Reproductive Tract Tumors Research Articles

Global burden of gynaecological cancers in 2022 and projections to 2050.

The incidence and mortality of gynaecological cancers can significantly impact women's quality of life and increase the health care burden for organisations globally. The objective of this study was to evaluate global inequalities in the incidence and mortality of gynaecological cancers in 2022, based on The Global Cancer Observatory (GLOBOCAN) 2022 estimates. The future burden of gynaecological cancers (GCs) in 2050 was also projected. Data regarding to the total cases and deaths related to gynaecological cancer, as well as cases and deaths pertaining to different subtypes of GCs, gathered from the GLOBOCAN database for the year 2022. Predictions for the number of cases and deaths in the year 2050 were derived from global demographic projections, categorised by world region and Human Development Index (HDI). In 2022, there were 1 473 427 new cases of GCs and 680 372 deaths. The incidence of gynecological cancer reached 30.3 per 100 000, and the mortality rate hit 13.2 per 100 000. The age-standardised incidence of GCs in Eastern Africa is higher than 50 per 100 000, whereas the age-standardised incidence in Northern Africa is 17.1 per 100 000. The highest mortality rates were found in East Africa (ASMR (age-standardised mortality rates) of 35.3 per 100 000) and the lowest in Australia and New Zealand (ASMR of 8.1 per 100 000). These are related to the endemic areas of HIV and HPV. Very High HDI countries had the highest incidence of GCs, with ASIR (age-standardised incidence rates) of 34.8 per 100 000, and low HDI countries had the second highest incidence rate, with an ASIR of 33.0 per 100 000. Eswatini had the highest incidence and mortality (105.4 per 100 000; 71.1 per 100 000) and Yemen the lowest (5.8 per 100 000; 4.4 per 100 000). If the current trends in morbidity and mortality are maintained, number of new cases and deaths from female reproductive tract tumours is projected to increase over the next two decades. In 2022, gynaecological cancers accounted for 1 473 427 new cases and 680 372 deaths globally, with significant regional disparities in incidence and mortality rates. The highest rates were observed in Eastern Africa and countries with very high and low HDI, with Eswatini recording the most severe statistics. If current trends continue, the number of new cases and deaths from gynaecological cancers is expected to rise over the next two decades, highlighting the urgent need for effective interventions.

Development and validation of a prognostic model for cervical cancer by combination of machine learning and high-throughput sequencing

BackgroundCervical cancer holds the highest morbidity and mortality rates among female reproductive tract tumors. However, the curative outcomes for patients with persistent, recurrent, or metastatic cervical cancer remain unsatisfactory. There is a lack of comprehensive prognostic indicators for cervical cancer. This study aims to develop a model that evaluates the prognosis of cervical cancer in combination of high-throughput sequencing and various machine learning algorithms. MethodsIn this study, we combined two single-cell RNA sequencing (scRNA-seq) projects and TCGA data for cervical cancer to obtain shared differentially expressed genes (DEGs). A LASSO regression and several learners were applied for signature feature selection. Six machine learning algorithms including Linear Discriminant Analysis, Naive Bayes, K Nearest Neighbors, Decision Tree, Random Forest, and eXtreme Gradient Boosting were utilized to construct a prognostic model for cervical cancer. External validation was conducted using the CGCI-HTMCP-CC dataset, and the accuracy of the model was assessed through ROC curve analysis. ResultsThe results demonstrated the successful construction of a prognostic model based on DEGs from bulk- and scRNA-seq data. Ten genes CXCL8, DLC1, GRN, MPLKIP, PRDX1, RUNX1, SNX3, TFRC, UBE2V2, and UQCRC1 were screened by feature selection and applied for model construction. Random Forest exhibited the best performance in predicting the risk of cervical cancer. Patients in the high-risk group presented worse overall survival compared to those in the low-risk group. ConclusionConclusively, our model based on DEGs from bulk-seq and scRNA-seq data effectively evaluates the prognosis of cervical cancer and provides valuable insights for comprehensive clinical management.

