Weakly supervised deep learning for prediction of treatment effectiveness on ovarian cancer from histopathology images.

Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70 % of advanced patients are with recurrent cancer and decease. Surgical debulking of tumors following chemotherapy is the conventional treatment for advanced carcinoma, but patients with such treatment remain at great risk for recurrence and developing drug resistance, and only about 30 % of the women affected will be cured. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Considering the cost, potential toxicity, and finding that only a portion of patients will benefit from these drugs, the identification of new predictive method for the treatment of ovarian cancer remains an urgent unmet medical need. In this study, we develop weakly supervised deep learning approaches to accurately predict therapeutic effect for bevacizumab of ovarian cancer patients from histopathological hematoxylin and eosin stained whole slide images, without any pathologist-provided locally annotated regions. To the authors' best knowledge, this is the first model demonstrated to be effective for prediction of the therapeutic effect of patients with epithelial ovarian cancer to bevacizumab. Quantitative evaluation of a whole section dataset shows that the proposed method achieves high accuracy, 0.882 ± 0.06; precision, 0.921 ± 0.04, recall, 0.912 ± 0.03; F-measure, 0.917 ± 0.07 using 5-fold cross validation and outperforms two state-of-the art deep learning approaches Coudray et al. (2018), Campanella et al. (2019). For an independent TMA testing set, the three proposed methods obtain promising results with high recall (sensitivity) 0.946, 0.893 and 0.964, respectively. The results suggest that the proposed method could be useful for guiding treatment by assisting in filtering out patients without positive therapeutic response to suffer from further treatments while keeping patients with positive response in the treatment process. Furthermore, according to the statistical analysis of the Cox Proportional Hazards Model, patients who were predicted to be invalid by the proposed model had a very high risk of cancer recurrence (hazard ratio = 13.727) than patients predicted to be effective with statistical signifcance (p < 0.05).

Verification of HPV16 as a good prognostic factor for cervical adeno-adenosquamous carcinoma via an international collaborative study.

OBJECTIVE: This study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC). MATERIALS AND METHODS: Patients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993-2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis. RESULTS: A total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1-15.8; HR5.8, 95% CI 1.6-20.5), lymph node metastasis (HR4.6, 95% CI 2.7-7.9; HR7.3, 95% CI 3.8-14.0), and HPV16-positivity (HR0.3, 95% CI 0.1-0.6; HR0.3, 95% CI 0.1-0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups. CONCLUSION: This study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.

A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker.

Ovarian cancer is a common malignant gynecological disease. Molecular target therapy, i.e., antiangiogenesis with bevacizumab, was found to be effective in some patients of epithelial ovarian cancer (EOC). Although careful patient selection is essential, there are currently no biomarkers available for routine therapeutic usage. To the authors' best knowledge, this is the first automated precision oncology framework to effectively identify and select EOC and peritoneal serous papillary carcinoma (PSPC) patients with positive therapeutic effect. From March 2013 to January 2021, we have a database, containing four kinds of immunohistochemical tissue samples, including AIM2, c3, C5 and NLRP3, from patients diagnosed with EOC and PSPC and treated with bevacizumab in a hospital-based retrospective study. We developed a hybrid deep learning framework and weakly supervised deep learning models for each potential biomarker, and the experimental results show that the proposed model in combination with AIM2 achieves high accuracy 0.92, recall 0.97, F-measure 0.93 and AUC 0.97 for the first experiment (66% training and 34%testing) and high accuracy 0.86 ± 0.07, precision 0.9 ± 0.07, recall 0.85 ± 0.06, F-measure 0.87 ± 0.06 and AUC 0.91 ± 0.05 for the second experiment using five-fold cross validation, respectively. Both Kaplan-Meier PFS analysis and Cox proportional hazards model analysis further confirmed that the proposed AIM2-DL model is able to distinguish patients gaining positive therapeutic effects with low cancer recurrence from patients with disease progression after treatment (p < 0.005).

