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Advances in Gynecological Oncology: From Pathogenesis to Therapy
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Advances in Gynecological Oncology: From Pathogenesis to Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 39068

Special Issue Editor

Dr. Andrea Ciavattini

E-Mail Website
Guest Editor
Woman's Health Sciences Department, Universita Politecnica delle Marche, 60121 Ancona, Italy
Interests: cervical intraepithelial neoplasia; HPV-related diseases; gynecological oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is now known that the histological categories of some gynecological tumors do not accurately differentiate the clinical course and response to therapy. Currently, a molecular profile study is being carried out to improve the risk stratification and targeted therapy for endometrial cancer. Biomarkers and molecular alterations are increasingly being used to choose the best systemic treatment. It is also now evident that the molecular characteristics affect the biological behavior and chemo sensitivity for ovarian carcinomas. Advanced cervical cancer and recurrences respond poorly to chemotherapy. The HPV vaccine plays a crucial role in preventing this disease, and its coverage should be implemented worldwide.
There is a further need to identify better biomarkers that allow for personalized therapy and combined therapeutic regimens, including immunotherapy, radiation therapy, and chemotherapy, and personalized fertility-sparing treatment in young women should be considered when feasible.
In several gynecological cancers, sentinel lymph node use showed decreased morbidity, high sensitivity, and high negative predictive value. Many surgeons reserve its use for intermediate/high risk patients, but further evidence is needed in this area.
This Special Issue aims to gather reviews and original contributions in one collection so as to illustrate recent advances in gynecological cancers, and the future directions of clinical and basic research.

Dr. Andrea Ciavattini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ovarian cancer
  • Uterine cancer
  • Cervical cancer
  • Vulvar cancer
  • Biomarkers
  • HPV vaccine
  • Sentinel lymph node evaluation
  • Fertility-sparing treatment
  • Recurrent gynecological cancer
  • Molecular profile
  • Immunotherapy
  • Chemotherapy
  • Radiotherapy
  • Hormonal therapy
  • Imaging

Published Papers (16 papers)

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Research

Jump to: Review, Other

14 pages, 2700 KiB  
Article
Relapsed Ovarian Cancer Patients with Ascites and/or Pleural Effusion Still Benefit from Treatment: A Real-Life Study
by Mariana Rebordão-Pires, Marta F. Estrada, António Gomes, Filipa Silva, Carlota Baptista, Maria João Ramos, Ana Fortuna, Pedro Simões, Gabriela Sousa, Ana Marreiros and Rita Fior
Cancers 2024, 16(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16010162 - 28 Dec 2023
Viewed by 1106
Abstract
(1) Background: Relapsed HGSOC with ascites and/or pleural effusion is a poor-prognostic population and poorly represented in clinical studies. We questioned if these patients are worth treating. In other words, if these patients received the most effective treatment, would it change the course [...] Read more.
(1) Background: Relapsed HGSOC with ascites and/or pleural effusion is a poor-prognostic population and poorly represented in clinical studies. We questioned if these patients are worth treating. In other words, if these patients received the most effective treatment, would it change the course of this disease? To our knowledge this is the first real-life study to evaluate this question in this low-survival population. (2) Methods: To tackle this question we performed a retrospective, multi-centric, real-life study, that reviewed relapsed HGSOC patients with ascites and/or pleural effusion. Our rationale was to compare the OS of two groups of patients: responders, i.e., patients who had an imagological response to treatment (complete/partial response/stable disease, RECIST criteria) versus non-responders (no response/progression upon treatment). We evaluated the predictive value of clinical variables that are available in a real-life setting (e.g., staging, chemotherapy, surgery, platinum-sensitivity). Multivariate logistic regression and survival analysis was conducted. A two-step