Diagnosis and Clinico-Surgical Management of Secondary Laminitis due to Ovarian Tumour in a Kathiawari Mare

Granulosa cell tumours (GCTs) are the most common ovarian tumours in equine which involves around 2.5% of all tumours of horses and 85% of reproductive tract tumours (McCue et al. 2006). Tumours may originate from tissue present within the equine ovary. GCTs are most often first detected during either routine reproductive examination for breeding or when behavioral changes caused by the presence of the tumour in ovary requiring further investigation (McKinnon and Barker, 2010). Mares with GCTs remain infertile due to atrophy of the contralateral ovary, which has been variably associated with elevated serum inhibin, testosterone or anti-Mullerian hormone concentrations (Ball et al., 2012). Surgical removal is regarded as the treatment of choice for GCTs (McCue et al., 2006). Surgical removal of the affected ovary almost always results in the resumption of normal heat cycles and the ability to carry a normal pregnancy. Lameness in mare which suffered from GCT was also reported earlier by Meagher et al. (1977). Various scientists reported different technique for removal of affected ovary. Standing laparoscopic ovariectomy is associated with a lower complication rate than other surgical methods like colpotomy (Colbern and Reagan 1987), flank, paramedian or ventral midline celiotomy (Lee and Hendrickson, 2008; Azizi et al., 2014). Most of GCTs are benign and affect the left ovary (McCue et al. 2006; Korany et al., 2020). The present document reports clinical diagnosis and surgical management of secondary laminitis due to ovarian tumour in a Kathiawari mare by left flank ovariectomy of the affected ovary.

Angiogenesis-related gene signatures reveal the prognosis of cervical cancer based on single cell sequencing and co-expression network analysis.

Cervical cancer ranks first in female reproductive tract tumors in terms of morbidity and mortality. Yet the curative effect of patients with persistent, recurrent or metastatic cervical cancer remains unsatisfactory. Although antitumor angiogenic drugs have been recommended as the first-line treatment options for cervical cancer, there are no comprehensive prognostic indicators for cervical cancer based on angiogenic signature genes. In this study, we aimed to develop a model to assess the prognosis of cervical cancer based on angiogenesis-related (AG) signature genes, and to provide some reference for the comprehensive treatment of cervical cancer in the clinical setting. First we screened the AG gene set from GeneCard website, and then performed angiogenesis-related scores (AGS) per cell from single cell sequencing dataset GSE168652, followed by performing weighted gene co-expression network analysis (WGCNA) for cervical cancer patients according to angiogenesis phenotype. Thus, we established a prognostic model based on AGS by taking the intersection of WGCNA angiogenic module gene and differential gene (DEGs) of GSE168652. The GSE44001 was selected as an external validation set, followed by performing ROC curve analysis to assess its accuracy. The results showed that we successfully constructed a prognostic model related to the AG genes. Patients in the high-AGS group in both the train, test and the validation sets had a worse prognosis than those in the low-AGS group, had lower expression of most immune checkpoint-associated genes and lower tumor mutational burden as well. Patients in the low-AGS group were more sensitive to AMG.706, Bosutinib, and Lenalidomide while Imatinib, Pazopanib, and Sorafenib were more recommended to patients in the high-AGS group. Finally, TXNDC12 and ZC3H13, which have high hazard ratio and poor prognosis in the model, were highly expressed in cervical cancer cell lines and tissue. Meanwhile, the results showed that TXNDC12 promoted the migration of cervical cancer cells and the tubule-forming ability of endothelial cells. In conclusion, our model based on genes with AG features can effectively assess the prognosis of cervical cancer, and can also provide reference for clinicians to choose immune-related treatments.

Canine testicular tumors: An 11-year retrospective study of 358 cases in Moscow Region, Russia.

Background and Aim:Canine testicular tumors are among the most common reproductive tract tumors in male dogs and have been studied in many countries. However, to the best of our knowledge, studies with a large sample size have not been conducted in Russia. This study aimed to provide the latest information on the prevalence of canine testicular tumors in the Veterinary Oncology Scientific Center for Small Animals “Biocontrol” in Moscow, Russia, in 2010-2020 and the characteristics of the affected canine population.Materials and Methods:A retrospective review of patients and histological reports was collected and analyzed from 358 dogs with 447 testicular tumors within 11 years.Results:The mean age of the affected dogs was 10.4 years, whereas that of dogs with Sertoli cell tumors was 9.4 years p=0.009. This study includes mixed-breed dogs (18.4%), Yorkshire Terriers (8.8%), Labrador Retrievers (7.9%), Golden Retrievers (5.0%), and Fox Terriers (3.4%). The most common tumors were interstitial cell tumors (n=227, 50.8%). In contrast, 107 (23.9%) seminomas, 80 (17.9%) Sertoli cell tumors, 19 (7.4%) mixed germ cell-sex cord-stromal tumors, and 26 (7.6%) testicular tumors developed from cryptorchid testes, which included 16 (61.5%) Sertoli cell tumors, 10 (38.5%) seminomas, and no interstitial cell tumors.Conclusion:This study provides baseline information on the prevalence of canine testicular tumors in the described population, including the median age of each tumor type and overrepresented dog breeds. We further found that the most common scrotal testicular tumor was interstitial cell tumor, whereas Sertoli cell tumor was the most common in cryptorchid testicles.

Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12.

Background/aimsUterine leiomyoma (ULM) is a kind of gene-involved benign tumor, which is located in the front of female reproductive tract. It is one of the most common reproductive tract tumors in women, which leads to abnormal menstruation, repeated pregnancy loss, and other serious gynecological diseases. Recently, microRNAs (miRNAs) have attracted much more attention in the process of exploring the molecular mechanisms of tumorigenesis. Furthermore, the deregulated miRNAs had been reported to play important roles in ULM pathology.MethodsIn this study, we assessed the expression level of microRNA-199a-5p (miR-199a-5p) in human ULM by quantitative polymerase chain reaction. After that cell counting kit 8, colony formation, 5-ethynyl-20-deoxyuridine, flow cytometry, and Western blot analyses were performed to investigate the effects of miR-199a-5p on ULM cell proliferation and apoptosis.ResultsWe confirmed that miR-199a-5p was significantly downregulated in human ULM. The results of function analyses showed that miR-199a-5p inhibited cell proliferation and induced cell apoptosis in vitro. Bioinformatics tool showed oncogene MED12 was one of the target genes of miR-199a-5p, which mediated the effect of miR-199a-5p on the ULM.ConclusionOur results showed that miR-199a-5p functioned as an antitumor factor in human ULM cells. These findings broaden the current findings on the function of miR-199a-5p into the ULM pathogenesis, and miR-199a-5p may serve as a prognosis and therapeutic target for the ULM and its related diseases.

Managing menopausal symptoms in patients with hormone receptor-positive gynecologic cancers

Young women with reproductive tract neoplasms who receive treatment leading to termination of ovarian function often suffer from menopause symptoms that contribute to dramatic drop in quality of life. Climacteric symptoms in women with iatrogenic menopause are more severe than in case of natural menopause, especially in women with reproductive tract neoplasms. They lead to dramatic drop in quality of life and are one of the main reasons to stop applying endocrine therapy in women with hormone-positive tumors, which leads to decrease in disease free survival and to decline the prognosis. The most effective treatment option for climacteric symptoms of moderate to severe degrees is menopause hormone therapy; however, such therapy is not suitable for patients with estrogen-dependent tumors in past medical history due to the likelihood risk of progression of cancer, as well as the risk of venous thrombosis, the frequency of which in cancer patients increases. Non-hormonal pharmacological and non-pharmacological correction methods are used as first-line therapy for menopause disorders in women with estrogen-dependent tumors of the reproductive system. Among non-hormonal non-pharmacological correction methods actively study such methods as acupuncture, yoga, exercise to control weight, and a diet rich in phytoestrogens. The most effective non-hormonal methods of correcting vasomotor symptoms are serotonin and norepinephrine reuptake inhibitors. However, currently in Russia these drugs can be prescribed only by a psychiatrist. The finding of effective and safe non-hormonal methods to correct menopause symptoms in women with hormone-positive reproductive tract tumors is the important task in practice among doctors in different specialties.

Constitutive expression of progesterone receptor isoforms promotes the development of hormone-dependent ovarian neoplasms.

Differences in the relative abundances of the progesterone receptor (PGR) isoforms PGRA and PGRB are often observed in women with reproductive tract cancers. To assess the importance of the PGR isoform ratio in the maintenance of the reproductive tract, we generated mice that overexpress PGRA or PGRB in all PGR-positive tissues. Whereas few PGRA-overexpressing mice developed reproductive tract tumors, all PGRB-overexpressing mice developed ovarian neoplasms that were derived from ovarian luteal cells. Transcriptomic analyses of the ovarian tumors from PGRB-overexpressing mice revealed enhanced AKT signaling and a gene expression signature similar to those of human ovarian and endometrial cancers. Treating PGRB-overexpressing mice with the PGR antagonist RU486 stalled tumor growth and decreased the expression of cell cycle-associated genes, indicating that tumor growth and cell proliferation were hormone dependent in addition to being isoform dependent. Analysis of the PGRB cistrome identified binding events at genes encoding proteins that are critical regulators of mitotic phase entry. This work suggests a mechanism whereby an increase in the abundance of PGRB relative to that of PGRA drives neoplasia in vivo by stimulating cell cycling.

