MicroRNAs (miRNA) are approximately 22-nucleotide noncoding RNAs that negatively regulate protein-coding gene expression in a sequence-specific manner via translational inhibition or mRNA ...degradation. Our recent studies showed that miRNAs exhibit genomic alterations at a high frequency and their expression is remarkably deregulated in ovarian cancer, strongly suggesting that miRNAs are involved in the initiation and progression of this disease. In the present study, we performed miRNA microarray to identify the miRNAs associated with chemotherapy response in ovarian cancer and found that let-7i expression was significantly reduced in chemotherapy-resistant patients (n = 69, P = 0.003). This result was further validated by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.015). Both loss-of-function (by synthetic let-7i inhibitor) and gain-of-function (by retroviral overexpression of let-7i) studies showed that reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum. Finally, using miRNA microarray, we found that decreased let-7i expression was significantly associated with the shorter progression-free survival of patients with late-stage ovarian cancer (n = 72, P = 0.042). This finding was further validated in the same sample set by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.001) and in an independent sample set by in situ hybridization (n = 53, P = 0.049). Taken together, our results strongly suggest that let-7i might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response and survival in patients with ovarian cancer.
Interim results from the two‐cohort, phase 2 KEYNOTE‐100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was ...associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4‐11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE‐100. Patients with epithelial ROC had received either 1‐3 prior chemotherapy lines and had platinum‐free interval or treatment‐free interval (PFI; TFI) of 3‐12 months (cohort A) or 4‐6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand‐1 (PD‐L1) tumor expression. The relationship between PD‐L1 expression (measured as combined positive score CPS) and ORR was assessed. Twenty‐one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37‐78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III‐IV disease. ORR was 19.0% (95% CI, 5.4‐41.9) and seemed to increase with increasing PD‐L1 expression. A total of 13 (61.9%) patients had treatment‐related adverse events (TRAE), and 5 (23.8%) had grade 3‐4 TRAE. There were no treatment‐related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD‐L1 expression among some patients with higher ORR.
This manuscript is a subgroup analysis of Japanese patients with advanced recurrent ovarian cancer (ROC) who were treated with pembrolizumab monotherapy from the KEYNOTE‐100 study. Pembrolizumab monotherapy was associated with antitumor activity in some Japanese patients with ROC, with no new safety signals identified in this subpopulation.
Study 309/KEYNOTE‐775 is a phase 3 open‐label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with ...progression after platinum‐based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression‐free survival (PFS) and overall survival (OS) in all‐comers (ie, regardless of mismatch repair MMR status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 QW 3 weeks on/1 week off). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow‐up, 11.8 range, 1.1–26.9 months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63–1.73) in patients with pMMR and 0.81 (0.50–1.31) in all‐comers. Hazard ratios for OS were 0.74 (0.41–1.34) with pMMR and 0.59 (0.33–1.04) for all‐comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE‐775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.
Study 309/KEYNOTE‐775 is a phase 3 open‐label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer with progression after platinum‐based therapy. We present results for the Japanese subset of this clinical trial. Similar to results from the global study, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.
We report the case of an adult woman who developed ovarian cancer during a follow-up for vestibular schwannoma. Volume reduction of the schwannoma was observed after chemotherapy for ovarian cancer. ...After ovarian cancer had been diagnosed, the patient was found to have a germline mutation of breast cancer susceptibility gene 1 (BRCA1). This is the first reported case of vestibular schwannoma in a patient with a germline mutation of BRCA1 and the first documented example of chemotherapy including olaparib to have shown efficacy for schwannoma.
One of the side effects of opioid administration is opioid-induced constipation (OIC). To address this side effect, the oral peripheral μ opioid receptor antagonist naldemedine was developed. As this ...drug does not cross the blood-brain barrier, it is thought that it does not lead to opioid withdrawal syndrome (OWS) with central nervous system symptoms.
Here, we report a cancer patient who presented with symptoms centered round anxiety and irritation 4 months after administration of naldemedine for OIC and who was diagnosed with OWS after close investigation.
The patient was a 65-year-old female who had surgery for stage IB endometrial cancer 4 years previously, but experienced recurrence involving the pelvis 2 years later. Medical narcotics were used to control pain, but naldemedine was started to control subsequent constipation. When naldemedine-related OWS was suspected and the administration of naldemedine discontinued, the above symptoms disappeared within two days, and no recurrence was observed thereafter.
