Editorial

3 pages, 178 KiB

Open AccessEditorial

Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer

by Naomi Nakayama

Biomedicines 2022, 10(5), 1014; https://doi.org/10.3390/biomedicines10051014 - 28 Apr 2022

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The number of patients with gynecological cancers, such as ovarian and endometrial cancer, has been increasing worldwide [...] Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

Research

Jump to: Editorial, Review

9 pages, 7457 KiB

Open AccessArticle

Biological Planning of Radiation Dose Based on In Vivo Dosimetry for Postoperative Vaginal-Cuff HDR Interventional Radiotherapy (Brachytherapy)

by Tamer Soror, Ramin Chafii, Valentina Lancellotta, Luca Tagliaferri and György Kovács

Biomedicines 2021, 9(11), 1629; https://doi.org/10.3390/biomedicines9111629 - 06 Nov 2021

Cited by 1 | Viewed by 1606

Abstract

(1) Background: Postoperative vaginal-cuff HDR interventional radiotherapy (brachytherapy) is a standard treatment in early-stage endometrial cancer. This study reports the effect of in vivo dosimetry-based biological planning for two different fractionation schedules on the treatment-related toxicities. (2) Methods: 121 patients were treated. Group [...] Read more.

(1) Background: Postoperative vaginal-cuff HDR interventional radiotherapy (brachytherapy) is a standard treatment in early-stage endometrial cancer. This study reports the effect of in vivo dosimetry-based biological planning for two different fractionation schedules on the treatment-related toxicities. (2) Methods: 121 patients were treated. Group A (82) received 21 Gy in three fractions. Group B (39) received 20 Gy in four fractions. The dose was prescribed at a 5 mm depth or to the applicator surface according to the distance between the applicator and the rectum. In vivo dosimetry measured the dose of the rectum and/or urinary bladder. With a high measured dose, the dose prescription was changed from a 5 mm depth to the applicator surface. (3) Results: The median age was 66 years with 58.8 months mean follow-up. The dose prescription was changed in 20.7% of group A and in 41% of group B. Most toxicities were grade 1–2. Acute urinary toxicities were significantly higher in group A. The rates of acute and late urinary toxicities were significantly higher with a mean bladder dose/fraction of >2.5 Gy and a total bladder dose of >7.5 Gy. One patient had a vaginal recurrence. (4) Conclusions: Both schedules have excellent local control and acceptable rates of toxicities. Using in vivo dosimetry-based biological planning yielded an acceptable dose to the bladder and rectum. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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14 pages, 1142 KiB

Open AccessArticle

Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women

by Jacqueline Ho Sze Lee, Joshua Jing Xi Li, Chit Chow, Ronald Cheong Kin Chan, Johnny Sheung Him Kwan, Tat San Lau, Ka Fai To, So Fan Yim, Suet Ying Yeung and Joseph Kwong

Biomedicines 2021, 9(10), 1385; https://doi.org/10.3390/biomedicines9101385 - 04 Oct 2021

Cited by 1 | Viewed by 2080

Abstract

To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. [...] Read more.

To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. Clinical characteristics and survival were determined. Association of MMR with survival and clinicopathological parameters were assessed. MMR deficiency (dMMR) was found in 43 cases (16.5%). dMMR was associated with poor prognostic factors including older age, higher stage, higher grade, larger tumor size and more radiotherapy usage. Long-term survival was worse in dMMR compared to the MMR proficient group. The dMMR group had more deaths, shorter disease-specific survival (DSS), shorter disease-free survival (DFS), less 10-year DSS, less 10-year DFS, and more recurrence. The 5-year DSS and 5-year DFS in the dMMR group only showed a trend of worse survival but did not reach statistical significance. In conclusion, dMMR is present in a significant number of endometrioid endometrial cancers patients and is associated with poorer clinicopathological factors and survival parameters in the long run. dMMR should be considered in the risk stratification of endometrial cancer to guide adjuvant therapy and individualisation for longer follow up plan. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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20 pages, 982 KiB

Open AccessArticle

A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes

by Ying-Cheng Chiang, Po-Han Lin, Tzu-Pin Lu, Kuan-Ting Kuo, Yi-Jou Tai, Heng-Cheng Hsu, Chia-Ying Wu, Chia-Yi Lee, Hung Shen, Chi-An Chen and Wen-Fang Cheng

