The Science

Advanced adult granulosa cell tumor with prominent fibromatous stroma: A case report

Implementation of Brachytherapy for Patients With Cervical Cancer in Ethiopia: A 3-Year Practice Report

PURPOSE Although cervical cancer is the second most commonly diagnosed cancer in Ethiopia, brachytherapy (BT) was not a component in patient treatment until 2015. The purpose of this study was to identify the patterns of utilization as well as to describe the practice of BT in Ethiopia. MATERIALS AND METHODS A retrospective descriptive data analysis of 138 patients with cervical cancer treated with a curative potential using BT from 2015 to 2018 at Tikur Anbassa Specialized Hospital, which housed the only BT facility in Ethiopia during the study period. RESULTS During the first 3-year period of BT service commencement, each year n = 37, n = 36, and n = 65 patients with cervical cancer were treated, respectively, with curative intention treatment. The median age of these 138 patients was 50 years (range, 22-75). All the patients were in International Federation of Gynecology and Obstetrics stage Ib–IIIb group, and stage IIb (66.4%) was the predominant. Majority (79%) of the patients were treated primarily with radiotherapy (RT), while 21% received RT after surgery. More than half of these patients (62%) received a total RT dose of 82 Gy in equivalent dose in 2 Gy fractions (EQD2), while the rest received a dose ranging from 76 to 86 Gy. Concurrent cisplatin with RT was given only for 36% of the patients for undocumented reasons. The overall treatment time including both external-beam RT and BT was greater than 8 weeks in 21% of the patients. CONCLUSION The utilization of BT service increased gradually and BT enabled the delivery of a higher RT dose to patients with cervical cancer (mostly stage IIB). However, there was protracted treatment duration and low concurrent chemotherapy utilization.

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

Differential effects of the LncRNA RNF157-AS1 on epithelial ovarian cancer cells through suppression of DIRAS3- and ULK1-mediated autophagy

AbstractAnalyses of several databases showed that the lncRNA RNF157 Antisense RNA 1 (RNF157-AS1) is overexpressed in epithelial ovarian cancer (EOC) tissues. In our study, suppressing RNF157-AS1 strikingly reduced the proliferation, invasion, and migration of EOC cells compared with control cells, while overexpressing RNF157-AS1 greatly increased these effects. By RNA pulldown assays, RNA binding protein immunoprecipitation (RIP) assays, and mass spectrometry, RNF157-AS1 was further found to be able to bind to the HMGA1 and EZH2 proteins. Chromatin immunoprecipitation (ChIP) assays showed that RNF157-AS1 and HMGA1 bound to the ULK1 promoter and prevented the expression of ULK1. Additionally, RNF157-AS1 interacted with EZH2 to bind to the DIRAS3 promoter and diminish DIRAS3 expression. ULK1 and DIRAS3 were found to be essential for autophagy. Combination autophagy inhibitor and RNF157-AS1 overexpression or knockdown, a change in the LC3 II/I ratio was found using immunofluorescence (IF) staining and western blot (WB) analysis. The autophagy level also was confirmed by autophagy/cytotoxicity dual staining. However, the majority of advanced EOC patients require platinum-based chemotherapy, since autophagy is a cellular catabolic response to cell stress. As a result, RNF157-AS1 increased EOC cell sensitivity to chemotherapy and death under cis-platinum (DDP) treatment by suppressing autophagy, as confirmed by cell count Kit-8 (CCK8) assays, flow cytometry, and autophagy/cytotoxicity dual staining. Therefore, the OS and PPS times were longer in EOC patients with elevated RNF157-AS1 expression. RNF157-AS1-mediated autophagy has potential clinical significance in DDP chemotherapy for EOC patients.

Blocking CD47-SIRPα Signal Axis as Promising Immunotherapy in Ovarian Cancer

Among the three primary gynecological malignancies, ovarian cancer has the lowest incidence but the worst prognosis. Because of the poor prognosis of ovarian cancer patients treated with existing treatments, immunotherapy is emerging as a potentially ideal alternative to surgery, chemotherapy, and targeted therapy. Among immunotherapies, immune checkpoint inhibitors have been the most thoroughly studied, and many drugs have been successfully used in the clinic. CD47, a novel immune checkpoint, provides insights into ovarian cancer immunotherapy. This review highlights the mechanisms of tumor immune evasion via CD47-mediated inhibition of phagocytosis and provides a comprehensive insight into the progress of the relevant targeted agents in ovarian cancer.