For patients receiving naldemedine, it is necessary to consider the possibility of OWS regardless of the period of administration in order to maintain patient quality of life.
Ovarian cancer has the highest mortality among gynecological cancers. High-grade serous carcinoma (HGSC) is the most common histotype of ovarian cancer regardless of ethnicity, whereas clear cell ...carcinoma (CCC) is more common in East Asians than Caucasians. The elucidation of predominant signaling pathways in these cancers is the first step towards understanding their molecular mechanisms and developing their clinical management.
RNA sequencing was performed for 27 clinical ovarian specimens from Japanese women. Principal component analysis (PCA) was conducted on the sequence data mapped on RefSeq with normalized read counts, and functional annotation analysis was performed on genes with substantial weights in PCA. Knockdown experiments were conducted on the selected genes on the basis of PCA.
Functional annotation analysis of PCA-defined genes showed predominant pathways, such as cell growth regulators and blood coagulators in CCC and transcription regulators in HGSC. Knockdown experiments showed that the inhibition of the calcium-dependent protein copine 8 (CPNE8) and the transcription factor basic helix-loop-helix family member e 41 (BHLHE41) repressed the proliferation of CCC- and HGSC-derived cells, respectively.
This study identified
and
as characteristic genes for CCC and HGSC, respectively. The systemic identification of differentially expressed genes in CCC and HGSC will provide useful information to understand transcriptomic differences in these ovarian cancers and to further develop potential diagnostic and therapeutic options for advanced disease.
Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public ...RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript
in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing
exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of
fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that
-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the
fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript.
Tumor growth results in hypoxia. Understanding the mechanisms of gene expression reprogramming under hypoxia may provide important clues to cancer pathogenesis. We studied miRNA genes that are ...regulated by hypoxia in ovarian cancer cell lines by TaqMan miRNA assay containing 157 mature miRNAs. MiR-210 was the most prominent miRNA consistently stimulated under hypoxic conditions. We provide evidence for the involvement of the HIF signaling pathway in miR-210 regulation. Biocomputational analysis and in vitro assays demonstrated that e2f transcription factor 3 (e2f3), a key protein in cell cycle, is regulated by miR-210. E2F3 was further confirmed to be downregulated at the protein level upon induction of miR-210. Importantly, we found remarkably high frequency of miR-210 gene copy deletions in ovarian cancer patients (64%, n=114) and that gene copy number correlates with miR-210 expression levels. Taken together, our results indicate that miR-210 plays a crucial role in tumor onset as a key regulator of the hypoxia response and provide evidence for a link between hypoxia and the regulation of cell cycle.
Thoracic endovascular aortic repair (TEVAR) is expected to be minimally invasive, especially in older patients. However, clinical results of TEVAR in octogenarians including medical costs are ...limited. Between 2010 and 2016, a total of 57 patients over 80 years of age (mean age 84.1 ± 3.4 years) underwent TEVAR at our hospital. The proximal landing zone (PLZ) was zone 0 in 7 patients (12.3%), zone 1 in 10 patients (17.5%), zone 2 in 9 patients (15.8%), zone 3 in 13 patients (22.8%), and zone 4 in 18 patients (31.6%). The mean follow-up time was 23 ± 19 months (range 1–71 months). The follow-up rate was 96.5%. The hospital mortality rate was 1.8%. Stroke occurred in three patients (zone 0: 2, zone 3: 1, 5.3%). The mean hospital stay was 21.8 ± 21.4 days (range 5–98 days), and the rate of being discharged home was 84.2%. The 1-year and 3-year survival rates were 76.1% and 55.1% and the 1-year and 3-year re-intervention-free rates of the thoracic aorta were 97.6% and 94.5%, respectively. The mean total cost by the time of hospital discharge was ¥5,360,000 ± 2,360,000. The clinical results of TEVAR in patients over 80 years of age are acceptable with early postoperative recovery, low mortality and morbidity, and midterm durability.
Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo ...administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC).
The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed ( https://portal.gdc.cancer.gov/ ). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant.
In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ
test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307).
In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.
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