High-grade endometrial stromal sarcoma in cesarean section scar isthmocele - case report.

OBJECTIVE: Cesarean section scar defect isthmocele, the pouchlike defect in the anterior uterine wall of the prior cesarean site. No previous report of malignant neoplasm in the isthmocele have been published. We reported a case of High-grade endometrial stromal sarcoma in isthmocele. CASE REPORT: A 45-year-old patient with gravida 4, parity 2, two previous cesarean section presents of recurrent heavy vaginal bleeding. Curettage and hormone therapy were unsuccessful. She underwent hysteroscopic isthmoplasty. The pathology revealed high-grade sarcoma. Patient was referred to a tertiary medical center and she underwent total hysterectomy with bilateral salpingo-oophorectomy, aortic & pelvic LNs dissection. The final diagnosis was High-grade endometrial stromal sarcoma (HG-ESS) stage IA (pT1a N0) involving isthmocele. CONCLUSION: The presence of this rare tumor in the isthmocele is very interested. We stress the necessity for a high degree of suspicion to diagnose the malignancy in perimenopausal women with isthmocele and persisted abnormal uterine bleeding.

Histopathological whole slide image dataset for classification of treatment effectiveness to ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer death among women. Regardless of the development made in the past two decades in the surgery and chemotherapy of ovarian cancer, most of the advanced-stage patients are with recurrent cancer and die. The conventional treatment for ovarian cancer is to remove cancerous tissues using surgery followed by chemotherapy, however, patients with such treatment remain at great risk for tumor recurrence and progressive resistance. Nowadays, new treatment with molecular-targeted agents have become accessible. Bevacizumab as a monotherapy in combination with chemotherapy has been recently approved by FDA for the treatment of epithelial ovarian cancer (EOC). Prediction of therapeutic effects and individualization of therapeutic strategies are critical, but to the authors' best knowledge, there are no effective biomarkers that can be used to predict patient response to bevacizumab treatment for EOC and peritoneal serous papillary carcinoma (PSPC). This dataset helps researchers to explore and develop methods to predict the therapeutic effect of patients with EOC and PSPC to bevacizumab.

Vitamin D in gynecological diseases.

BACKGROUND: Most reproductive system studies suggest the protective effects of vitamin D, but vitamin D deficiency and insufficiency are growing global health issues. The present study investigates the association between vitamin D deficiency/insufficiency and gynecologic diseases to identify illness risks at different serum vitamin D levels in Taiwan. METHODS: A total of 7699 female adults aged ≥20 years with results for both serum vitamin D and gynecologic-associated diseases were drawn from the Taiwan MJ cohort. We analyzed the correlation between serum vitamin D levels and results from reproductive system evaluations, including history of dysmenorrhea, results of Pap smear, high-risk human papillomavirus (HPV) infection of the cervix, mammography, and ultrasound of breast and pelvis. RESULTS: Over 80% of participants showed vitamin D deficiency/insufficiency. Participants with abnormal Pap smear results, high-risk HPV infection, and history of dysmenorrhea showed significantly lower levels of serum vitamin D (p < 0.001-0.05). Serum vitamin D deficiency was significantly associated with positive high-risk HPV infection of the cervix (p < 0.05) and dysmenorrhea (p < 0.001). After controlling for age as a confounding variable for each gynecologic disease, level of serum vitamin D was significantly associated with abnormal breast ultrasound (odds ratio = 0.724) and uterus ultrasound (odds ratio = 0.673 - 0.8), and dysmenorrhea (odds ratio = 0.829). CONCLUSION: Associations were found between vitamin D deficiency and endometriosis, uterine myoma, dysmenorrhea, abnormal Pap smear results, and high-risk HPV infection of the cervix. Therefore, vitamin D supplements may present a cost-effective benefit for the prevention and treatment of gynecologic diseases, and thus reduction of healthcare expenditures.

