Stage IA1 HPV-associated cervical squamous cell carcinoma metastasizing to ovary by special pathway: a case report and literature review.

BACKGROUND: As the leading cancer of the female reproductive tract, it is not uncommon for human papilloma virus (HPV)-associated cervical squamous cell carcinoma (HPV-CSCC) to metastasize to pelvic organs and lymph nodes in advanced stages. However, herein, we present a rare case in which superficial invasive HPV-CSCC metastasized to the unilateral ovary as a large mass by spreading directly through the endometrium and fallopian tubes and lymph-vascular space invasion. The case is so unexpected that the misdiagnosis most likely could be proceeded as a primary ovarian cancer. CASE PRESENTATION: A 58-year-old postmenopausal woman presented vaginal bleeding for more than 4 months, never received hormonal treatment and had no family history of malignant diseases. Routine ultrasound revealed a 12 × 10 × 10 cm right ovarian mass. Intraoperative frozen section was diagnosed as a borderline Brenner tumour with local highly suspected invasive carcinoma. Accordingly, omentectomy surgery then occurred. Unbelievably, by observation under a microscope, immunohistochemistrial staining, and HPV RNA scope, we found that the carcinoma originated from the uterine cervix. In the uterine cervix, stage IA1 superficial invasive squamous carcinoma was found, and the carcinoma directly spread to the endometrium and bilateral fallopian tube, was planted into the right ovary and eventually grew as a large mass. Moreover, lymph-vascular space invasion (LVSI) was also discovered. To date, the patient has been given 6 cycles of chemotherapy and has experienced no recurrence. CONCLUSIONS: The diagnosis of superficial invasive cervical squamous cell carcinoma metastasizing to the ovary is very challenging for pathological doctors, especially in intraoperative consultations.

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS: Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS: Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS: Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.

Human papillomavirus and ovarian cancer (review of literature and meta-analysis).

Many factors are involved in carcinogenesis of the ovary, such human genetic and physiological characteristics as lifestyle, existing diseases of the reproductive system, and, as suggested, the human papillomavirus (HPV). It is well known that the human papillomavirus virus of high carcinogenic risk (HCR) plays a crucial role in the onset and development of cervical cancer, as well as cases of HPV positive breast cancer and endometrial cancer. The data on the presence of HPV in ovarian cancer are ambiguous: the researchers claim that there is no complete effect of the virus on the development of this type of cancer, and the detection of HPV in 60-80% of tumors. In this regard, there is a need to systematize the currently available research results on this controversial issue and conduct a meta-analysis of the association of HPV infection with the risk of ovarian cancer.

Chlamydia trachomatis, Pelvic Inflammatory Disease, and Epithelial Ovarian Cancer.

Epidemiologic, clinical, molecular and translational research findings support an interrelationship between Chlamydia trachomatis, pelvic inflammatory disease (PID), and epithelial ovarian cancer (EOC). Overall, the link between C. trachomatis, PID, and EOC seems to be relatively weak, although nondifferential misclassification bias may have attenuated the results. The predominant tubal origin of EOC and the role of chronic inflammation in tumorigenesis suggest that the association is biologically plausible. Thus, C. trachomatis and PID may represent potential risk factors or risk markers for EOC. However, many steps in this chain of events are still poorly understood and need to be addressed in future studies. Research gaps include time of exposure in relation to the long-term consequences and lag time to EOC. Data of differential risk for EOC between chlamydial and nonchlamydial PID is also needed. Another major research gap has been the absence of high-performance biomarkers for C. trachomatis, PID, and EOC, as well as EOC precursors. Biomarkers for C. trachomatis and PID leading to increased risk of EOC should be developed. If the association is confirmed, C. trachomatis and PID prevention efforts may play a role in reducing the burden of EOC.

Prevalence of human papillomavirus detection in ovarian cancer: a meta-analysis.