cluster analysis SPSS tool was used for subgroup analysis. Platinum sensitivity/resistance was also analyzed, as well as multivariate and cluster analysis. (3) Results: We included 57 patients, 41.4% first line responders and 59.6% non-responders. The median OS of responders was 23 months versus 8 months in non-responders (p < 0.001). This difference was verified in platinum-sensitive (mOS 28 months vs. 8 months, p < 0.001) and platinum-resistant populations (mOS 16 months vs. 7 months, p < 0.001). Thirty-one patients reached the second line, of which only 10.3% responded to treatment. Three patients out of thirty-one who did not respond in the first line of relapse, responded in the second line. In the second line, the mOS for the responders’ group vs. non-responders was 31 months versus 13 months (p = 0.02). The two step cluster analysis tool found two different subgroups with different prognoses based on overall response rate, according to consolidation chemotherapy, neoadjuvant chemotherapy, FIGO staging and surgical treatment. Cluster analysis showed that even patients with standard clinical and treatment variables associated with poor prognosis might achieve treatment response (the opposite being also true). (4) Conclusions: Our data clearly show that relapsed HGSOC patients benefit from treatment. If given an effective treatment upfront, this can lead to a ~3 times increase in mOS for these patients. Moreover, this was irrespective of patient disease and treatment characteristics. Our results highlight the urgent need for a sensitivity test to tailor treatments and improve efficacy rates in a personalized manner. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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14 pages, 2906 KiB  
Article
Label-Free Quantification Mass Spectrometry Identifies Protein Markers of Chemotherapy Response in High-Grade Serous Ovarian Cancer
by Georgia Arentz, Parul Mittal, Manuela Klingler-Hoffmann, Mark R. Condina, Carmela Ricciardelli, Noor A. Lokman, Gurjeet Kaur, Martin K. Oehler and Peter Hoffmann
Cancers 2023, 15(7), 2172; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072172 - 06 Apr 2023
Cited by 2 | Viewed by 1857
Abstract
Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy [...] Read more.
Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy resistant. Data-independent acquisition nano-flow liquid chromatography–mass spectrometry (DIA LC-MS) identified the three protein markers: gelsolin (GSN), calmodulin (CALM1), and thioredoxin (TXN), to be elevated in high-grade serous ovarian cancer (HGSOC) tissues from patients that responded to chemotherapy compared to those who did not; the differential expression of the three protein markers was confirmed by immunohistochemistry. Analysis of the online GENT2 database showed that mRNA levels of GSN, CALM1, and TXN were decreased in HGSOC compared to fallopian tube epithelium. Elevated levels of GSN and TXN mRNA expression correlated with increased overall and progression-free survival, respectively, in a Kaplan–Meier analysis of a large online repository of HGSOC patient data. Importantly, differential expression of the three protein markers was further confirmed when comparing parental OVCAR-5 cells to carboplatin-resistant OVCAR-5 cells using DIA LC-MS analysis. Our findings suggest that GSN, CALM1, and TXN may be useful biomarkers for predicting chemotherapy response and understanding the mechanisms of chemotherapy resistance. Proteomic data are available via ProteomeXchange with identifier PXD033785. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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15 pages, 12814 KiB  
Article
Glucose-Regulated Protein 78 Is a Potential Serum and Imaging Marker for Early Detection of Ovarian Cancer
by Elizabeth A. Paris, Janice M. Bahr, Jacques S. Abramowicz, Sanjib Basu and Animesh Barua
Cancers 2023, 15(4), 1140; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041140 - 10 Feb 2023
Cited by 2 | Viewed by 1307
Abstract
Background: Understanding malignant transformation associated with ovarian cancer (OVCA) is important to establish early detection tests. This study examined whether expression of glucose-regulated protein 78 (GRP78, marker of cellular stress) increases during OVCA development, and whether GRP78 can be detected by targeted-transvaginal ultrasound [...] Read more.