Loss of ten-eleven translocation 1 (TET1) expression as a diagnostic and prognostic biomarker of endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynecological cancer. However, there is currently no routinely used biomarker for differential diagnosis of malignant and premalignant endometrial lesions. Ten-eleven translocation (TET) proteins, especially TET1, were found to play a significant role in DNA demethylation, via conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1, 5-mC, and 5-hmC expression profiles in endometrial carcinogenesis are currently unclear. We conducted a hospital-based retrospective review of the immunohistochemical expression of TET1, 5-mC, and 5-hmC in 181 endometrial samples. A "high" TET1 and 5-hmC expression score was observed in all cases of normal endometrium (100.0% and 100.0%, respectively) and in most samples of endometrial hyperplasia without atypia (90.9% and 78.8%, respectively) and atypical hyperplasia (90.6% and 93.8%, respectively), but a "high" score was found in only less than half of the EC samples (48.8% and 46.5%, respectively). The TET1 and 5-hmC expression scores were significantly higher in normal endometrium and premalignant endometrial lesions than in ECs (p < 0.001). A "high" 5-mC expression score was observed more frequently for ECs (81.4%) than for normal endometrium (40.0%), endometrial hyperplasia without atypia (51.5%), and atypical hyperplasia (53.1%) (p < 0.001). We also found that TET1 mRNA expression was lower in ECs compared to normal tissues (p = 0.0037). TET1 immunohistochemistry (IHC) scores were highly proportional to the TET1 mRNA levels and we summarize that the TET1 IHC scoring can be used for biomarker determinations. Most importantly, a higher TET1 score in EC cases was associated with a good overall survival (OS) rate, with a hazard ratio (HR) of 0.31 for death (95% confidence interval: 0.11-0.84). Our findings suggest that TET1, 5-mC, and 5-hmC expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. TET1 is also a potential prognostic marker for EC.

AIM2 Inflammasome in Tumor Cells as a Biomarker for Predicting the Treatment Response to Antiangiogenic Therapy in Epithelial Ovarian Cancer Patients.

Antiangiogenic therapy, such as bevacizumab (BEV), has improved progression-free survival (PFS) and overall survival (OS) in high-risk patients with epithelial ovarian cancer (EOC) according to several clinical trials. Clinically, no reliable molecular biomarker is available to predict the treatment response to antiangiogenic therapy. Immune-related proteins can indirectly contribute to angiogenesis by regulating stromal cells in the tumor microenvironment. This study was performed to search biomarkers for prediction of the BEV treatment response in EOC patients. We conducted a hospital-based retrospective study from March 2013 to May 2020. Tissues from 78 Taiwanese patients who were newly diagnosed with EOC and peritoneal serous papillary carcinoma (PSPC) and received BEV therapy were collected. We used immunohistochemistry (IHC) staining and analyzed the expression of these putative biomarkers (complement component 3 (C3), complement component 5 (C5), and absent in melanoma 2 (AIM2)) based on the staining area and intensity of the color reaction to predict BEV efficacy in EOC patients. The immunostaining scores of AIM2 were significantly higher in the BEV-resistant group (RG) than in the BEV-sensitive group (SG) (355.5 vs. 297.1, p < 0.001). A high level of AIM2 (mean value > 310) conferred worse PFS after treatment with BEV than a low level of AIM2 (13.58 vs. 19.36 months, adjusted hazard ratio (HR) = 4.44, 95% confidence interval (CI) = 2.01-9.80, p < 0.001). There were no significant differences in C3 (p = 0.077) or C5 (p = 0.326) regarding BEV efficacy. AIM2 inflammasome expression can be a histopathological biomarker to predict the antiangiogenic therapy benefit in EOC patients. The molecular mechanism requires further investigation.

A symptomatic near-term pregnant woman recovered from SARS-CoV-2 infection.

