Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-ß2 signaling.

BACKGROUND: Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. METHODS: Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. RESULTS: Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin ß3 and integrin ß5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1ß, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-ß2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. CONCLUSIONS: Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.

A Cationic Amphipathic Tilapia Piscidin 4 Peptide-Based Antimicrobial Formulation Promotes Eradication of Bacterial Vaginosis-Associated Bacterial Biofilms.

Bacterial vaginosis (BV) is prevalent among women of reproductive age and has a high rate of recurrence, which can be largely attributed to ineffective BV biofilm eradication by current first-line antibiotics. In this study, we report that the Nile tilapia piscidin 4 (TP4) exhibits broad-spectrum antimicrobial and antibiofilm activity against BV-associated bacteria, but not beneficial lactobacilli. In addition, BV-associated Gardnerella vaginalis remains susceptible to TP4 even after continual exposure to the peptide for up to 22 passages. Gardnerella vaginalis and Streptococcus anginosus are both biofilm-forming BV-associated bacteria, and we found that combining TP4 peptide and disodium EDTA with the biofilm-disrupting agent, chitosan, can eradicate biofilms formed by single or mixed G. vaginalis and S. anginosus. In addition, long-term storage of TP4 peptide in chitosan did not diminish its bactericidal activity toward G. vaginalis. Preformulation studies were performed using High performance liquid chromatography (HPLC) and Circular Dichroism (CD). The long-term stability of TP4 peptide was assessed under various conditions, such as different temperatures and ionic strengths, and in the presence of H2O2 and lactic acid. When exposed to sodium dodecyl sulfate (SDS), TP4 maintained its secondary structure at various temperatures, salt and disodium EDTA concentrations. Furthermore, the TP4 microbicide formulation significantly reduced the colonization density of BV-associated bacteria in mice infected with single or mixed bacteria (G. vaginalis and S. anginosus). The TP4 microbicide formulation showed biocompatibility with beneficial human vaginal lactobacilli and female reproductive tissues in C57BL/6 mice. These results suggest that the TP4 microbicide formulation could be a promising topical microbicide agent for BV treatment.

Changes in Depression and Sleep Quality and Associated Factors in Women Receiving Chemotherapy for Ovarian Cancer: An Observational Study.

BACKGROUND: Although women with ovarian cancer experience depression and poor sleep quality, little is known about how various factors, particularly self-efficacy, might be associated with these conditions. OBJECTIVES: The aim of this study was to examine the prevalence of and changes in depression and sleep quality and the factors associated with these conditions in a cohort of women with ovarian cancer before, during, and after chemotherapy. METHODS: A prospective repeated-measures design was adopted in this study. Participants were women with ovarian cancer who were expected to receive 4 to 6 cycles of chemotherapy and were recruited at a medical center in Taiwan. The participants were asked to complete a questionnaire that included the Symptom Distress Scale, Center for Epidemiologic Studies Depression Scale, General Self-efficacy Scale, and Pittsburgh Sleep Quality Index. The data were collected before, during, and after the course of chemotherapy. RESULTS: Overall, 24.6% to 36.9% of women were at risk for depression; 75.4% to 80.0% of women had poor sleep quality. There were no significant changes in depressive symptoms and sleep quality throughout the course of chemotherapy. More severe depressive symptoms were associated with higher levels of symptom distress and lower self-efficacy. Poorer sleep quality was associated with higher levels of symptom distress. CONCLUSIONS: Among participants, more depressive symptoms and poorer sleep quality were associated with higher levels of symptom distress or lower self-efficacy. IMPLICATIONS FOR PRACTICE: Healthcare providers should continuously assess depression and sleep quality in women with ovarian cancer. These symptoms may be improved by strengthening self-efficacy and relieving symptom distress.

Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy.

PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. PBX1 is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies. Cancer cells with elevated PBX1 signaling are particularly vulnerable to PBX1 withdrawal. We designed a series of small molecule compounds capable of docking to the interface between PBX1 and its cognate DNA target sequence. Among them, T417 is found to be a lead compound. In cell-based assays, T417 significantly suppressed self-renewal and proliferation of cancer cells expressing high levels of PBX1. T417 also re-sensitized platinum-resistant ovarian tumors to carboplatin. T417 did not affect healthy tissues likely due to their lower PBX1 expression levels. Therefore, targeting PBX-DNA interface can be a promising strategy for treating human tumors reliant on PBX1 for survival.

Synergistic therapeutic effect of low-dose bevacizumab with cisplatin-based chemotherapy for advanced or recurrent cervical cancer.