Construction of Ovarian Cancer Prognostic Model Based on the Investigation of Ferroptosis-Related lncRNA

(1) Background: Ovarian cancer (OV) has the high mortality rate among gynecological cancers worldwide. Inefficient early diagnosis and prognostic prediction of OV leads to poor survival in most patients. OV is associated with ferroptosis, an iron-dependent form of cell death. Ferroptosis, believed to be regulated by long non-coding RNAs (lncRNAs), may have potential applications in anti-cancer treatments. In this study, we aimed to identify ferroptosis-related lncRNA signatures and develop a novel model for predicting OV prognosis. (2) Methods: We downloaded data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression, and Gene Expression Omnibus (GEO) databases. Prognostic lncRNAs were screened by least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, and a prognostic model was constructed. The model’s predictive ability was evaluated by Kaplan–Meier (KM) survival analysis and receiver operating characteristic (ROC) curves. The expression levels of these lncRNAs included in the model were examined in normal and OV cell lines using quantitative reverse transcriptase polymerase chain reaction. (3) Results: We constructed an 18 lncRNA prognostic prediction model for OV based on ferroptosis-related lncRNAs from TCGA patient samples. This model was validated using TCGA and GEO patient samples. KM analysis showed that the prognostic model was able to significantly distinguish between high- and low-risk groups, corresponding to worse and better prognoses. Based on the ROC curves, our model shows stronger prediction precision compared with other traditional clinical factors. Immune cell infiltration, immune checkpoint expression levels, and Tumor Immune Dysfunction and Exclusion analyses are also insightful for OV immunotherapy. (4) Conclusions: The prognostic model constructed in this study has potential for improving our understanding of ferroptosis-related lncRNAs and providing a new tool for prognosis and immune response prediction in patients with OV.

ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer

Background Ovarian cancer is the deadliest type of malignant gynecological tumor. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are involved ovarian cancer and are closely related to adverse outcomes. However, the immunosuppressive mechanism of PMN-MDSCs remains elusive. Methods The types and numbers of ANKRD22-expressing cells were investigated by bioinformatics analysis and immunohistochemical staining. Ankrd22-/- C57BL/6 mice were constructed with CRISPR-Cas9 technology. Mouse PMN-MDSCs were obtained from bone marrow (BM)-derived CD11b+Ly6G+Ly6Clow cells sorted by fluorescence-activated cell sorting with treatment of GM-CSF and IL-6, and the immunosuppressive activity of PMN-MDSCs was evaluated by flow cytometry (FCM) and ELISA. The expression level of CCR2 and the exogenous glucose uptake capacity were determined by FCM. RT-qPCR was used to detect ANKRD22 expression in CD11b+HLA-DR-CD14-CD15+ cells from human ovarian cancer tissues, and the correlations of ANKRD22 expression with the clinical characteristics and prognosis of patients were evaluated by the χ2 test. Results We identified a novel protein involved in regulating the immunosuppressive ability of PMN-MDSCs, ANKRD22. Ankrd22 expression was high in mouse CD11b+Ly6G+Ly6Clow cells and could be significantly downregulated after exposure to a simulated microenvironmental stimulus. Knockout of Ankrd22 increased the expression level of CCR2 of CD11b+Ly6G+Ly6Clow cells and the immunosuppressive activity of PMN-MDSCs. BM-derived CD11b+Ly6G+Ly6Clow cells of Ankrd22-/- mice significantly promoted the proliferation of ovarian cancer cells in tumor xenograft mouse models. Mechanistically, RNA sequencing showed that Wdfy1 expression was obviously increased in Ankrd22-knockout BM-derived CD11b+Ly6G+ Ly6Clow cells and that ectopic expression of Wdfy1 increased the levels of Arg1, Inos, Ido and Pdl1 in Ankrd22+/+ PMN-MDSCs derived from BM-derived CD11b+Ly6G+Ly6Clow cells. Surprisingly, an ANKRD22-activating candidate small-molecule compound attenuated the immunosuppressive activity of Ankrd22+/+ PMN-MDSCs. Finally, we found that low ANKRD22 levels in CD11b+HLA-DR-CD14-CD15+ cells derived from primary ovarian tissues were associated with a more advanced International Federation of Gynecology and Obstetrics stage, a higher recurrence rate, and a higher neutrophil-to-lymphocyte ratio. Conclusions These results suggest that ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs.