OBJECTIVE: Coronavirus-2019 (COVID-19) is a global health crisis. Although pregnant women are a vulnerable population during the infectious pandemics, extremely rare cases of pregnant women infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are described in Taiwan. We share our experience to manage a pregnant women with COVID-19 in the third trimester and subsequent delivery at term. CASE REPORT: A 43-year-old woman presented with sore throat, cough and rhinorrhea was diagnosed as laboratory-confirmed SARS-CoV-2 infection at the 35 gestational weeks (GW). During the hospitalization, the disease progressed with a need of oxygen supplement and prednisolone therapy. She was discharged uneventfully at 37 GW. Finally, she delivered a female baby with Apgar score of 8-9 points at 38 GW by cesarean section due to the deformity of pelvic cavity resulted from previous surgery for pelvic bone tumor. Both mother and her offspring (without SARS-CoV-2 infection) were discharged uneventfully. CONCLUSION: Our report adds the growing body of experience toward management of pregnant women with SARS-CoV-2 infection. Decision making of timing and method of delivery is regarding to individualized condition and hospital setting.

Artificial intelligence-assisted fast screening cervical high grade squamous intraepithelial lesion and squamous cell carcinoma diagnosis and treatment planning.

Every year cervical cancer affects more than 300,000 people, and on average one woman is diagnosed with cervical cancer every minute. Early diagnosis and classification of cervical lesions greatly boosts up the chance of successful treatments of patients, and automated diagnosis and classification of cervical lesions from Papanicolaou (Pap) smear images have become highly demanded. To the authors' best knowledge, this is the first study of fully automated cervical lesions analysis on whole slide images (WSIs) of conventional Pap smear samples. The presented deep learning-based cervical lesions diagnosis system is demonstrated to be able to detect high grade squamous intraepithelial lesions (HSILs) or higher (squamous cell carcinoma; SQCC), which usually immediately indicate patients must be referred to colposcopy, but also to rapidly process WSIs in seconds for practical clinical usage. We evaluate this framework at scale on a dataset of 143 whole slide images, and the proposed method achieves a high precision 0.93, recall 0.90, F-measure 0.88, and Jaccard index 0.84, showing that the proposed system is capable of segmenting HSILs or higher (SQCC) with high precision and reaches sensitivity comparable to the referenced standard produced by pathologists. Based on Fisher's Least Significant Difference (LSD) test (P < 0.0001), the proposed method performs significantly better than the two state-of-the-art benchmark methods (U-Net and SegNet) in precision, F-Measure, Jaccard index. For the run time analysis, the proposed method takes only 210 seconds to process a WSI and is 20 times faster than U-Net and 19 times faster than SegNet, respectively. In summary, the proposed method is demonstrated to be able to both detect HSILs or higher (SQCC), which indicate patients for further treatments, including colposcopy and surgery to remove the lesion, and rapidly processing WSIs in seconds for practical clinical usages.

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

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

Dysregulated Immunological Functionome and Dysfunctional Metabolic Pathway Recognized for the Pathogenesis of Borderline Ovarian Tumors by Integrative Polygenic Analytics.

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.

Herlyn-Werner-Wünderlich syndrome: An unusual case with presentation of menorrhagia.

OBJECTIVE: Herlyn-Werner-Wünderlich (HWW) syndrome is a rare condition in which patients present with a palpable pelvic mass and pain caused by an obstructed hemivagina. Here we present a case of HWW syndrome characterized by prolonged menstrual bleeding. CASE REPORT: A 19-year-old nonsexually active unmarried women experienced irregular menstrual cycles and menorrhagia. The duration of menstrual bleeding was 10-14 days. She also suffered from mild dysmenorrhea since menarche at the age of 13. Transabdominal sonography revealed a double uterus and a heterogeneous myoma-mimicking mass over the left cervical region. The left kidney was absent. Magnetic resonance imaging revealed a double uterus, a double vagina with an unperforated left hemivagina, and ipsilateral renal agenesis. The patient underwent cervicovaginal orifice reconstruction surgery. CONCLUSION: Left hematocolpos compression, a partially obstructed right vaginal channel, and an orifice with local venous drainage abnormalities resulted in prolonged menstrual bleeding. In HWW syndrome, the occurrence of a pelvic mass and pain is common; however, prolonged menstrual bleeding is rare.