Abstract IA28: Nanodisc platform technology for cancer vaccination

Abstract Recent innovations in DNA/RNA sequencing have allowed for the identification of patient-specific tumor neo-antigens, ushering in the new era of personalized cancer vaccines. Peptide vaccines in general may serve as an ideal platform for neo-antigen vaccines, but the therapeutic efficacy of peptide vaccines have been limited in clinical trials. Here we present an alternative strategy where preformed nanodiscs based on synthetic high density lipoproteins, with an established clinical manufacturing procedure and excellent safety profiles in humans, are readily formulated with adjuvants and antigen peptides. We show that these nanodiscs can efficiently deliver immunostimulatory molecules and antigens, including neo-antigens to draining lymph nodes. Notably, nanodiscs elicited up to 47-fold greater frequency of tumor neoantigen-specific CD8+ T lymphocytes (CTLs) than soluble vaccines in mice and even 31-fold greater than the standard adjuvant in clinical trials (i.e. CpG in Montanide). When nanodisc vaccination was combined with anti-PD-1 immune checkpoint inhibitor, ~88% complete response was observed in MC-38 tumor-bearing mice, compared with 25% response rate in the control group that received soluble vaccine plus anti-PD-1 therapy. In more aggressive B16F10 melanoma model, nanodiscs delivering multiple MHC class I and class II neo-epitopes were combined with α-PD-1/α-CTLA-4 therapy, leading ~90% complete response in B16F10 tumor-bearing mice, compared with ~38% response rate in the control group with soluble vaccine plus α-PD-1/α-CTLA-4 therapy. Furthermore, we have demonstrated the efficacy of nanodisc technology using shared tumor antigens in murine models of HPV+ mucosal tumors. The reproductive tract tumor model was established in C57BL/6 mice by intravaginal administration of luciferase-expressing TC-1 cells, a surrogate for HPV-induced human tumors, such as cervical carcinoma. The lung metastasis model was established by intravenous injection of luciferase-expressing TC-1 tumor cells. In mice bearing intravaginal or lung TC-1 tumors, two nanodisc vaccinations with HPV16 E7 antigen generated the peak frequency of ~35% tetramer+ CTLs in peripheral blood and eliminated established TC-1 tumors in the majority of animals (without immune checkpoint blockade). Owning to the facile production process, robust therapeutic efficacy, and good safety profiles, our nano-vaccine technology offers a powerful and convenient platform for vaccination using personalized as well as shared tumor antigens. Citation Format: James J. Moon. Nanodisc platform technology for cancer vaccination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA28.

Uterine Fibroids and the Risk of Cardiovascular Disease in the Coronary Artery Risk Development in Young Adult Women's Study.

Uterine fibroids, the most common reproductive tract tumor in women, have been associated with hypertension and atherosclerotic cardiovascular disease (CVD). Prior studies of fibroids and CVD have examined the subset of women with symptomatic fibroids who undergo hysterectomy, itself a risk factor for CVD. We aimed to study the risk of subclinical CVD, as determined by coronary artery calcification (CAC), carotid intima media thickness (CIMT), and left ventricular (LV) mass, in women with ultrasound-diagnosed uterine fibroids. Participants were 972 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort recruited in 1985-1986. CARDIA screened black and white women aged 35-49 years by ultrasound for fibroids at 16 years of follow-up (2002-2004). Demographics and CVD risk factors were collected in 2000-2001 at 15 years of follow-up (baseline for this analysis). Women were tested at years 15, 20, and 25 for CAC, at year 20 for CIMT, and at year 25 for echocardiographic LV mass. Multivariable logistic regression was used to estimate the odds of CAC, CIMT, and LV mass. Fifty-two percent of women had fibroids (61.7% in black, 38.3% in white women). Most CVD risk factors were more common in women with fibroids. Adjusted odds of subclinical CVD, such as elevated CIMT and elevated LV mass, were not different for women with fibroids compared with those without (CIMT odds ratio [OR] = 1.03; confidence interval [95% CI] 0.7-1.5 and LV mass OR = 1.14; 95% CI 0.77-1.68), when adjusted for confounders. Although women with fibroids had more CVD risk factors, presence of fibroids was not associated with subclinical CVD.