Recurrence, Reoperation, Pregnancy Rates, and Risk Factors for Recurrence after Ovarian Endometrioma Surgery: Long-Term Follow-Up of 756 Women

The aims of this study were to evaluate the cumulative recurrence, reoperation, and pregnancy rates after ovarian endometrioma surgery at a single institution for more than a 5-year follow-up period. This study was conducted as a retrospective chart review of patients with ovarian endometrioma who underwent surgery between January 2008 and March 2016. Study subjects included premenopausal women with at least 5 years of follow-up. Exclusion criteria were patients with stage I or II ovarian endometrioma, those who underwent hysterectomy or bilateral oophorectomy, and presence of residual ovarian lesions on the first postoperative ultrasonography at 3-6 months. Recurrence was defined as a cystic mass by ultrasonography. A total of 756 patients were recruited. The median follow-up duration was 85.5 months (interquartile range, 71-107 months). Recurrent endometrioma was detected in 27.9% patients, and reoperation was performed in 8.3% patients. Cumulative rates at 24, 36, 60, and 120 months were 5.8%, 8.7%, 15.5% and 37.6%, respectively, for recurrence and 0.1%, 0.5%, 2.9%, and 15.1%, respectively, for reoperation. After multivariable analysis, age ≤31 years [hazard ratio (HR)=2.108; 95% confidence interval (CI)=1.522-2.921; Considering that longer postoperative hormonal treatment is the sole modifiable factor for recurrent endometrioma, we recommend long-term hormonal treatment until subsequent pregnancy, especially in younger women.

Circulating CD4+ Treg, CD8+ Treg, and CD3+ γδ T Cell Subpopulations in Ovarian Cancer

Background and Objectives: Regulatory T cells (Tregs) are usually enriched in ovarian cancer (OC), and their immunosuppressive function plays a key role in tumorigenesis and progression. We mainly explored the phenotypical characterization of Treg-related markers on αβ and γδ T cell subsets in patients with OC. Materials and Methods: Thirty-six untreated patients with OC at the Women’s Hospital of Nanjing Medical University from September 2019 to August 2021 were enrolled. Phenotypical characterization of Tregs-related markers were detected by flow cytometry (FCM). Enzyme-linked immunosorbent assay was used to detect the levels of carbohydrate antigen (CA125) and transforming growth factor β (TGF-β). The level of human epididymis protein 4 (HE4) was detected by electrochemiluminescence immunoassay. Results: Circulating CD4+ Tregs, CD8+ Tregs, and CD3+γδ T cell subpopulations from OC patients have elevated Foxp3, CD25, CD122, Vδ1, and reduced CD28 expression compared to benign ovarian tumor (BOT) patients and healthy controls (HC). The upregulation of Foxp3 and Vδ1 and the downregulation of CD28 were highly specific for maintaining the immunosuppression function of CD4+ Tregs, CD3+γδ T cells, and CD8+ Tregs in OC patients. These Treg subpopulations were able to discriminate OC from BOT and HC. The levels of CA125, HE4, and TGF-β were increased in OC patients. A significant positive correlation between Treg subpopulations and CA125, HE4, and TGF-β was revealed. Conclusions: Proportions of CD4+ Tregs, CD8+ Tregs, and CD3+γδ T cell subsets were significantly increased in OC patients and were positively correlated with FIGO stage/metastasis status, CA125, HE4, and TGF-β. These indicators have the potential to be used as immunosurveillance biomarkers for OC.