Using Deep Learning with Convolutional Neural Network Approach to Identify the Invasion Depth of Endometrial Cancer in Myometrium Using MR Images: A Pilot Study.

Myometrial invasion affects the prognosis of endometrial cancer. However, discrepancies exist between pre-operative magnetic resonance imaging staging and post-operative pathological staging. This study aims to validate the accuracy of artificial intelligence (AI) for detecting the depth of myometrial invasion using a deep learning technique on magnetic resonance images. We obtained 4896 contrast-enhanced T1-weighted images (T1w) and T2-weighted images (T2w) from 72 patients who were diagnosed with surgico-pathological stage I endometrial carcinoma. We used the images from 24 patients (33.3%) to train the AI. The images from the remaining 48 patients (66.7%) were used to evaluate the accuracy of the model. The AI then interpreted each of the cases and sorted them into stage IA or IB. Compared with the accuracy rate of radiologists' diagnoses (77.8%), the accuracy rate of AI interpretation in contrast-enhanced T1w was higher (79.2%), whereas that in T2w was lower (70.8%). The diagnostic accuracy was not significantly different between radiologists and AI for both T1w and T2w. However, AI was more likely to provide incorrect interpretations in patients with coexisting benign leiomyomas or polypoid tumors. Currently, the ability of this AI technology to make an accurate diagnosis has limitations. However, in hospitals with limited resources, AI may be able to assist in reading magnetic resonance images. We believe that AI has the potential to assist radiologists or serve as a reasonable alternative for pre-operative evaluation of the myometrial invasion depth of stage I endometrial cancers.

Plasma Level of Circular RNA hsa_circ_0000190 Correlates with Tumor Progression and Poor Treatment Response in Advanced Lung Cancers.

Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines' transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size (p < 0.0001), worse histological type of adenocarcinoma (p = 0.0028), later stage (p < 0.0001), more distant metastatic organs (p = 0.0039), extrathoracic metastasis (p = 0.0004), and poor survival (p = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level (p < 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor (p = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy (p = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.

The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis.

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients' survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

The recent progress and therapy in endometriosis-associated ovarian cancer.

Endometriosis-associated ovarian cancers (EAOCs) including endometrioid and clear cell ovarian carcinoma are subgroups of epithelial ovarian carcinomas (EOCs), which is generally acknowledged as the most lethal gynecological malignancy. Endometriosis (ES), a common clinical disease among women, presents with clinical symptoms of pelvic pain, infertility, or adnexal masses with the formation of endometrioma. It has long been considered to be a potential risk factor for developing EOCs, mainly of endometrioid and clear cell subtypes. Here, we compiled data from previous researches on deregulated molecular functions among ES and EOCs using gene set-based integrative analysis to decipher molecular and genetic relationships between ovarian ES and EOCs, especially EAOCs. We conclude that epidermal growth factor receptor (ERBB) and Phosphoinositide 3-kinases (PI3K)-related pathways are important in the carcinogenesis of type I EOCs, including clear cell, endometrioid, and mucinous ovarian carcinoma. Dysfunctional molecular pathways, such as deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response, and cell-cell signaling, played key roles in the malignant transformation of EAOCs. Nine genes related to inflammasome complex and inflammasome-related pathway were identified, indicating the importance of inflammation/immunity in EAOC transformation. We also collect progressive treatments of EAOC focused on targeted therapies and immunotherapy so far. This summarized information can contribute toward effective detection and treatment of EAOCs in the future.

Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer.