BACKGROUND: Cisplatin-based chemotherapy (CBC) is highly efficacious for advanced cervical cancer; its efficacy can be enhanced by combining with 15 mg/kg (standard dose) bevacizumab (BEV). However, this standard dose is associated with various adverse events (AEs). Therefore, in this retrospective study, we analyzed the survival outcomes and AEs in patients with advanced or recurrent cervical cancer treated with CBC in combination with BEV 7.5 mg/kg. METHODS: Registered patient data were retrieved between October 2014 and September 2019, and 64 patients with advanced or recurrent cervical cancer treated with CBC + BEV (n = 21) or CBC alone (n = 43) were analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were the frequency and severity of AEs. The Cox proportional-hazards model was applied to explore prognostic factors associated with PFS and OS. RESULTS: The 1-, 2-, and 3-year PFS rates (95% CI) were 36.24% (22.0-50.5), 20.7% (9.8-34.2), and 17.7% (7.7-31.1) for the CBC group; and 71.4% (47.1-86.0), 51.0% (27.9-70.1), and 51.0% (27.9-70.1) for the CBC + BEV group, respectively. The 1-, 2-, and 3-year OS rates were 62.6% (46.4-75.18), 32.4% (18.8-46.9), and 23.2% (11.2-37.6) for the CBC group; and 85.7% (61.9-95.1), 66.6% (42.5-82.5), and 55.5% (27.1-76.7) for the CBC + BEV group, respectively. The CBC + BEV group presented higher PFS and OS rates, p = 0.003 and p = 0.005, respectively. Proteinuria (6 vs 9, p = 0.025) and hypertension (0 vs 10, p < 0.001) were less common, but anemia was more common in the CBC group (35 vs 11, p = 0.021). CONCLUSION: Overall, CBC + BEV significantly improved the PFS and OS compared with CBC alone. CBC + BEV also prevents severe AEs and hence is an efficacious and safe therapeutic option.

Factors related to changes in resilience and distress in women with endometrial cancer.

The purpose of the study is to explore changes in resilience and physical and psychological distress and their related factors over time in women with endometrial cancer. This study adopted a repeated measures design using purposive sampling and was conducted in a hospital in Taiwan. Data were collected before surgery, 2 weeks after surgery, and 3 months after surgery. The measured variables consisted of demographic and disease characteristics, social support, resilience, and physical and psychological distress. A total of 48 women participated in the study, of whom 42 (mean age = 54.2 years old) completed all of the questionnaires. The results showed that resilience and physical distress in women with endometrial cancer was not statistically significantly changed over time. Rather, their psychological distress was significantly alleviated 2 weeks and 3 months after surgery as compared to before surgery. Women with less social support showed a lower level of resilience. In addition, those with a lower level of resilience experienced greater psychological distress. Compared with those who received only surgical treatment, women who had undergone surgery combined with chemotherapy and radiotherapy had more physical distress. Clinical medical staff should conduct continuing assessments of the resilience, physical distress, and psychological distress of women with endometrial cancer. Interventions related to resilience-enhancing and self-care should be implemented to avoid worsening or to improve women's resilience and distress.

Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers.

Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.

Evaluation of a Simple and Safe Tumor Drilling Technique to Potentiate the Effect of Intraperitoneal Chemotherapy in the Treatment of Recurrent Epithelial Ovarian, Tubal, and Peritoneal Cancer: A Matched Retrospective Cohort Study.

Frontline intraperitoneal chemotherapy (IPCT) in the treatment of epithelial ovarian cancer has been well established. However, the role of second-line IPCT is yet to be confirmed. With a view to implementing IPCT to treat recurrent disease, a prerequisite is to perform a cytoreductive procedure to minimize residual tumor size. However, the role of cytoreductive procedure is still in debate due to a higher chance of complications. A matched retrospective cohort study was conducted. From 2008 to 2015, we adopted a relatively simple and safe tumor drilling technique to maximize tumor exposure to second-line IPCT. Patients who received tumor drilling followed by second-line IPCT constituted the cohort group. Concurrently, patients who received standard second-line systemic chemotherapy were selected as the comparison group. After propensity score matching, 85 patients in each group entered into the final analysis. The median progression-free survival was 7.3 months (95% confidence interval [CI], 6.2-7.8) for the cohort group versus 4.1 months (95% CI, 4.0-4.3) for the comparison group (hazard ratio = 0.25 [95% CI, 0.17-0.36]; P < .001, by log-rank test). The median overall survival was 33.6 months (32.1-36.6) for the cohort group versus 25.9 months (20.5-26.9) for the comparison group (hazard ratio = 0.33 [95% CI, 0.23-0.48]; P < .001, by log-rank test). Toxicities in the cohort group were not different from those that were published in reports of IPCT for ovarian cancer. The most commonly observed toxicity was gastrointestinal origin (51.7%), and it may be attributed to the intraperitoneal pharmacokinetic clearance of cisplatin and taxol and we also discussed the mechanism of gastrointestinal toxicity. Tumor drilling followed by second-line IPCT may confer a survival advantage over standard second-line systemic chemotherapy in the treatment of recurrent ovarian cancer.