Background: Understanding malignant transformation associated with ovarian cancer (OVCA) is important to establish early detection tests. This study examined whether expression of glucose-regulated protein 78 (GRP78, marker of cellular stress) increases during OVCA development, and whether GRP78 can be detected by targeted-transvaginal ultrasound (TVUS) imaging. Methods: Normal ovaries (n = 10), benign (n = 10) and malignant ovarian tumors at early (n = 8) and late stages (n = 16), hens with and without ovarian tumors at early and late stages (n = 10, each) were examined for GRP78 expression during OVCA development by immunohistochemistry, immunoblotting, gene expression and immunoassay. Feasibility of GRP78-targeted TVUS imaging in detecting early OVCA was examined. Results: Compared with normal ovaries and benign tumors, intensity of GRP78 expression was higher (p < 0.0001) in OVCA patients. Compared with normal (9007.76 ± 816.54 pg/mL), serum GRP78 levels were significantly higher (p < 0.05) in patients with early (12,730.59 ± 817.35 pg/mL) and late-stage OVCA (13,930.12 ± 202.35) (p < 0.01). Compared with normal (222.62 ± 181.69 pg/mL), serum GRP78 levels increased (p < 0.05) in hens with early (590.19 ± 198.18 pg/mL) and late-stage OVCA (1261.38 ± 372.85) (p < 0.01). Compared with non-targeted, GRP78-targeted imaging enhanced signal intensity of TVUS (p < 0.0001). Conclusions: Tissue and serum levels of GRP78 increase in association with OVCA. GRP78 offers a potential serum and imaging marker for early OVCA detection. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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17 pages, 3383 KiB  
Article
FOXP3 Isoforms Expression in Cervical Cancer: Evidence about the Cancer-Related Properties of FOXP3Δ2Δ7 in Keratinocytes
by Natalia Garcia-Becerra, Marco Ulises Aguila-Estrada, Luis Arturo Palafox-Mariscal, Georgina Hernandez-Flores, Adriana Aguilar-Lemarroy and Luis Felipe Jave-Suarez
Cancers 2023, 15(2), 347; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020347 - 05 Jan 2023
Viewed by 2011
Abstract
Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune [...] Read more.
Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune system to favor cell transformation. FOXP3, a critical transcription factor involved in the biology of regulatory T cells, has been detected as highly expressed in the tumor cells of CC patients. However, its biological role in CC, particularly in the keratinocytes, remained unclarified. Therefore, this work aimed to uncover the effect of FOXP3 on the biology of the tumoral cells. First, public databases were analyzed to identify the FOXP3 expression levels and the transcribed isoforms in CC and normal tissue samples. The study’s findings demonstrated an increased expression of FOXP3 in HPV16+ CC samples. Additionally, the FOXP3Δ2 variant was detected as the most frequent splicing isoform in tumoral cells, with a high differential expression level in metastatic samples. However, the analysis of FOXP3 expression in different CC cell lines, HPV+ and HPV-, suggests no relationship between the presence of HPV and FOXP3 expression. Since the variant FOXP3Δ2Δ7 was found highly expressed in the HPV16+ SiHa cell line, a model with constitutive expression of FOXP3Δ2Δ7 was established to evaluate its role in proliferation, migration, and cell division. Finally, RNAseq was performed to identify differentially expressed genes and enriched pathways modulated by FOXP3Δ2Δ7. The exogenous expression of FOXP3Δ2Δ7 promotes cell division, proliferation, and migration. The transcriptomic analyses highlight the upregulation of multiple genes with protumor activities. Moreover, immunological and oncogenic pathways were detected as highly enriched. These data support the hypothesis that FOXP3Δ2Δ7 in epithelial cells induces cancer-related hallmarks and provides information about the molecular events triggered by this isoform, which could be important for developing CC. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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11 pages, 853 KiB  
Article
Unresectable Ovarian Cancer Requires a Structured Plan of Action: A Prospective Cohort Study
by Gatske M. Nieuwenhuyzen-de Boer, Malika Kengsakul, Ingrid A. Boere, Helena C. van Doorn and Heleen J. van Beekhuizen
Cancers 2023, 15(1), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010072 - 22 Dec 2022
Viewed by 1216
Abstract
Background: Patients with unresectable disease during cytoreductive surgery (CRS) for advanced-stage ovarian cancer are underreported. Knowledge of treatment and survival after surgery is limited. The aim of this study is to address the knowledge gap about postoperative treatment and survival of patients whose [...] Read more.
