relevant information about the study design, or results if completed. More effort is needed to foster trials on GCTs, as well as to optimize the management of the registrations and foster the publication of research results.