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors.

BACKGROUND: Liposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions. RESULTS: The T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response. CONCLUSION: This phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial. TRIAL REGISTRATION: Taiwan FDA MA1101G0 (Jan 31, 2012).

Epinecidin-1: A marine fish antimicrobial peptide with therapeutic potential against Trichomonas vaginalis infection in mice.

Trichomoniasis is caused by infection with the protozoan parasite Trichomonas vaginalis, and prolonged persistence may lead to serious ill effects in patients. Thus, the development of new therapeutic strategies to combat drug-resistant T. vaginalis would be clinically beneficial. Antimicrobial peptides (AMPs) comprise an emerging class of molecules that may serve as effective alternatives to antibiotics. In this report, we demonstrate that the synthetic fish AMP, Epinecidin-1 (Epi-1), acts against T. vaginalis both in vitro and in vivo. Under in vitro conditions, Epi-1 disrupted the membrane of metronidazole-resistant T. vaginalis and completely killed the pathogen. To mimic human infection in vivo, estradiol-stimulated mice with vaginal Lactobacillus acidophilus colonization were infected with T. vaginalis, followed by treatment with Epi-1, Vigill, metronidazole or furazolidone. After seven days, the T. vaginalis content was effectively decreased in Epi-1 treated mice, as measured by acridine orange staining of wet smears and tissue biopsies, as well as qPCR of vaginal discharge DNA. Taken together, our results demonstrate that Epi-1 is a strong candidate for development as an alternative therapeutic for T. vaginalis infection.

Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma with fetal gut differentiation: a rare case report and literature review.

BACKGROUND: Alpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed. CASE PRESENTATION: We report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review. CONCLUSIONS: A total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Neurofibroma involving obturator nerve mimicking an adnexal mass: a rare case report and PRISMA-driven systematic review.

BACKGROUND: Pelvic masses are a common gynecologic problem, and majority of them are diagnosed as ovarian tumors finally. Sometimes, it is hard to distinguish the origin of these pelvic masses. The following case is a solitary neurofibroma arising from the right-side obturator nerve, which was impressed as a right-side ovarian tumor initially. We reported this case, and also performed a PRISMA-driven systematic review to summary the similar cases in the literature. This review includes image, molecular and pathological findings and outcome of neurofibroma. CASE PRESENTATION: A 33-year-old woman with a regular menstrual period denied any symptoms or signs. During her physical check-up, image examination revealed a right-side heterogeneous pelvic mass; it was suggestive of a complex of right-side ovarian tumor. A provisional diagnosis of retroperitoneal pelvic mass, probably a benign ovarian tumor, was made. Excision of the right-side pelvic mass was performed. We sent the specimens for frozen pathology, which indicated neurofibroma and lipomatous tumor and that the possibility of liposarcoma cannot be excluded. A segment of the obturator nerve was attached to the tumor and was severed. A right-side obturator nerve tear during tumor excision was observed, and a neurosurgeon was consulted for obturator nerve grafting and repair. The patient complained of mild weakness and paresthesia affecting the right leg, and we consulted a rehabilitation doctor for neuron injury. The patient's recovery was uneventful, and she was discharged eight days after the drain was removed. Further rehabilitation treatment was arranged. CONCLUSION: A neurofibroma is an uncommon pelvic retroperitoneal tumor, and it can be misdiagnosed as an adnexal mass. To our knowledge, this is a rare case of a solitary neurofibroma arising from the obturator nerve. It usually does not have any neurological deficit. We present this case to demonstrate that pelvic neurofibroma can be mistaken for an adnexal mass. This fact should be borne in mind during the diagnosis process.

Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis.

The clinical characteristics of clear cell carcinoma (CCC) and endometrioid carcinoma EC) are concomitant with endometriosis (ES), which leads to the postulation of malignant transformation of ES to endometriosis-associated ovarian carcinoma (EAOC). Different deregulated functional areas were proposed accounting for the pathogenesis of EAOC transformation, and there is still a lack of a data-driven analysis with the accumulated experimental data in publicly-available databases to incorporate the deregulated functions involved in the malignant transformation of EOAC. We used the microarray gene expression datasets of ES, CCC and EC downloaded from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database. Then, we investigated the pathogenesis of EAOC by a data-driven, function-based analytic model with the quantified molecular functions defined by 1454 Gene Ontology (GO) term gene sets. This model converts the gene expression profiles to the functionome consisting of 1454 quantified GO functions, and then, the key functions involving the malignant transformation of EOAC can be extracted by a series of filters. Our results demonstrate that the deregulated oxidoreductase activity, metabolism, hormone activity, inflammatory response, innate immune response and cell-cell signaling play the key roles in the malignant transformation of EAOC. These results provide the evidence supporting the specific molecular pathways involved in the malignant transformation of EAOC.