Background: Patients with unresectable disease during cytoreductive surgery (CRS) for advanced-stage ovarian cancer are underreported. Knowledge of treatment and survival after surgery is limited. The aim of this study is to address the knowledge gap about postoperative treatment and survival of patients whose surgery was abandoned due to unresectability after abdominal exploration. Methods: Women with FIGO stage IIIB-IV epithelial ovarian cancer whose disease was considered to be unresectable during surgery were included in this prospective study, a post hoc analysis of the PlaComOv study. The unresectable disease was defined as the inability to achieve at least suboptimal CRS without attempted CRS after careful inspection of the entire abdomen. Preoperative clinical data, perioperative findings, postoperative treatment and survival data were analyzed. Results: From 2018 to 2020, 27 patients were included in this analysis. Treatment ranged from the cessation of treatment to one or several lines of chemotherapy with or without maintenance therapy. The median overall survival was 16 (IQR 5–21) months (95%CI 14–18). At 24 months of follow-up, four patients (15%) were alive. Conclusions: This study indicated a two-year survival of 15%. Optimal treatment strategies in terms of survival benefits are still ill-defined. Further study of this specific group of patients is warranted. We advocate an (inter)national registry of patients with unresectable cancer and comprehensive follow-up. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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16 pages, 849 KiB  
Article
Preoperative Cancer Antigen 125 Level as Predictor for Complete Cytoreduction in Ovarian Cancer: A Prospective Cohort Study and Systematic Review
by Puck E. Brons, Gatske M. Nieuwenhuyzen-de Boer, Christian Ramakers, Sten Willemsen, Malika Kengsakul and Heleen J. van Beekhuizen
Cancers 2022, 14(23), 5734; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235734 - 22 Nov 2022
Cited by 3 | Viewed by 1390
Abstract
Background: The tumor marker ‘cancer antigen 125’ (CA-125) plays a role in the management of women with advanced stage ovarian cancer. This study aims to describe the predictive value of pre-treatment CA-125 level and the reduction after neoadjuvant chemotherapy (NACT) on surgical outcome. [...] Read more.
Background: The tumor marker ‘cancer antigen 125’ (CA-125) plays a role in the management of women with advanced stage ovarian cancer. This study aims to describe the predictive value of pre-treatment CA-125 level and the reduction after neoadjuvant chemotherapy (NACT) on surgical outcome. Methods: A systematic review and a prospective clinical study were performed. Multiple databases were searched from database inception to April 2022. The clinical study is part of a randomized controlled trial named “PlaComOv-study”. A regression analysis was performed to demonstrate correlations between preoperative CA-125 levels, CA-125 reduction after NACT, and surgical outcome. Results: Fourteen relevant articles were analyzed of which eleven reported that lower preoperative CA-125 levels were associated with a higher probability of complete cytoreduction. In the clinical study, 326 patients with FIGO stage IIIB-IV ovarian cancer who underwent CRS were enrolled from 2018 to 2020. Patients who underwent interval CRS with preoperative CA-125 levels ≤35 kU/L had higher odds of achieving complete CRS than patients with CA-125 level >35 kU/L (85% vs. 67%, OR 2.79, 95%CI 1.44–5.41, p = 0.002). In multivariable analysis with presence of ascites and peritoneal carcinomatosis, normalized preoperative CA-125 did not appear as a significant predictor for complete CRS. Conclusions: In literature, preoperative CA-125 levels ≤35 kU/L were associated with a significant higher percentage of complete CRS in univariable analysis. According to our cohort study, preoperative CA-125 level ≤35 kU/L cannot independently predict surgical outcome either for primary or interval CRS. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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13 pages, 1589 KiB  
Article
Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network
by José Antonio López-Guerrero, Marta Mendiola, José Alejandro Pérez-Fidalgo, Ignacio Romero, Ana Torres, Delia Recalde, Elena Molina, César Gómez-Raposo, Ana M. Levin, Ana Herrero, Jesús Alarcón, Carmen Esteban, Gloria Marquina, María Jesús Rubio, Eva Guerra, Luisa Sánchez-Lorenzo, Fernando Gálvez-Montosa, Ana de Juan, Cristina Churruca, Alejandro Gallego and Antonio González-Martínadd Show full author list remove Hide full author list
Cancers 2022, 14(8), 1965; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081965 - 13 Apr 2022
Cited by 1 | Viewed by 2043
Abstract
Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated [...] Read more.
Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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15 pages, 1143 KiB  
Communication
Multi-Disciplinary Care Planning of Ovarian Cancer in Older Patients: General Statement—A Position Paper from SOFOG-GINECO-FRANCOGYN-SFPO
by Leila Bengrine, Naoual Bakrin, Frédérique Rousseau, Vincent Lavoué and Claire Falandry
Cancers 2022, 14(5), 1295; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051295 - 02 Mar 2022
Cited by 4 | Viewed by 3066
Abstract
In this position paper the Société Francophone d’OncoGériatrie (SOFOG; French-speaking oncogeriatric society), the Société Française de Pharmacie Oncologique (SFPO, French society for oncology pharmacy), the Groupe d’Investigateurs Nationaux pour l’Étude des Cancers de l’Ovaire et du sein (GINECO, National Investigators’ Group for Studies [...] Read more.