MiR-363 confers taxane resistance in ovarian cancer by targeting the Hippo pathway member, LATS2.

Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (paclitaxel; TX) is widely used for ovarian cancer treatment. However, ovarian cancers often acquire chemoresistance. MicroRNAs (miR) have been reported to mediate many tumours’chemoresistance. We investigated the role of miR-363 in the chemoresistance of the ovarian cancer cell line, KF, and its TX-resistant derivative (KF-TX) cells. QRT-PCR indicated that miR-363 was upregulated in KF-TX cells, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assay and expression analysis. Furthermore, we validated the role of LATS2 in TX-response by sh-based silencing, which also confers TX-resistance to the ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX in the resistant cells. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while it was downregulated in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.

HPV-ASSOCIATED DISEASES IN THE STRUCTURE OF FEMALE REPRODUCTIVE TRACT TUMORS AND SEXUALLY TRANSMITTED INFECTIONS IN MOSCOW AND RUSSIA

The group of female reproductive tract tumors includes cancers of corpus uteri, ovary, cervix, vulva and vagina (the last three are associated with HPV). Among the large group of sexually transmitted infections (STIs) there are only six infections, which subject to registration in the official statistical data in Russia: syphilis, gonorrhea, trichomoniasis, chlamydia, urogenital herpes and anogenital warts (AGWs). Occurrence of AGWs in 95–100% of cases caused by HPV types 6 and 11. Objectives: our aim was to determine the prevalence of HPV-associated diseases (cervical cancer and anogenital warts) in the structure of female reproductive tract tumors and STIs in recent years in Moscow, and to compare it with the prevalence in population of Russia. Methods: we analyzed retrospective data with diagnostic codes related to cancers of corpus uteri, ovary, cervix, vulva and vagina from the official statistic of cancer register using incidence and mortality rates between January 2007 and December 2015 in Russia and Moscow. We also analyzed retrospective data of STIs (incl. syphilis, gonorrhea, trichomoniasis, chlamydia, urogenital herpes and AGWs) incidence rates between January 2003 and December 2015. Results: average rate of cervical cancer incidence among the female reproductive tract tumors accounted for 23.7% in Moscow (29.8% in Russia). Average rate of cervical cancer mortality among the female reproductive tract tumors accounted for 24.1% in Moscow (28.3% in Russia). The rate of AGWs in the STIs structure (for both sexes) in Moscow increased from 11.5% in 2003 to 25.7% in 2015 (the maximum was 31.0% in 2014). The highest rate of AGWs was detected in the age group 15–17 years (up to 59.8% in 2012), followed by 18–29 years (up to 37.3% in 2014). The rate of AGWs was 11.7% among all STIs (in both sexes) in Russia in 2015. Conclusion: HPV-associated diseases (cervical cancer and AGWs) take up a significant place in the structure of female reproductive tract tumors and STIs. And in the structure of the STI for Moscow, AGWs moved from the 5th (in 2003) to the 1st (in 2015) ranked place, surpassing syphilis, gonorrhea, trichomoniasis and chlamydia. The effective prevention of HPV-infection would be able to improve the situation.

Abstract LB-323: Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2

Abstract Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (TX) is widely used for ovarian cancer treatment. However, ovarian cancer often acquire chemoresistance. MicroRNAs (miR) have been reported to regulate many tumours’ chemoresistance. Here, we investigated the comparative microRNA expression profile between the ovarian cancer cells and their taxane-resistant counterpart, KF-TX to get novel markers for taxane resistance in ovarian cancer. The array data revealed that miR-486, miR143,miR145 and miR363 are the most upregulated miRNAs in association with TX resistance. However, miR-155, miR-100, miR-31 and miR-629 are the most significantly downregulated miRNAs after resistance development. We then focused on the role of miR-363 in chemoresistance of the ovarian cancer. qRT-PCR indicated that miR-363 was upregulated in KF-TX cells, confirming the array data, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assays and expression analysis. Furthermore, we validated the role of LATS2 in the TX-response by sh-based silencing, which also confers TX-resistance in the responsive ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while downregulation of the same gene in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance and poor prognosis. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance. Note: This abstract was not presented at the meeting. Citation Format: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba. Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-323. doi:10.1158/1538-7445.AM2017-LB-323

Ovarian down Regulation by GnRF Vaccination Decreases Reproductive Tract Tumour Size in Female White and Greater One-Horned Rhinoceroses.