Brenner Tumor of the Ovary: A 10-Year Single Institution Experience and Comprehensive Review of the Literature

Brenner tumors (BTs) are surface-epithelial stromal cell tumors that are categorized by the World Health Organization as benign, borderline, and malignant. Due to the rarity of BTs, the published literature on these tumors is comprised primarily of case reports and small retrospective studies. We performed a pathology database review spanning the last ten years at our institution revealing nine reported benign BTs. We collected the clinical and pathological data of patients associated with those BTs, describing the clinical presentation and imaging results, and assessing the possible risk factors associated with them. The average age at diagnosis was 58 years. BTs were discovered incidentally in 7/9 cases. The tumor was multifocal and bilateral in 1/9 cases and ranged in size from 0.2 cm to 7.5 cm. Associated Walthard rests were found in 6/9 cases and transitional metaplasia of surface ovarian and/or tubal epithelium was found in 4/9 cases. One patient had an associated mucinous cystadenoma in the ipsilateral ovary. Another patient had an associated mucinous cystadenoma in the contralateral ovary. In conclusion, we found that Walthard rests and transitional metaplasia are common findings in association with BTs. Additionally, pathologists and surgeons need to be aware of the association between mucinous cystadenomas and BTs.

Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study

AbstractBackgroundAnti‐angiogenic therapy with bevacizumab (BEV), an anti‐VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed.MethodsTo overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient‐derived xenografts (PDXs) of immunodeficient mice.ResultsBEV/CCR2i demonstrated a significant effect of growth suppression in the BEV‐resistant serous PDX and BEV‐sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti‐α‐SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV‐resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased‐dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B‐MAPK pathway.ConclusionsBEV/CCR2i showed a sustained anticancer immunity‐independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma.

Identification of an Autophagy-Related Signature for Prognosis and Immunotherapy Response Prediction in Ovarian Cancer

Background: Ovarian cancer (OC) is one of the most malignant tumors in the female reproductive system, with a poor prognosis. Various responses to treatments including chemotherapy and immunotherapy are observed among patients due to their individual characteristics. Applicable prognostic markers could make it easier to refine risk stratification for OC patients. Autophagy is closely implicated in the occurrence and development of tumors, including OC. Whether autophagy -related genes can be used as prognostic markers for OC patients remains unclear. Methods: The gene transcriptome data of 374 OC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between the autophagy levels and outcomes of OC patients was identified through the single sample gene set enrichment analysis (ssGSEA). Recognized molecular markers of autophagy in different clinical specimens were detected by immunohistochemistry (IHC) assay. The gene set enrichment analysis (GSEA), ESTIMATE, and CIBERSORT analysis were applied to explore the correlation of autophagy with the tumor immune microenvironment (TIME). Single-cell RNA-sequencing (scRNA-seq) data from seven OC patients were included for characterizing cell-cell interaction patterns of autophagy-high or low tumor cells. Machine learning, Stepwise Cox regression and LASSO-Cox analysis were used to screen autophagy hub genes, which were used to establish an autophagy-related signature for prognosis evaluation. Four tumor immunotherapy cohorts were obtained from the GEO (Gene Expression Omnibus) database and the literature for autophagy risk score validation. Results: The autophagy levels were closely related to the prognosis of the OC patients. Additionally, the autophagy levels were correlated with TIME status including immune score, and immune-cell infiltration. The scRNA-seq analysis found that tumor cells with high or low autophagy levels had different interactions with immune cells, especially macrophages. Eight autophagy-hub genes (ZFYVE1, AMBRA1, LAMP2, TRAF6, PDPK1, ATG2B, DAPK1 and TP53INP2) were screened for an autophagy-related signature. According to this signature, higher risk score was correlated with poor prognosis and better immunotherapy response in the OC patients. Conclusions: The autophagy-related signature is applicable to predict the prognosis and immune checkpoint inhibitors (ICIs) therapy efficiency in OC patients. It is possible to identify OC patients who will respond to ICIs therapy and have a favorable prognosis, although more verification is needed.

Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics

AbstractFunctional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer’s proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer.

Recent breakthroughs in the management of locally advanced and recurrent/metastatic cervical cancer

Cervical cancer continues to be a global threat affecting individuals in resource poor communities disproportionately. The treatment paradigm for this disease is ever evolving with recent innovations propelling oncologic outcomes to a new frontier offering survival benefits for patients struggling with locally advanced disease and metastatic/recurrent carcinoma. Immunologic checkpoint inhibitors and anti-body drug conjugates represent two novel drug classes that have demonstrable activity in this disease, particularly in the first-line and second-line treatment paradigm for recurrence. The tolerability of these novel medicines and associated durable responses underscore regulatory approval by the U.S. Food and Drug Administrations and their implementation in clinic.

Development of handheld induction heaters for magnetic fluid hyperthermia applications and in-vitro evaluation on ovarian and prostate cancer cell lines

Abstract Objective: Magnetic fluid hyperthermia (MFH) is a still experimental technique found to have a potential application in the treatment of cancer. The method aims to reach around 41 °C–47 °C in the tumor site by exciting magnetic nanoparticles with an externally applied alternating magnetic field (AMF), where cell death is expected to occur. Applying AMFs with high spatial resolution is still a challenge. The AMFs from current and prospective MFH applicators cover relatively large areas; being not suitable for patients having metallic implants near the treatment area. Thus, there will be a clinical need for smaller magnetic field applicators. To this end, a laparoscopic induction heater (LIH) and a transrectal induction heater (TRIH) were developed. Methods: Miniature ‘pancake’ coils were wound and inserted into 3D printed enclosures. Ovarian (SKOV-3, A2780) and prostate (PC-3, LNCaP) cancer cell lines were used to evaluate the instruments’ capabilities in killing cancer cells in vitro, using Synomag®-D nanoparticles as the heat mediators. NIH3T3 normal cell lines were also used with both devices to observe if these cells tolerated the conditions applied. Results: Magnetic field intensities reached by the LIH and TRIH were 42.6 kA m−1 at 326 kHz and 26.3 kA m−1 at 303 kHz, respectively. Temperatures reached in the samples were 41 °C by the LIH and 43 °C by the TRIH. Both instruments successfully accomplished killing cancer cells, with minimal effects on normal cells. Conclusion: This work presents the first line of handheld medical induction heaters and have the potential to be a complement to existing cancer therapies. Significance: These instruments could enable the development of MFH modalities that will facilitate the clinical translation of this thermal treatment.

Ultra-High-Risk Gestational Choriocarcinoma of the Ovary Associated with Ectopic Pregnancy

Gestational choriocarcinoma of the ovary is an exceptionally rare and highly aggressive tumor. Preoperative diagnosis of extrauterine choriocarcinoma is difficult due to nonspecific clinical presentation and its resemblance to ectopic pregnancy. Without molecular genetic analysis, it is not possible to reliably differentiate gestational from non-gestational choriocarcinoma. Here, we present a case of a 44-year-old woman who presented to our emergency department with complaints of pelvic pain, vaginal bleeding, and amenorrhea. Because of a recent history of conservatively managed ectopic pregnancy, the patient underwent emergency laparoscopy. Right-sided salpingo-oophorectomy was performed due to intraoperatively suspected ovarian ectopic pregnancy. Histopathology results revealed the diagnosis of ovarian choriocarcinoma of possible gestational origin. It was classified as FIGO stage IV and WHO ultra-high-risk, and she underwent multi-agent chemotherapy without major complications. She has remained in complete remission after a 12-month follow-up. Considering the rarity of this diagnosis, we conducted a literature review including all published cases of suspected gestational choriocarcinomas of the ovary. We conclude that due to the rarity of this entity, preoperative differentiating between ovarian ectopic pregnancy and ovarian choriocarcinoma is extremely challenging, and without molecular genetic analysis, it is not possible to identify the genetic origin of the tumor.