In this position paper the Société Francophone d’OncoGériatrie (SOFOG; French-speaking oncogeriatric society), the Société Française de Pharmacie Oncologique (SFPO, French society for oncology pharmacy), the Groupe d’Investigateurs Nationaux pour l’Étude des Cancers de l’Ovaire et du sein (GINECO, National Investigators’ Group for Studies in Ovarian and Breast Cancer) and the Groupe Français de chirurgie Oncologique et Gynécologique (FRANCOGYN) propose a multi-disciplinary care planning of ovarian cancer in older patients. The treatment pathway is based on four successive decisional nodes (diagnosis, resectability assessment, operability assessment, adjuvant, and maintenance treatment decision) implying multidisciplinarity and adaptation of the treatment plan according to the patient’s geriatric covariates and her motivation towards treatment. Specific attention must be paid to geriatric intervention, supportive care and pharmaceutical conciliation. Studies are needed to prospectively evaluate the impact of geriatric vulnerability parameters at each step of the treatment agenda and the impact of geriatric interventions on patient outcomes. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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14 pages, 2288 KiB  
Article
EP4 as a Negative Prognostic Factor in Patients with Vulvar Cancer
by Anna Buchholz, Aurelia Vattai, Sophie Fürst, Theresa Vilsmaier, Christina Kuhn, Elisa Schmoeckel, Doris Mayr, Christian Dannecker, Sven Mahner, Udo Jeschke and Helene H. Heidegger
Cancers 2021, 13(6), 1410; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061410 - 19 Mar 2021
Cited by 4 | Viewed by 2575
Abstract
New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In [...] Read more.
New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients’ survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2′-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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Review

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19 pages, 1180 KiB  
Review
Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine
by Giulia Spagnol, Francesca Sensi, Orazio De Tommasi, Matteo Marchetti, Giulio Bonaldo, Livia Xhindoli, Marco Noventa, Marco Agostini, Roberto Tozzi and Carlo Saccardi
Cancers 2023, 15(7), 2059; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072059 - 30 Mar 2023
Cited by 5 | Viewed by 2586
Abstract
Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies due to the high prevalence of advanced stages of diagnosis and the high rate of recurrence. Furthermore, the heterogeneity of OC tumors contributes to the rapid development of resistance to conventional [...] Read more.
Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies due to the high prevalence of advanced stages of diagnosis and the high rate of recurrence. Furthermore, the heterogeneity of OC tumors contributes to the rapid development of resistance to conventional chemotherapy. In recent years, in order to overcome these problems, targeted therapies have been introduced in various types of tumors, including gynecological cancer. However, the lack of predictive biomarkers showing different clinical benefits limits the effectiveness of these therapies. This requires the development of preclinical models that can replicate the histological and molecular characteristics of OC subtypes. In this scenario, organoids become an important preclinical model for personalized medicine. In fact, patient-derived organoids (PDO) recapture tumor heterogeneity with the possibility of performing drug screening. However, to best reproduce the patient’s characteristics, it is necessary to develop a specific extracellular matrix (ECM) and introduce a tumor microenvironment (TME), which both represent an actual object of study to improve drug screening, particularly when used in targeted therapy and immunotherapy to guide therapeutic decisions. In this review, we summarize the current state of the art for the screening of PDOs, ECM, TME, and drugs in the setting of OC, as well as discussing the clinical implications and future perspectives for the research of OC organoids. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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18 pages, 1806 KiB  
Review
Recent Advances in Cervical Cancer Management: A Review on Novel Prognostic Factors in Primary and Recurrent Tumors
by Angela Santoro, Frediano Inzani, Giuseppe Angelico, Damiano Arciuolo, Emma Bragantini, Antonio Travaglino, Michele Valente, Nicoletta D’Alessandris, Giulia Scaglione, Stefania Sfregola, Alessia Piermattei, Federica Cianfrini, Paola Roberti and Gian Franco Zannoni
Cancers 2023, 15(4), 1137; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041137 - 10 Feb 2023
Cited by 8 | Viewed by 2207
Abstract
Background: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able [...] Read more.