Biomedicines 2021, 9(10), 1384; https://doi.org/10.3390/biomedicines9101384 - 03 Oct 2021

Cited by 3 | Viewed by 1806

Abstract

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of [...] Read more.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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14 pages, 8694 KiB

Open AccessArticle

NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44

by Rüdiger Klapdor, Shuo Wang, Michael A. Morgan, Katharina Zimmermann, Jens Hachenberg, Hildegard Büning, Thilo Dörk, Peter Hillemanns and Axel Schambach

Biomedicines 2021, 9(10), 1339; https://doi.org/10.3390/biomedicines9101339 - 28 Sep 2021

Cited by 18 | Viewed by 2948

Abstract

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor [...] Read more.

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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11 pages, 13584 KiB

Open AccessArticle

Preliminary Study on the Expression of Testin, p16 and Ki-67 in the Cervical Intraepithelial Neoplasia

by Aneta Popiel, Aleksandra Piotrowska, Patrycja Sputa-Grzegrzolka, Beata Smolarz, Hanna Romanowicz, Piotr Dziegiel, Marzenna Podhorska-Okolow and Christopher Kobierzycki

Biomedicines 2021, 9(8), 1010; https://doi.org/10.3390/biomedicines9081010 - 13 Aug 2021

Cited by 6 | Viewed by 2831

Abstract

Cervical cancer is one of the most common malignant cancers in women worldwide. The 5-year survival rate is 65%; nevertheless, it depends on race, age, and clinical stage. In the oncogenesis of cervical cancer, persistent HPV infection plays a pivotal role. It disrupts [...] Read more.

Cervical cancer is one of the most common malignant cancers in women worldwide. The 5-year survival rate is 65%; nevertheless, it depends on race, age, and clinical stage. In the oncogenesis of cervical cancer, persistent HPV infection plays a pivotal role. It disrupts the expression of key proteins as Ki-67, p16, involved in regulating the cell cycle. This study aimed to identify the potential role of testin in the diagnosis of cervical precancerous lesions (CIN). The study was performed on selected archival paraffin-embedded specimens of CIN1 (31), CIN2 (75), and CIN3 (123). Moderate positive correlation was observed between testin and Ki-67 as well as testin and p16 expression in all dysplastic lesions (r = 0.4209, r = 0.5681; p < 0.0001 for both). Statistical analysis showed stronger expression of the testin in dysplastic lesions vs. control group (p < 0.0001); moreover, expression was significantly higher in HSIL than LSIL group (p < 0.0024). In addition, a significantly stronger expression of testin was observed in CIN3 vs. CIN1 and CIN3 vs. CIN2. In our study, expression of Ki-67, p16, and testin increased gradually as the lesion progressed from LSIL to HSIL. The three markers complemented each other effectively, which may improve test sensitivity and specificity when used jointly. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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30 pages, 5425 KiB

Open AccessArticle

Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis

by Kuo-Min Su, Hong-Wei Gao, Chia-Ming Chang, Kai-Hsi Lu, Mu-Hsien Yu, Yi-Hsin Lin, Li-Chun Liu, Chia-Ching Chang, Yao-Feng Li and Cheng-Chang Chang

Biomedicines 2021, 9(8), 866; https://doi.org/10.3390/biomedicines9080866 - 22 Jul 2021

Cited by 5 | Viewed by 2375

Abstract

Epithelial ovarian cancers (EOCs) are fatal and obstinate among gynecological malignancies in advanced stage or relapsed status, with serous carcinomas accounting for the vast majority. Unlike EOCs, borderline ovarian tumors (BOTs), including serous BOTs, maintain a semimalignant appearance. Using gene ontology (GO)-based integrative [...] Read more.