The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

An important role of genetic factors in the development of breast cancer (BC) or ovarian cancer (OC) in Taiwanese (ethnic Chinese) patients has been suggested. However, other than germline BRCA1 or BRCA2 mutations, which are related to hereditary breast-ovarian cancer (HBOC), cancer-predisposition genes have not been well studied in this population. The aim of the present study was to more accurately summarize the prevalence of genetic mutations in HBOC patients using various gene panels ranging in size from BRCA1/2 alone to multi-gene panels. Among 272 HBOC patients analyzed, the prevalence of BRCA1, BRCA2 and non-BRCA1/2 pathogenic mutations was 7.7% (21/272), 6.8% (16/236) and 8.2% (13/159), respectively. The total mutation rate was 18.4% (50/272). Although no founder mutations were identified in this study, two recurrent mutations, BRCA1 (c.3607C>T) and BRCA2 (c.5164_5165 delAG), were found. The main pathogenic/likely pathogenic mutations in non-BRCA1/2 genes included ATM, BRIP1, FANCI, MSH2, MUYTH, RAD50, RAD51C and TP53. The prevalence rate of gene mutations in HBOC patients did not differ with respect to whether BC or OC was the first diagnosis or they presented a family history of the disease or their age at diagnosis. HBOC patients with both BC and OC exhibited a higher prevalence rate of mutations (50.0%) than patients with OC (25.0%) or BC (8.6%) alone. In conclusion, evaluation of hereditary cancer risk in Taiwan HBOC patients, particularly individuals with double cancer, is strongly encouraged. Panel testing can yield additional genomic information, and widespread and well-designed panel testing will help in assessing more accurate mutational prevalence of risk genes.

188Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept.

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

Salvage intraperitoneal chemotherapy for relapsed type II endometrial cancer: A pilot case-control study.

OBJECTIVE: Epithelial ovarian cancer and relapsed type II endometrial cancer share common characteristics. Although the role of intraperitoneal (IP) chemotherapy in the treatment of epithelial ovarian cancer has been well-established, its role in the treatment of relapsed type II endometrial cancer remains to be elucidated. MATERIAL AND METHODS: From January 2000 to December 2012, patients who were diagnosed with relapsed type II endometrial cancer and underwent secondary cytoreductive surgery, patients with residual tumors less than 1 cm in diameter were initially screened for this study. Of the screened patients, consecutive patients who received salvage IP chemotherapy (IP platinum plus intravenous paclitaxel) were considered the case group. The case study group was matched to a control group that was composed of patients who received salvage systemic chemotherapy (intravenous platinum plus intravenous paclitaxel) in a 1:2 ratio. The overall survival was compared between the case group and the control group, and the IP treatment-related toxicities were reported. RESULTS: In total, 11 patients were assigned into the case group and 22 patients were assigned into the control group. The median overall survival (95% confidence interval) was 40.5 (25.5-56.2) months for the case group versus 28.0 (18.0-37.0) for the control group (hazard ratio=0.37 (95% confidence interval, 0.15-0.95); p=0.032, by the log-rank test). The most commonly observed toxicity was of gastrointestinal origin (81.8%). Toxicities that stemmed from hematological, cardiovascular, neurological, and catheter-related complications were similar to results published in other studies on IP chemotherapy for ovarian cancer. CONCLUSION: Salvage IP chemotherapy may potentially confer a longer overall survival than conventional systemic chemotherapy in the treatment of relapsed type II endometrial cancer.

Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.

Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

Gene Set-Based Functionome Analysis of Pathogenesis in Epithelial Ovarian Serous Carcinoma and the Molecular Features in Different FIGO Stages.

Serous carcinoma (SC) is the most common subtype of epithelial ovarian carcinoma and is divided into four stages by the Federation of Gynecologists and Obstetrics (FIGO) staging system. Currently, the molecular functions and biological processes of SC at different FIGO stages have not been quantified. Here, we conducted a whole-genome integrative analysis to investigate the functions of SC at different stages. The function, as defined by the GO term or canonical pathway gene set, was quantified by measuring the changes in the gene expressional order between cancerous and normal control states. The quantified function, i.e., the gene set regularity (GSR) index, was utilized to investigate the pathogenesis and functional regulation of SC at different FIGO stages. We showed that the informativeness of the GSR indices was sufficient for accurate pattern recognition and classification for machine learning. The function regularity presented by the GSR indices showed stepwise deterioration during SC progression from FIGO stage I to stage IV. The pathogenesis of SC was centered on cell cycle deregulation and accompanied with multiple functional aberrations as well as their interactions.