Background: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. Methods: A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words “cervical cancer”, “prognostic factors”, “pathology”, and “outcome” were used. Results: The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. Conclusions: According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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26 pages, 1824 KiB  
Review
Green Tea in Reproductive Cancers: Could Treatment Be as Simple?
by Maclaine Parish, Gaelle Massoud, Dana Hazimeh, James Segars and Md Soriful Islam
Cancers 2023, 15(3), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030862 - 30 Jan 2023
Cited by 11 | Viewed by 4296
Abstract
Green tea originates from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. Green tea polyphenols, commonly known as catechins, are the major bioactive ingredients and account for green tea’s unique health benefits. Epigallocatechin-3-gallate (EGCG), is the [...] Read more.
Green tea originates from the tea plant Camellia sinensis and is one of the most widely consumed beverages worldwide. Green tea polyphenols, commonly known as catechins, are the major bioactive ingredients and account for green tea’s unique health benefits. Epigallocatechin-3-gallate (EGCG), is the most potent catechin derivative and has been widely studied for its pro- and anti-oxidative effects. This review summarizes the chemical and chemopreventive properties of green tea in the context of female reproductive cancers. A comprehensive search of PubMed and Google Scholar up to December 2022 was conducted. All original and review articles related to green tea or EGCG, and gynecological cancers published in English were included. The findings of several in vitro, in vivo, and epidemiological studies examining the effect of green tea on reproductive cancers, including ovarian, cervical, endometrial, and vulvar cancers, are presented. Studies have shown that this compound targets specific receptors and intracellular signaling pathways involved in cancer pathogenesis. The potential benefits of using green tea in the treatment of reproductive cancers, alone or in conjunction with chemotherapeutic agents, are examined, shedding light on new therapeutic strategies for the management of female reproductive cancers. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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24 pages, 1332 KiB  
Systematic Review
Beyond Platinum, ICIs in Metastatic Cervical Cancer: A Systematic Review
by Brigida Anna Maiorano, Mauro Francesco Pio Maiorano, Davide Ciardiello, Annamaria Maglione, Michele Orditura, Domenica Lorusso and Evaristo Maiello
Cancers 2022, 14(23), 5955; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235955 - 01 Dec 2022
Cited by 6 | Viewed by 2226
Abstract
Background: Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario [...] Read more.
Background: Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety. Methods: The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs). Results: A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6–94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs. Conclusion: Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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11 pages, 2249 KiB  
Study Protocol
PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System
by Anouk Corbeau, Remi A. Nout, Jan Willem M. Mens, Nanda Horeweg, Jérémy Godart, Ellen M. Kerkhof, Sander C. Kuipers, Mariette I. E. van Poelgeest, Judith R. Kroep, Ingrid A. Boere, Helena C. van Doorn, Mischa S. Hoogeman, Uulke A. van der Heide, Hein Putter, Marij J. P. Welters, Sjoerd H. van der Burg, Carien L. Creutzberg and Stephanie M. de Boer
Cancers 2021, 13(20), 5179; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205179 - 15 Oct 2021
Cited by 8 | Viewed by 2532
Abstract
External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant [...] Read more.
External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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13 pages, 1512 KiB  
Systematic Review
Survival in Advanced-Stage Epithelial Ovarian Cancer Patients with Cardiophrenic Lymphadenopathy Who Underwent Cytoreductive Surgery: A Systematic Review and Meta-Analysis
by Malika Kengsakul, Gatske M. Nieuwenhuyzen-de Boer, Anna H. J. Bijleveld, Suwasin Udomkarnjananun, Stephen J. Kerr, Christa D. Niehot and Heleen J. van Beekhuizen
Cancers 2021, 13(19), 5017; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13195017 - 07 Oct 2021
Cited by 6 | Viewed by 2455
Abstract
Purpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive surgery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar databases were searched for articles from the database [...] Read more.
Purpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive surgery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar databases were searched for articles from the database inception to June 2021. Meta-analysis was conducted to determine the prognostic impact of surgical outcome, postoperative complication, and survival using random-effects models. Results: A total of 15 studies involving 727 patients with CPLN adenopathy and 981 patients without CPLN adenopathy were included. The mean size of preoperative CPLN was 9.1± 3.75 mm. Overall, 82 percent of the resected CPLN were histologically confirmed pathologic nodes. Surgical outcomes and perioperative complications did not differ between both groups. The median OS time was 42.7 months (95% CI 10.8–74.6) vs. 47.3 months (95% CI 23.2–71.2), in patients with and without CPLN adenopathy, respectively. At 5 years, patients with CPLN adenopathy had a significantly increased risk of disease recurrence (HR 2.14, 95% CI 1.82–2.52, p < 0.001) and dying from the disease (HR 1.74, 95% CI 1.06–2.86, p = 0.029), compared with those without CPLN adenopathy. CPLN adenopathy was significantly associated with ascites (OR 3.30, 95% CI 1.90–5.72, p < 0.001), pleural metastasis (OR 2.58, 95% CI 1.37–4.82, p = 0.003), abdominal adenopathy (OR 2.30, 95% CI 1.53–3.46, p < 0.001) and extra-abdominal metastasis (OR 2.30, 95% CI 1.61–6.67, p = 0.001). Conclusions: Enlarged CPLN in preoperative imaging is highly associated with metastatic involvement. Patients with CPLN adenopathy had a lower survival rate, compared with patients without CPLN adenopathy. Further randomized controlled trials should be conducted to definitively demonstrate whether CPLN resection at the time of cytoreductive surgery is beneficial. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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16 pages, 1307 KiB  
Systematic Review
Malignant Transformation of Postmenopausal Endometriosis: A Systematic Review of the Literature
by Luca Giannella, Chiara Marconi, Jacopo Di Giuseppe, Giovanni Delli Carpini, Mariasole Fichera, Camilla Grelloni, Lucia Giuliani, Michele Montanari, Salvatore Insinga and Andrea Ciavattini
Cancers 2021, 13(16), 4026; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164026 - 10 Aug 2021
Cited by 16 | Viewed by 4318
Abstract
Objective: This study aimed to systematically review the existing literature on malignant transformation of postmenopausal endometriosis to provide information about patient characteristics, hormonal replacement therapy (HRT) use, and outcomes over a period of 52 years (1969–2021). Methods: According to PRISMA guidelines, we searched [...] Read more.
Objective: This study aimed to systematically review the existing literature on malignant transformation of postmenopausal endometriosis to provide information about patient characteristics, hormonal replacement therapy (HRT) use, and outcomes over a period of 52 years (1969–2021). Methods: According to PRISMA guidelines, we searched for (endometriosis OR endometriotic) AND (cancer OR malignancy OR malignant transformation) AND (menopause OR menopausal OR postmenopause OR postmenopausal) in Pubmed (all fields) (accessed on 12 February 2021) and Scopus (Title/Abstract/Keywords) (accessed on 12 February 2021) databases. The only filter used was the English language. Relevant articles were obtained in full-text format and screened for additional references. Eligibility/inclusion criteria: studies including full case description of malignant transformation of endometriosis-related lesions in postmenopause. Results: 75 studies, including 90 cases, were retrieved. The mean age was 55.8 ± 8.5 years. Overall, about 65% of women had a positive personal history of endometriosis/adenomyosis, and 64% of women underwent previous hysterectomy ± bilateral salpingo-oophorectomy. Forty-nine of 74 women used HRT (66.2%). Among the women who used HRT, estrogen-only treatment was taken by approximately 75%. Duration of HRT was longer than five years in 63.3% of cases. About 70% of subjects had histology of endometrioid adenocarcinoma or clear cell carcinoma. Follow-up outcome, available for 61 women, showed a survival rate of 78.7%, recurrence of 9.8%, death of 11.5%. The duration of follow-up had a median of 12 months (interquartile range, 6.75–25 months). Interestingly, over the years of case publication there was a significant inverse correlation with previous history of endometriosis (r = −0.28, p = 0.007), HRT use (r = −0.31, p = 0.006), and previous definitive surgery (r = −0.42, p < 0.001). Conclusions: In the malignant transformation of postmenopausal endometriosis, there are some recurrent clinical conditions: previous endometriosis, major definitive surgery before menopause, and estrogen-only HRT for a relatively long time. However, these clinical conditions have shown a drastic decrease over time. This could likely be the consequence of different attitudes and management of gynecologists linked to up-to-date scientific evidence about the use of major surgery in gynecological pathologies. Malignant transformation of postmenopausal endometriosis is a clinical challenge to be explored further. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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