Epithelial ovarian cancers (EOCs) are fatal and obstinate among gynecological malignancies in advanced stage or relapsed status, with serous carcinomas accounting for the vast majority. Unlike EOCs, borderline ovarian tumors (BOTs), including serous BOTs, maintain a semimalignant appearance. Using gene ontology (GO)-based integrative analysis, we analyzed gene set databases of serous BOTs and serous ovarian carcinomas for dysregulated GO terms and pathways and identified multiple differentially expressed genes (DEGs) in various aspects. The SRC (SRC proto-oncogene, non-receptor tyrosine kinase) gene and dysfunctional aryl hydrocarbon receptor (AHR) binding pathway consistently influenced progression-free survival and overall survival, and immunohistochemical staining revealed elevated expression of related biomarkers (SRC, ARNT, and TBP) in serous BOT and ovarian carcinoma samples. Epithelial–mesenchymal transition (EMT) is important during tumorigenesis, and we confirmed the SNAI2 (Snail family transcriptional repressor 2, SLUG) gene showing significantly high performance by immunohistochemistry. During serous ovarian tumor formation, activated AHR in the cytoplasm could cooperate with SRC, enter cell nuclei, bind to AHR nuclear translocator (ARNT) together with TATA-Box Binding Protein (TBP), and act on DNA to initiate AHR-responsive genes to cause tumor or cancer initiation. Additionally, SNAI2 in the tumor microenvironment can facilitate EMT accompanied by tumorigenesis. Although it has not been possible to classify serous BOTs and serous ovarian carcinomas as the same EOC subtype, the key determinants of relevant DEGs (SRC, ARNT, TBP, and SNAI2) found here had a crucial role in the pathogenetic mechanism of both tumor types, implying gradual evolutionary tendencies from serous BOTs to ovarian carcinomas. In the future, targeted therapy could focus on these revealed targets together with precise detection to improve therapeutic effects and patient survival rates. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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20 pages, 4092 KiB

Open AccessArticle

Platelet-Activating Factor Acetylhydrolase Expression in BRCA1 Mutant Ovarian Cancer as a Protective Factor and Potential Negative Regulator of the Wnt Signaling Pathway

by Yue Liao, Susann Badmann, Till Kaltofen, Doris Mayr, Elisa Schmoeckel, Eileen Deuster, Mareike Mannewitz, Sarah Landgrebe, Thomas Kolben, Anna Hester, Susanne Beyer, Alexander Burges, Sven Mahner, Udo Jeschke, Fabian Trillsch and Bastian Czogalla

Biomedicines 2021, 9(7), 706; https://doi.org/10.3390/biomedicines9070706 - 22 Jun 2021

Cited by 5 | Viewed by 2708

Abstract

Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated [...] Read more.

Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3β, and β-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3β (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and β-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/β-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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21 pages, 2452 KiB

Open AccessArticle

Nucleus Accumbens-Associated Protein 1 Binds DNA Directly through the BEN Domain in a Sequence-Specific Manner

by Naomi Nakayama, Gyosuke Sakashita, Takashi Nagata, Naohiro Kobayashi, Hisashi Yoshida, Sam-Yong Park, Yuko Nariai, Hiroaki Kato, Eiji Obayashi, Kentaro Nakayama, Satoru Kyo and Takeshi Urano

Biomedicines 2020, 8(12), 608; https://doi.org/10.3390/biomedicines8120608 - 14 Dec 2020

Cited by 8 | Viewed by 2655

Abstract

Nucleus accumbens-associated protein 1 (NAC1) is a nuclear protein that harbors an amino-terminal BTB domain and a carboxyl-terminal BEN domain. NAC1 appears to play significant and diverse functions in cancer and stem cell biology. Here we demonstrated that the BEN domain of NAC1 [...] Read more.

Nucleus accumbens-associated protein 1 (NAC1) is a nuclear protein that harbors an amino-terminal BTB domain and a carboxyl-terminal BEN domain. NAC1 appears to play significant and diverse functions in cancer and stem cell biology. Here we demonstrated that the BEN domain of NAC1 is a sequence-specific DNA-binding domain. We selected the palindromic 6 bp motif ACATGT as a target sequence by using a PCR-assisted random oligonucleotide selection approach. The interaction between NAC1 and target DNA was characterized by gel shift assays, pull-down assays, isothermal titration calorimetry (ITC), chromatin-immunoprecipitation assays, and NMR chemical shifts perturbation (CSP). The solution NMR structure revealed that the BEN domain of human NAC-1 is composed of five conserved α helices and two short β sheets, with an additional hitherto unknown N-terminal α helix. In particular, ITC clarified that there are two sequential events in the titration of the BEN domain of NAC1 into the target DNA. The ITC results were further supported by CSP data and structure analyses. Furthermore, live cell photobleaching analyses revealed that the BEN domain of NAC1 alone was unable to interact with chromatin/other proteins in cells. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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Review