Reproductive tract tumours, specifically leiomyoma, are commonly found in female rhinoceroses. Similar to humans, tumour growth in rhinoceroses is thought to be sex hormone dependent. Tumours can form and expand from the onset of ovarian activity at puberty until the cessation of sex-steroid influences at senescence. Extensive tumour growth results in infertility. The aim of this study was to down regulate reproductive function of tumour-diseased and infertile females to stop further tumour growth using a Gonadotropin releasing factor (GnRF) vaccine. Four infertile southern white (Ceratotherium simum simum) and three Greater one-horned rhinoceroses (rhinoceros unicornis) with active ovaries and 2.7 ± 0.9 and 14.0 ± 1.5 reproductive tract tumours respectively were vaccinated against GnRF (Improvac®, Zoetis, Germany) at 0, 4 and 16 weeks and re-boostered every 6–8 months thereafter. After GnRF vaccination ovarian and luteal activity was suppressed in all treated females. Three months after vaccination the size of the ovaries, the number of follicles and the size of the largest follicle were significantly reduced (P<0.03). Reproductive tract tumours decreased significantly in diameter (Greater-one horned rhino: P<0.0001; white rhino: P<0.01), presumably as a result of reduced sex-steroid influence. The calculated tumour volumes were reduced by 50.8 ± 10.9% in Greater one-horned and 48.6 ± 12.9% in white rhinoceroses. In conclusion, GnRF vaccine effectively down regulated reproductive function and decreased the size of reproductive tract tumours in female rhinoceros. Our work is the first to use down regulation of reproductive function as a symptomatic treatment against benign reproductive tumour disease in a wildlife species. Nonetheless, full reversibility and rhinoceros fertility following GnRF vaccination warrants further evaluation.

Tumor specific epitopes on Podocalyxin as a target for ADC and CAR T cell therapy

Abstract Podocalyxin (Podxl) is a heavily glycosylated sialomucin type 1 membrane protein that has been shown to be involved in cell adhesion, migration, and polarity. Although Podxl is found on a variety of normal cell types, it is aberrantly expressed in acute myeloid leukemia (AML) blasts, and its presence in breast, colorectal and glial malignancies is correlated with poor clinical outcome. Using the human triple negative breast cancer line MDA-MB-231, we have demonstrated a functional role for Podxl in tumor growth and metastasis in xenografted mice, and have recently developed high affinity antibodies to a tumor-specific post-translational modification of Podxl. Preliminary IHC data suggests that this post-translational modification on Podxl may found in glioblastoma, melanoma, and female reproductive tract tumors, but not on matched normal tissue. Staining intensity in melanoma samples correlates with stage of disease and is strongest in tissues collected from metastatic lesions. Preliminary experiments indicate that expression of this glyco-epitope is increased in myeloid leukemia cells lines by co-culture with bone marrow stromal cells or hypoxia, suggesting that the tumor microenvironment may contribute to the observed reactivity. Our lead antibody, Podo447, binds this tumor-associated glycoform of Podxl with high affinity and induces cytotoxicity in various tumor cell lines as an antibody drug conjugate (ADC), and when expressed as a human IgG1 Fc chimera stimulates antibody dependent cellular cytotoxicity. With its exquisite specificity for malignant tissues, and the number of potential indications, Podo447 is an ideal targeting arm for an antibody drug conjugate or CAR-T enabled therapeutic.

Ocena funkcji układu moczowego oraz komfortu życia kobiet po skojarzonym leczeniu raka endometrium

Endometrial cancer is currently the most common form of female reproductive tract tumors. The efficacy of treatment, which involves surgery,...