Histopathological subtyping of high-grade serous ovarian cancer using whole slide imaging

We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

Abortion and Female Cancer Risks among Women Aged 20 to 45 Years: A 10-Year Longitudinal Population-Based Cohort Study in Taiwan

Background: Female cancers, including breast, cervical, uterine, and ovarian cancer, remain among the ten most common cancers among women worldwide, but the relationship between female cancers and abortion from previous studies is inconsistent. This study aimed to investigate risks of incident female cancers among women aged 20 to 45 years who underwent abortion in Taiwan compared with those who did not. Method: A longitudinal observational cohort study was conducted using three nationwide population-based databases in Taiwan, focusing on 20- to 45-year-old women, with 10 years of follow-up. Matched cohorts were identified with propensity score 1-to-3 matching between 269,050 women who underwent abortion and 807,150 who did not. Multivariable Cox proportional hazard modeling was used for analysis after adjusting for covariates including age, average monthly payroll, fertility, diabetes mellitus, polycystic ovarian syndrome, endometrial hyperplasia, endometriosis, hormone-related drugs, and Charlson comorbidity index. Results: We found lower risk of uterine cancer (hazard ratio [HR]: 0.77, 95% CI: 0.70–0.85) and ovarian cancer (HR: 0.81, 95% CI: 0.75–0.88), but no significant difference in risk of breast cancer or cervical cancer, among matched abortion compared with non-abortion cohorts. Regarding subgroup analysis, cervical cancer risk was higher for parous women who underwent abortion, and uterine cancer risk was lower for nulliparous women who underwent abortion compared with non-abortion groups. Conclusions: Abortion was related to lower uterine and ovarian cancer risk but was not associated with risks of incident breast cancer or cervical cancer. Longer follow-up may be necessary to observe risks of female cancers at older ages.

Intelligent Theranostic Systems Enabled by Aggregation‐Induced Emission in Precision Medicine

The DNA damage response in advanced ovarian cancer: functional analysis combined with machine learning identifies signatures that correlate with chemotherapy sensitivity and patient outcome

AbstractBackgroundOvarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants.MethodsWe profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods.ResultsDR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS.ConclusionsWhilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

Exploring the role of a multidisciplinary hereditary gynecologic oncology clinic in epithelial ovarian cancer risk‐reducing surgical decision‐making practices: A mixed‐methods study

AbstractIndividuals that have gynecologic reproductive organs with pathogenic variants in BRCA1 or BRCA2 (“BRCA‐positive”) have an increased risk of developing high‐grade serous ovarian cancer (HGSOC). The majority of HGSOC develops in the fallopian tubes and later spreads to the ovaries and peritoneal cavity. Therefore, risk‐reducing salpingo‐oophorectomy (RRSO) is recommended for those who are BRCA‐positive to preventatively remove their ovaries and fallopian tubes. The Hereditary Gynecology Clinic (HGC) is a provincial program in Winnipeg, Canada, that specifically targets care to the unique needs of such individuals through an interdisciplinary team of gynecological oncologists, menopause specialists, and registered nurses. A mixed‐methods study design was used to explore the decision‐making processes of these BRCA‐positive individuals who have been recommended (or who completed) RRSO and experiences with healthcare providers at the HGC influenced this decision. Individuals who are BRCA‐positive without a previous diagnosis of HGSOC and who had previously received genetic counselling were recruited from the HGC and the provincial cancer genetics program (Shared Health Program of Genetics & Metabolism). Forty‐three people completed a survey and 15 participated in an in‐depth interview about their experiences and decisions surrounding RRSO. Surveys were analyzed to compare scores on validated scales related to decision‐making and cancer‐related worry. Qualitative interviews were transcribed, coded, and analyzed using interpretive description. Participants described the complex decisions faced by those who are BRCA‐positive, which are intertwined with life experiences and circumstances including age, marital status, and family disease history. Participants interpreted their HGSOC risk through a personalized “lens” of contextual factors that impacted perceptions about the practical and emotional implications of RRSO and the need for surgery. Mean scores on validated scales evaluating the HGC's impact on decisional outcomes and preparedness for decision‐making about RRSO were not significant, indicating that the HGC played a supportive role, rather than helping with decision‐making itself. Therefore, we present a novel framework that consolidates the various influences on decision‐making and connects them to the psychological and practical implications of RRSO in the context of the HGC. Strategies for improving support, decisional outcomes, and the overall experiences of individuals who are BRCA‐positive attending the HGC are also described.