We conducted a meta-analysis of published data to update and estimate the prevalence of HPV in ovarian cancer. A comprehensive literature search was performed according to the PRISMA guidelines. Eligible articles published from 1989 until 2020 by searching Web of Sciences, Pubmed, Embase, and the Cochrane Library Central databases were gathered. A pooled estimation of HPV prevalence with a 95% confidence interval (CI) was calculated based on a random effect model. Quantitative assessment of heterogeneity was explored using Cochrane test and I2. Additionally, publication bias, sensitivity, meta-regression, and subgroup analyses were also performed. Twenty-nine studies involving 2280 patients with ovarian cancer were included. The statistical heterogeneity was high (I2 = 88%, P<0.0001). The pooled prevalence of HPV in ovarian cancer cases was 15.9% (95% CI, 11-22). In subgroup analyses, the highest prevalence of HPV was reported by studies from Asia (30.9%; 95% CI, 20-44) and Eastern Europe (29.3%; 95% CI, 4.4-78). Furthermore, the most frequently detected HPV genotype was HPV16 (54%; 95% CI, 27.9-55), followed by HPV18 (23.2%; 95% CI, 18.8-28.2). Our meta-analysis suggests a great difference in the prevalence of HPV detected in ovarian cancer by different studies, which is not seen in strongly HPV-associated cancers such as cervical cancer. However, the prevalence varied markedly by geographic region. Considering the substantial heterogeneity found, more studies with control groups and precise assays measuring HPV mRNA expression are needed to further evaluate the link and causative aetiology between HPV and ovarian cancer.

Human papillomavirus infection: Is it associated with epithelial ovarian cancer?

PURPOSE: Human papillomavirus (HPV), the causative agent of cervical cancer, is associated with several other epithelial malignancies. Previous reports on HPV infection and its association with ovarian cancer are highly contradicting. Reports on HPV association with ovarian cancer in Indian women are also rare. Hence, the purpose of this study was to screen women with serous epithelial ovarian cancer for possible HPV infection. METHODS: Tumor samples, collected at the time of surgery from 88 women with serous epithelial ovarian cancer were screened using a specific and sensitive PCR. The PCR results were confirmed with Southern blotting using HPV genome-specific probes, both of high-risk HPV type 16 and 18 and low-risk HPV type 6 and 11. All the samples were again tested for another 14 high-risk HPV genotypes with a commercially available qRT-PCR. RESULTS: All the samples screened and confirmed by various tests did not show presence of either low-risk or high-risk HPV DNA, indicating the absence of HPV infections in these ovarian cancer tissues. CONCLUSIONS: The present study shows that HPV infection may not be associated with epithelial ovarian cancer. The result of the current investigation strongly supports the results of earlier research that, HPV is not associated with ovarian cancer.

Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors.

In this work, we are reporting that "Shock and Kill", a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7/8-NFκB, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of TLR7 and HERV-V1/V2 curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies.

Natural killer T cell immunotherapy combined with oncolytic vesicular stomatitis virus or reovirus treatments differentially increases survival in mouse models of ovarian and breast cancer metastasis.

BACKGROUND: Oncolytic viruses reduce tumor burden in animal models and have generated promising results in clinical trials. However, it is likely that oncolytic viruses will be more effective when used in combination with other therapies. Current therapeutic approaches, including chemotherapeutics, come with dose-limiting toxicities. Another option is to combine oncolytic viruses with immunotherapeutic approaches. METHODS: Using experimental models of metastatic 4T1 breast cancer and ID8 ovarian peritoneal carcinomatosis, we examined natural killer T (NKT) cell-based immunotherapy in combination with recombinant oncolytic vesicular stomatitis virus (VSV) or reovirus. 4T1 mammary carcinoma cells or ID8 ovarian cancer cells were injected into syngeneic mice. Tumor-bearing mice were treated with VSV or reovirus followed by activation of NKT cells via the intravenous administration of autologous dendritic cells loaded with the glycolipid antigen α-galactosylceramide. The effects of VSV and reovirus on immunogenic cell death (ICD), cell viability and immunogenicity were tested in vitro. RESULTS: VSV or reovirus treatments followed by NKT cell activation mediated greater survival in the ID8 model than individual therapies. The regimen was less effective when the treatment order was reversed, delivering virus treatments after NKT cell activation. In the 4T1 model, VSV combined with NKT cell activation increased overall survival and decreased metastatic burden better than individual treatments. In contrast, reovirus was not effective on its own or in combination with NKT cell activation. In vitro, VSV killed a panel of tumor lines better than reovirus. VSV infection also elicited greater increases in mRNA transcripts for proinflammatory cytokines, chemokines, and antigen presentation machinery compared with reovirus. Oncolytic VSV also induced the key hallmarks of ICD (calreticulin mobilization, plus release of ATP and HMGB1), while reovirus only mobilized calreticulin. CONCLUSION: Taken together, these results demonstrate that oncolytic VSV and NKT cell immunotherapy can be effectively combined to decrease tumor burden in models of metastatic breast and ovarian cancers. Oncolytic VSV and reovirus induced differential responses in our models which may relate to differences in virus activity or tumor susceptibility.

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

BACKGROUND: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer. METHODS: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated. RESULTS: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%. CONCLUSIONS: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.

Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.

PURPOSE: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. EXPERIMENTAL DESIGN: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models (n = 9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response (n = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo. RESULTS: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. CONCLUSIONS: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.

Cytomegalovirus and systemic inflammation at time of surgery is associated with worse outcomes in serous ovarian cancer.

OBJECTIVES: Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. METHODS: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. RESULTS: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV-/CRP+, and 23 (21.7%) CMV-/CRP-. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0-21.1) and 31.7 months (95% CI: 25.0-48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05-3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17-3.82, P = 0.01) compared to CMV-/CRP- (RFS = 31.2 months (95% CI: 16.0-56.4) and OS = 63.8 months (95% CI: 50.7-87.0)). CMV+/CRP- group displayed the longest OS (89.3 months). CONCLUSIONS: Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP- group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.

Evidence of human cytomegalovirus infection and expression of 5-lipoxygenase in borderline ovarian tumors.

Borderline ovarian tumors (BOTs) belong to a group of tumors that are distinctly different from ovarian carcinomas. There is an increased risk of BOTs in patients with pelvic inflammatory disease. Human cytomegalovirus (HCMV) has been detected in ovarian cancer tissue specimens. This virus favors the inflammatory milieu by inducing expression of the potent inflammatory factor 5-lipoxygenase (5LO), which stimulates cellular viability, cellular proliferation and activates antiapoptotic signaling pathways. Here, we aimed to examine presence of HCMV and 5LO in BOTs. Expression levels of HCMV proteins (IE and pp65) and 5LO were examined in paraffin embedded BOT tissue sections by immunohistochemistry staining and HCMV immunoglobulin M and immunoglobulin G (IgG) levels were determined by serology in blood samples obtained from 15 patients with BOTs identified in a prospective study at Karolinska University Hospital. Extensive expression of HCMV-IE, pp65, and 5LO were detected in 87%, 40%, and 90% of examined BOT tissue sections, respectively. HCMV-IgG prevalence and antibody levels were significantly higher in patients with BOT compared to age matched healthy women (83.3% vs. 65,6%, respectively, p = .01). Whether HCMV can induce inflammation and affect the pathogenesis of BOTs should therefore be further investigated.

Analysis of KAP1 expression patterns and human endogenous retrovirus Env proteins in ovarian cancer.

BACKGROUND: Human endogenous retroviruses (HERVs) constitute around 8% of the human genome and have important roles in human health and disease, including cancers. Previous studies showed that HERV envelope (Env) proteins are highly expressed in cancer tissues and co-related with cancer progression. KAP1 has been reported to play a key role in regulating retrotransposons, including HERV-K, through epigenetic silencing. OBJECTIVE: The relationship between KAP-1 and HERV Envs expressions was analyzed only in tumor cell lines and has not yet been studied in cancer tissues. In this study, we analyzed the expression patterns and relationship between KAP1 and HERV Env proteins in ovarian cancer tissues. METHOD: The expression patterns of KAP-1 and HERV Env proteins, including HERV-K and HERV-R, were analyzed in ovarian cancer tissue microarrays that contained 80 surgical specimens, including normal ovary and malignant ovarian cancers. RESULTS: The expression of HERV-R Env and KAP1 proteins is significantly higher in ovarian cancer compared with normal ovary tissues. However, the expression of HERV-K Env did not change significantly in cancer tissues. The expression patterns of HERV-K Env and HERV-R Env significantly increased in early stages of cancer and KAP1 expression was higher in certain stage and types of cancers. However, the expression of HERV-K Env, HERV-R Env, and KAP1 did not change in different age groups. The correlation between the expression of KAP1 and HERV-Env, including HERV-K and HERV-R, was not significantly correlated. CONCLUSIONS: The results of this study showed that there was no significant correlation between the expression of KAP1 and HERV Env proteins in ovarian cancer tissues, unlike studies with cell lines in vitro. These results suggest that the actual expression of HERV Env proteins in ovarian cancer tissues may be regulated through various complex factors as well as KAP1.

Anti-tumor effect of a dual cancer-specific recombinant adenovirus on ovarian cancer cells.

BACKGROUND: Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) acts as a tumor-specific promoter, triggering certain genes to replicate or express only in tumor cells, conferring specific replication and killing abilities. This study aimed at investigating the anticancer potential of the recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) in ovarian cancer treatment. METHODS: Crystal Violet staining and WST-1 assays were used to analyze the inhibitory effect of Ad-VT on ovarian cancer SKOV3 and OVCAR-3 cells. Ad-VT-induced apoptosis of ovarian cancer cells, was detected using Hoechst, Annexin V-FITC/PI, JC-1 staining. Cell migration and invasion of ovarian cancer cells were detected using cell-scratch and Transwell assays. The pGL4.51 plasmid was used to transfect and to generate SKOV3-LUC cells, that stably express luciferase. The in vivo tumor inhibition effect of Ad-VT was subsequently confirmed using a tumor-bearing nude mouse model. RESULTS: Ad-VT had a strong apoptosis-inducing effect on SKOV3 and OVCAR-3 cells, that was mainly mediated through the mitochondrial apoptotic pathway. The Ad-VT could significantly increase the inhibition of ovarian cancer cell migration and invasion. The Ad-VT also can inhibit tumor growth and reduce toxicity in vivo. CONCLUSIONS: The recombinant adenovirus, comprising the apoptin protein and the hTERTp promoter, was able to inhibit the growth of ovarian cancer cells and promote their apoptosis.

Management of patients with ovarian cancer in the COVID-19 era.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) spreads worldwide. Patients with ovarian cancer should be considered at high-risk of developing severe morbidity related to COVID-19. Most of them are diagnosed in advanced stages of disease, and they are fragile. Here, we evaluated the major impact of COVID-19 on patients with ovarian cancer, discussing the effect of the outbreak on medical and surgical treatment.

Association between the microbiota and women's cancers - Cause or consequences?

Breast, ovarian and uterine cancers are the most common neoplasms among women. Several mechanisms may be involved in oncogenesis and these include environmental and genetic factors. Bacteria may affect the development of some cancers, with bacterial components, their products and metabolites interacting with susceptible tissues. Commensalism and dysbiosis are important potential mechanisms involved in oncogenesis, and an effective strategy for diagnosis and treatment is required. The purpose of this review was to analyze the complex associations between these cancers in women, and the microbiota, specifically bacterial microbes. However, several cancers have an increased prevalence among individuals with HIV and HPV so the relationship between viral infections and malignancies in women is also referred to. We described how different phylum of bacteria, particularly in the gut, mammary tissue and vaginal microbiome may be involved in carcinogenesis; and we discuss the potential pathways involved: (I), that lead to cell proliferation, (II), immune system perturbation, (III), cell metabolic changes (e.g., hormonal factors), and (IV), DNA damage. Studies investigating the differences between the composition of the bacterial microbiota of healthy women compared to that present in various conditions, and the clinical trials are summarized for the few studies that have addressed the microbiota and related conditions, are also reviewed.

Mitochondria Participate in Chemoresistance to Cisplatin in Human Ovarian Cancer Cells.

Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of cases, a majority of them discontinues treatment owing to side effects and to the emergence of resistance. In this study, we focused on resistance to cisplatin and investigated whether metabolic changes could be involved. As models, we used matched pairs of cisplatin-sensitive (SKOV-3 and COV-362) and cisplatin-resistant (SKOV-3-R and COV-362-R) human ovarian carcinoma cells that were selected in vitro following exposure to increasing doses of the chemotherapy. Metabolic comparison revealed that resistant cells undergo a shift toward a more oxidative metabolism. The shift goes along with a reorganization of the mitochondrial network, with a generally increased mitochondrial compartment. More functional mitochondria in cisplatin-resistant compared with cisplatin-sensitive cells were associated to enzymatic changes affecting either the electron transport chain (SKOV-3/SKOV-3-R model) or mitochondrial coupling (COV-362/COV-362-R model). Our findings further indicate that the preservation of functional mitochondria in these cells could be due to an increased mitochondrial turnover rate, suggesting mitophagy inhibition as a potential strategy to tackle cisplatin-resistant human ovarian cancer progression. IMPLICATIONS: Besides classical mechanisms related to drug efflux and target modification, we report that preserving functional mitochondria is a strategy used by human ovarian cancer cells to resist to cisplatin chemotherapy.

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.