A critical examination of the mode of action of quinacrine in the reproductive tract in a 2-year rat cancer bioassay and its implications for human clinical use

A rat carcinogenicity bioassay (CaBio) of quinacrine was reanalyzed to investigate its mode of tumor induction. Quinacrine’s effects in the rat uterus when administered as a slurry in methylcellulose were contrasted with the human clinical experience which uses a solid form of the drug, to determine the relevance of the tumors produced in the rat to safe clinical use of quinacrine for permanent contraception (QS). A review was performed of the study report, dose feasibility studies, and clinical evaluations of women who had undergone the QS procedure. The top three doses of quinacrine in the CaBio exceeded the maximum tolerated dose, and produced chronic damage, including inflammation, resulting in reproductive tract tumors. Chronic inflammation was significantly correlated with the tumors; there was no evidence of treatment-related tumors in animals without chronic inflammation or other reproductive system toxicity. Because such permanent uterine damage and chronic toxicity have not been observed in humans under therapeutic conditions, we conclude that this mode of action for tumor production will not occur at clinically relevant doses in women who choose quinacrine for permanent contraception.

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5–120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral–vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral–vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Reproductive Tract Tumours: The Scourge of Woman Reproduction Ails Indian Rhinoceroses

In Indian rhinoceros, extensive leiomyoma, a benign smooth muscle tumour, was sporadically diagnosed post mortem and commonly thought of as contributing factor for reduced fecundity of this species in captivity. However, to date, the prevalence of reproductive tract tumours and their relevance for fecundity are unknown. Our analysis of the international studbook now reveals that females cease reproducing at the age of 18.1±1.2 years; equivalent to a reproductive lifespan of just 9.5±1.3 years. This short reproductive life is in sharp contrast to their longevity in captivity of over 40 years. Here we show, after examining 42% of the captive female population, that age-related genital tract tumours are highly prevalent in this endangered species. Growth and development of these tumours was found to be age-related, starting from the age of 10 years. All females older than 12 years had developed genital tumours, just 7–9 years past maturity. Tumour sizes ranged from 1.5–10 cm. With age, tumours became more numerous, sometimes merging into one large diffuse tumour mass. These tumours, primarily vaginal and cervical, presumably cause widespread young-age infertility by the age of 18 years. In few cases, tumour necrosis suggested possible malignancy of tumours. Possible consequences of such genital tract tumour infestation are hindered intromission, pain during mating, hampered sperm passage, risk of ascending infection during pregnancy, dystocia, or chronic vaginal bleeding. In humans, leiomyoma affect up to 80% of pre-menopause women. While a leading cause for infertility, pregnancy is known to reduce the risk of tumour development. However, different from human, surgical intervention is not a viable treatment option in rhinoceroses. Thus, in analogy to humans, we suggest early onset and seamless consecutive pregnancies to help reduce prevalence of this disease, better maintain a self-sustained captive population and improve animal welfare.

Evidence of a Chemopreventive Effect of Progestin Unrelated to Ovulation on Reproductive Tract Cancers in the Egg-laying Hen

Epidemiologic, laboratory, and animal evidence suggests that progestins and vitamin D may be potent ovarian cancer preventives. Our objectives were to evaluate progestins as reproductive tract cancer chemopreventives in the chicken, determine whether restricted ovulation affected the incidence of reproductive tract tumors, and assess whether vitamin D would confer cancer protection either alone or in addition to progestin. A total of 2,400 two-year-old Single Comb White Leghorns were randomized into six groups (400 each) with hormonal and dietary manipulation for 2 years as follows: (i) no intervention, regular feed/caloric intake, (ii) control, (iii) vitamin D, (iv) the progestin levonorgestrel, (v) vitamin D plus levonorgestrel, and (vi) the progestin Provera (medroxyprogesterone acetate). Groups 2 to 6 were caloric restricted to inhibit ovulation. Our results indicated that caloric restriction decreased egg production by more than 60%, and was associated with a greater than 70% decrease in reproductive tract cancers. Ovulatory events did not differ among the caloric-restricted groups (groups 2-6), except for the group receiving levonorgestrel, which had fewer ovulatory events than controls (P = 0.046). After correcting for egg production, birds receiving progestins had significantly fewer reproductive tract cancers [OR, 0.61; confidence interval (CI), 0.39-0.95; P = 0.03], with similar proportionate reductions in tumors arising in either the ovary or oviduct. Vitamin D did not significantly affect cancer incidence overall, or add to the cancer preventive effect of progestins. This study suggests a protective effect of progestins against ovarian and oviductal cancers. These data support the concept that progestins provide a chemopreventive effect unrelated to ovulation.