DNA methylation alteration, such as global hypomethylation and localized hypermethylation, within the promoters of tumor suppressor genes, is an important risk factor in cervical cancer. The potential use of DNA methylation detection, in cervical cancer screening or triage of mildly abnormal cytology, has recently been demonstrated. In particular, PAX1 DNA methylation testing was approved as an adjunct to cytology, in Taiwan, and is now undergoing registration trials in China. However, the function of PAX1 in cancer biology remains largely unknown. Here, we show that PAX1 inhibits malignant phenotypes upon oncogenic stress. Specifically, PAX1 expression inhibited the phosphorylation of multiple kinases, after challenges with oncogenic growth factors such as EGF and IL-6. Analogously, PAX1 activated a panel of phosphatases, including DUSP1, 5, and 6, and inhibited EGF/MAPK signaling. PAX1 also interacted with SET1B, increasing histone H3K4 methylation and DNA demethylation of numerous phosphatase-encoding genes. Furthermore, hypermethylated PAX1 associated with poor prognosis in cervical cancer. Taken together, this study reveals, for the first time, the functional relevance of PAX1 in cancer biology, and further supports the prospect of targeting multifold oncogenic kinase cascades, which jointly contribute to multiresistance, via epigenetic reactivation of PAX1.

Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells.

p21, an inhibitor of cyclin-dependent kinase, functions as an oncogene or tumor suppressor depending on the context of a variety of extracellular and intracellular signals. The expression of p21 could be regulated at the transcriptional and/or post-translational levels. The p21 gene is well-known to be regulated in both p53-dependent and -independent manners. However, the detailed regulatory mechanisms of p21 messenger RNA and protein expression via statins remain unknown, and the possible application of statins as anticancer reagents remains to be controversial. Our data showed that the statins-fluvastatin and lovastatin-induced p21 expression as general histone deacetylase inhibitors in a p53-independent manner, which is mediated through various pathways, such as apoptosis, autophagy, cell cycle progression, and DNA damage, to be involved in the function of p21 in HeLa cells. The curative effect repositioning of digoxin, a cardiovascular medication, was combined with fluvastatin and lovastatin, and the results further implied that p21 induction is involved in a p53-dependent and p53-independent manner. Digoxin modified the effects of statins on ATF3, p21, p53, and cyclin D1 expression, while fluvastatin boosted its DNA damage effect and lovastatin impeded its DNA damage effect. Fluvastatin and lovastatin combined with digoxin further support the localization specificity of their interactivity with our subcellular localization data. This study will not only clarify the regulatory mechanisms of p21 induction by statins but will also shed light on the repurposing of widely cardiovascular medications for the treatment of cervical cancer.

Outcomes of hypogastric artery ligation and transcatheter uterine artery embolization in women with postpartum hemorrhage.

OBJECTIVE: This study aimed to report our experience of emergent bilateral hypogastric (internal iliac) artery ligation (HAL) in the management of intractable postpartum hemorrhage (PPH) in a tertiary care center. MATERIALS AND METHODS: Patients with severe postpartum hemorrhage that could not be controlled with conservative management were retrospectively reviewed from January 2013 to December 2017. Data were retrieved from patients' hospital records. Two cases involving both transcatheter uterine artery embolization (TAE) and HAL were excluded. A total of 40 patients were included in the analysis during this period. The inclusion criteria were gestational age ≥24 weeks and primary severe PPH (blood loss ≥1500 mL within 24 h after birth). RESULTS: A total of 40 patients with intractable PPH were included after a thorough review of their medical records. Nine of them required HAL during the study period. Causes of PPH included uterine atony, placental abruption, vaginal/cervical laceration, uterine rupture, and placenta accreta. Hemorrhage was effectively controlled in 8 of 9 patients (88.9%) in the group undergoing bilateral HAL even though their initial conditions were poor. All patients with HAL did not have to undergo hysterectomy. No immediate complications developed. There were two maternal deaths in the group undergoing TAE. CONCLUSION: Bilateral HAL is an effective life-saving procedure for severe intractable PPH and should be performed as soon as possible when obstetric emergency conditions are indicated.