Jump to: Editorial, Research

31 pages, 1850 KiB

Open AccessReview

Current Treatments and New Possible Complementary Therapies for Epithelial Ovarian Cancer

by Maritza P. Garrido, Allison N. Fredes, Lorena Lobos-González, Manuel Valenzuela-Valderrama, Daniela B. Vera and Carmen Romero

Biomedicines 2022, 10(1), 77; https://doi.org/10.3390/biomedicines10010077 - 31 Dec 2021

Cited by 16 | Viewed by 3116

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest gynaecological malignancies. The late diagnosis is frequent due to the absence of specific symptomatology and the molecular complexity of the disease, which includes a high angiogenesis potential. The first-line treatment is based on optimal [...] Read more.

Epithelial ovarian cancer (EOC) is one of the deadliest gynaecological malignancies. The late diagnosis is frequent due to the absence of specific symptomatology and the molecular complexity of the disease, which includes a high angiogenesis potential. The first-line treatment is based on optimal debulking surgery following chemotherapy with platinum/gemcitabine and taxane compounds. During the last years, anti-angiogenic therapy and poly adenosine diphosphate-ribose polymerases (PARP)-inhibitors were introduced in therapeutic schemes. Several studies have shown that these drugs increase the progression-free survival and overall survival of patients with ovarian cancer, but the identification of patients who have the greatest benefits is still under investigation. In the present review, we discuss about the molecular characteristics of the disease, the recent evidence of approved treatments and the new possible complementary approaches, focusing on drug repurposing, non-coding RNAs, and nanomedicine as a new method for drug delivery. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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19 pages, 321 KiB

Open AccessReview

Circulating Exosomal miRNAs as Biomarkers in Epithelial Ovarian Cancer

by Meng-Shin Shiao, Jia-Ming Chang, Arb-Aroon Lertkhachonsuk, Naparat Rermluk and Natini Jinawath

Biomedicines 2021, 9(10), 1433; https://doi.org/10.3390/biomedicines9101433 - 10 Oct 2021

Cited by 12 | Viewed by 2064

Abstract

Failure to detect early-stage epithelial ovarian cancer (EOC) is a major contributing factor to its low survival rate. Increasing evidence suggests that different subtypes of EOC may behave as distinct diseases due to their different cells of origins, histology and treatment responses. Therefore, [...] Read more.

Failure to detect early-stage epithelial ovarian cancer (EOC) is a major contributing factor to its low survival rate. Increasing evidence suggests that different subtypes of EOC may behave as distinct diseases due to their different cells of origins, histology and treatment responses. Therefore, the identification of EOC subtype-specific biomarkers that can early detect the disease should be clinically beneficial. Exosomes are extracellular vesicles secreted by different types of cells and carry biological molecules, which play important roles in cell-cell communication and regulation of various biological processes. Multiple studies have proposed that exosomal miRNAs present in the circulation are good biomarkers for non-invasive early detection of cancer. In this review, the potential use of exosomal miRNAs as early detection biomarkers for EOCs and their accuracy are discussed. We also review the differential expression of circulating exosomal miRNAs and cell-free miRNAs between different biofluid sources, i.e., plasma and serum, and touch on the issue of endogenous reference miRNA selection. Additionally, the current clinical trials using miRNAs for detecting EOCs are summarized. In conclusion, circulating exosomal miRNAs as the non-invasive biomarkers have a high potential for early detection of EOC and its subtypes, and are likely to be clinically important in the future. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

19 pages, 23382 KiB

Open AccessReview

Vulvar and Vaginal Melanomas—The Darker Shades of Gynecological Cancers

by Elena-Codruța Dobrică, Cristina Vâjâitu, Carmen Elena Condrat, Dragoș Crețoiu, Ileana Popa, Bogdan Severus Gaspar, Nicolae Suciu, Sanda Maria Crețoiu and Valentin Nicolae Varlas

Biomedicines 2021, 9(7), 758; https://doi.org/10.3390/biomedicines9070758 - 30 Jun 2021

Cited by 12 | Viewed by 54740

Abstract

Melanomas of the skin are poorly circumscribed lesions, very frequently asymptomatic but unfortunately with a continuous growing incidence. In this landscape, one can distinguish melanomas originating in the mucous membranes and located in areas not exposed to the sun, namely the vulvo-vaginal melanomas. [...] Read more.

Melanomas of the skin are poorly circumscribed lesions, very frequently asymptomatic but unfortunately with a continuous growing incidence. In this landscape, one can distinguish melanomas originating in the mucous membranes and located in areas not exposed to the sun, namely the vulvo-vaginal melanomas. By contrast with cutaneous melanomas, the incidence of these types of melanomas is constant, being diagnosed in females in their late sixties. While hairy skin and glabrous skin melanomas of the vulva account for 5% of all cancers located in the vulva, melanomas of the vagina and urethra are particularly rare conditions. The location in areas less accessible to periodic inspection determines their diagnosis in advanced stages, often metastatic. Moreover, despite the large number of drugs newly approved in recent decades for the treatment of cutaneous melanoma, especially in the category of biological drugs, the mortality of vulvo-vaginal melanomas has remained almost constant. This, together with the absence of specific treatment guidelines due to the lack of a sufficient number of cases to conduct randomized clinical trials, makes melanomas with this localization a discouraging diagnosis, associated with a very poor prognosis. Our aim is therefore to draw attention to this oftentimes overlooked entity in order to encourage the community to employ various strategies meant to increase research in this area. By highlighting the main risk factors of vulvar and vaginal melanomas, as well as the clinical manifestations and molecular changes underlying these neoplasms, ideally novel therapeutic schemes will, in time, be brought into effect. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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16 pages, 478 KiB

Open AccessReview

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology

by Sandrine Rousset-Rouviere, Philippe Rochigneux, Anne-Sophie Chrétien, Stéphane Fattori, Laurent Gorvel, Magali Provansal, Eric Lambaudie, Daniel Olive and Renaud Sabatier

Biomedicines 2021, 9(6), 632; https://doi.org/10.3390/biomedicines9060632 - 02 Jun 2021

Cited by 29 | Viewed by 6777

Abstract

Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a [...] Read more.

Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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16 pages, 1292 KiB

Open AccessReview

Potential Impact of Human Cytomegalovirus Infection on Immunity to Ovarian Tumours and Cancer Progression

by Momodou Cox, Apriliana E. R. Kartikasari, Paul R. Gorry, Katie L. Flanagan and Magdalena Plebanski

Biomedicines 2021, 9(4), 351; https://doi.org/10.3390/biomedicines9040351 - 30 Mar 2021

Cited by 16 | Viewed by 3072

Abstract

Ovarian cancer (OC) is one of the most common, and life-threatening gynaecological cancer affecting females. Almost 75% of all OC cases are diagnosed at late stages, where the 5-year survival rate is less than 30%. The aetiology of the disease is still unclear, [...] Read more.

Ovarian cancer (OC) is one of the most common, and life-threatening gynaecological cancer affecting females. Almost 75% of all OC cases are diagnosed at late stages, where the 5-year survival rate is less than 30%. The aetiology of the disease is still unclear, and there are currently no screening method nor effective treatment strategies for the advanced disease. A growing body of evidence shows that human cytomegalovirus (HCMV) infecting more than 50% of the world population, may play a role in inducing carcinogenesis through its immunomodulatory activities. In healthy subjects, the primary HCMV infection is essentially asymptomatic. The virus then establishes a life-long chronic latency primarily in the hematopoietic progenitor cells in the bone marrow, with periodic reactivation from latency that is often characterized by high levels of circulating pro-inflammatory cytokines. Currently, infection-induced chronic inflammation is considered as an essential process for OC progression and metastasis. In line with this observation, few recent studies have identified high expressions of HCMV proteins on OC tissue biopsies that were associated with poor survival outcomes. Active HCMV infection in the OC tumour microenvironment may thus directly contribute to OC progression. In this review, we highlight the potential impact of HCMV infection-induced immunomodulatory effects on host immune responses to OC that may promote OC progression. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gynecologic Cancer)

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