Survival Outcomes of Patients with International Federation of Gynecology and Obstetrics Stage IV Ovarian Cancer: Cytoreduction Still Matters

Purpose There is still no consensus on the therapeutic strategies for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer (OC). We aim to outline the clinical characteristics and optimal therapeutic strategies of patients with FIGO stage IV OC. Methods This single center retrospective study analyzed the clinical features and survival of patients with FIGO stage IV OC that underwent cytoreduction or received at least one course of chemotherapy between January 2014 and December 2020. Results One hundred and twenty patients were included. Surgery, especially optimal cytoreduction without residual mass improved the overall survival of patients in surgery group ( P = .047, HR .432, 95% CI .181-.987). Secondly, the completion of chemotherapy improved median overall survival of patients either with (53.0 months vs 25.0 months, P < .001, HR 7.015, 95% CI 1.372-35.881) or without cytoreduction (43.0 months vs 6.0 months, P = .006, HR 5.969, 95% CI 1.115-31.952). In patients with FIGO stage IVB, those with only extra-abdominal lymph node metastases had better survival. Conclusions In patients with FIGO stage IV, complete resection of intra-abdominal tumor foci and completion of chemotherapy provided considerable survival benefits to patients with FIGO stage IV OC. Among patients with FIGO stage IVB, those with only extra-abdominal lymph node metastases had a better prognosis.

Effectiveness and safety of nab-paclitaxel and platinum as first-line chemotherapy for ovarian cancer: a retrospective study

To evaluate the effectiveness and safety of nab-paclitaxel plus platinum as first-line chemotherapy for ovarian cancer (OC). Patients administered platinum combined with nab-paclitaxel as first-line chemotherapy for epithelial OC, fallopian tube cancer, or primary peritoneal cancer from July 2018 to December 2021 were retrospectively evaluated. The primary outcome was progression-free survival (PFS). Adverse events (AEs) were examined. Subgroup analysis was performed. Seventy-two patients (median age, 54.5 years; range, 20.0-79.0 years) were evaluated, including 12 and 60 administered neoadjuvant therapy and primary surgery with subsequent chemotherapy, respectively. The median follow-up duration was 25.6 months, and the median PFS was 26.7 (95% confidence interval [CI]=24.0-29.3) months in the whole patient population. In the neoadjuvant subgroup, the median PFS was 26.7 (95% CI=22.9-30.5) months vs. 30.1 (95% CI=23.1-37.1) months in the primary surgery subgroup. Twenty-seven patients were administered nab-paclitaxel plus carboplatin and had a median PFS of 30.3 (95% CI=not available [NA]-NA) months. The commonest grade 3-4 AEs included anemia (15.3%), white blood cell decreased (11.1%), and neutrophil count decreased (20.8%). No drug-related hypersensitivity reactions occurred. Nab-paclitaxel plus platinum as first-line treatment in OC was associated with a favorable prognosis and was tolerable in patients with OC.

Self-enhancing triplex lateral flow assay for simultaneous detection of influenza A, influenza B, and SARS-CoV-2.

Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer

Abstract Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 “superagonist” (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.

Purine Intake and All-Cause Mortality in Ovarian Cancer: Results from a Prospective Cohort Study

Background: Current biological evidence suggests that purine involvement in purine metabolism may contribute to the development and progression of ovarian cancer (OC), but the epidemiological association is currently unknown. Methods: A total of 703 newly diagnosed patients with OC aged 18–79 years were included in this prospective cohort study. Utilizing a verified food-frequency questionnaire, the participants’ dietary consumption was gathered. Using medical records and ongoing follow-up, the deaths up until 31 March 2021 were determined. To assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of purine intake with OC mortality, Cox proportional-hazard models were utilized. Results: During the median follow-up of 31 months (interquartile: 20–47 months), 130 deaths occurred. We observed an improved survival for the highest tercile of total purine intake compared with the lowest tercile (HR = 0.39, 95% CI = 0.19–0.80; p trend < 0.05), and this protective association was mainly attributed to xanthine intake (HR = 0.52, 95% CI = 0.29–0.94, p trend < 0.05). Additionally, we observed a curving relationship in which OC mortality decreased with total purine intake, and the magnitude of the decrease was negatively correlated with intake (p non-linear < 0.05). Significant inverse associations were also observed in subgroup analyses and sensitivity analyses according to demographic and clinical characteristics. Moreover, we observed that xanthine intake and hypoxanthine intake had a multiplicative interaction with ER and PR expression (p < 0.05), respectively. Conclusion: A high total purine and xanthine intake was linked to a lower risk of OC mortality. Further clarification of these findings is warranted.

An Assessment of Serum Selenium Concentration in Women with Ovarian Cancer

Background: Available studies on the effect of serum selenium levels on the risk of malignancies show some conflicting results. In this study, we investigated the correlation between serum selenium levels and ovarian cancer occurrence. Methods: 314 women (157 diseased patients and 157 healthy ones) matched in terms of age and BMI were included in the study. The measurements of selenium in the collected blood samples were performed using an ICP mass spectrometer. Univariable and multivariable analyzes were performed to determine the relationship between the factors under the study and the occurrence of ovarian cancer. Results: The mean concentration of selenium was lower among diseased ones than among controls (53.31 μg/L vs. 78.99 μg/L). A decrease in selenium concentration was noticed with the advancement of ovarian cancer. In univariable and multivariable analyzes, a clear relationship between low selenium concentration and the occurrence of ovarian cancer was found (35.3 (95% CI: 11.2–111; p < 0.001) and 45.8 (95% CI: 12.8–164; p < 0.001)). Conclusion: The studied patients with ovarian cancer are characterized by statistically significant lower serum selenium levels than patients from the control group. Among the study group, a decrease in selenium concentration was observed with an increase in the FIGO stage. The determination of the role of selenium as a prophylactic factor in ovarian cancer requires further prospective studies.

Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in BRCA2

Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).

Effect of within-endobag method during laparoscopic ovarian cystectomy of dermoid cyst: A retrospective study

This study aimed to evaluate the effect of within-endobag cystectomy during and after laparoscopic ovarian cystectomy in patients with dermoid cysts. We retrospectively analyzed 84 patients with ovarian dermoid cysts who underwent laparoscopic ovarian cystectomy. In 30 patients, the affected ovary was placed in an endobag before cystectomy and cystectomy was performed within an endobag (within-endobag group), while the remaining 54 patients underwent standard cystectomy without this step (without-endobag group). After cystectomy, the cyst wall was placed in an endobag and was removed from the abdomen. Compared with the without-endobag group, the within-endobag group had a significantly lower rate of cyst content spillage (23.3% vs 72.2%, P < .001) and significantly shorter operation times when the cysts ruptured (23.4 ± 8.6 minutes vs 51.2 ± 28.6 minutes, P < .001). Whereas there was no significant difference in operation time in the absence of cyst rupture between 2 groups (21.2 ± 8.8 minutes vs 31.1 ± 17.4 minutes, P = .111). In patients with cyst rupture, according to the cyst size increase, the operation time was significantly prolonged without-endobag, whereas no significant prolongation was observed in within-endobag cystectomy. Except for operation time, there were no significant differences in cyst length, pain on the first day after surgery, hemoglobin loss, hospital stay, and inflammatory markers (C-reactive protein and white blood cell counts) in both ruptured and unruptured cases between the 2 groups. There were no postoperative complications in the within-endobag group, but 2 cases of perioperative complications occurred in the without-endobag group. No chemical peritonitis due to spillage of the cyst contents was observed in either group. Laparoscopic ovarian cystectomy performed within-endobag can reduce both the spillage rate of cyst contents and operation time regardless of cyst size in patients with ruptured cysts. Therefore, this technique is a good surgical option for the laparoscopic ovarian cystectomy of large dermoid ovarian cysts.

Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions

The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested.