Publications by authors named "Kosei Hasegawa"

157 Publications

Visualization of Intratumor Pharmacokinetics of [fam-] Trastuzumab Deruxtecan (DS-8201a) in HER2 Heterogeneous Model Using Phosphor-integrated Dots Imaging Analysis.

Clin Cancer Res 2021 May 12. Epub 2021 May 12.

Division of Molecular Pharmacology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Purpose: We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody-drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism.

Experimental Design: We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, and (ii) a homogeneous model in which both cell types were transplanted separately into the same mouse. PID imaging involved immunostaining using novel high-intensity fluorescent nanoparticles. The distribution of T-DXd was assessed by PID imaging targeting the parent antibody, trastuzumab, and the payload, DXd, in serial frozen sections, respectively.

Results: After T-DXd administration in the heterogeneous model, HER2 expression tended to decrease in a time-dependent manner. The distribution of trastuzumab and DXd was observed by PID imaging along the HER2-positive area throughout the observation period. A detailed comparison of the PID distribution between trastuzumab and DXd showed that trastuzumab matched almost perfectly with the HER2-positive area. In contrast, DXd exhibited widespread distribution in the surrounding HER2-negative area as well. In the HER2-negative tumor of the homogeneous model, the PID distribution of trastuzumab and DXd remained extremely low throughout the observation period.

Conclusions: Our results suggest that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then to adjacent HER2-negative areas. We successfully visualized the intratumor distribution of T-DXd and its mechanism of action, the so-called "bystander effect."
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0397DOI Listing
May 2021

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands.

Mol Genet Genomic Med 2021 May 3:e1675. Epub 2021 May 3.

Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: Osteogenesis imperfecta (OI) is a rare connective-tissue disorder characterized by bone fragility. Approximately 90% of all OI cases are caused by variants in COL1A1 or COL1A2. Additionally, IFITM5 variants are responsible for the unique OI type 5. We previously analyzed COL1A1/2 variants in 22 Japanese families with OI through denaturing high-performance liquid chromatography screening, but our detection rate was low (41%).

Methods: To expand the genotype-phenotype correlations, we performed a genetic analysis of COL1A1/2 and IFITM5 in 96 non-consanguineous Japanese OI probands by Sanger sequencing.

Results: Of these individuals, 54, 41, and 1 had type 1 (mild), type 2-4 (moderate-to-severe), and type 5 phenotypes, respectively. In the mild group, COL1A1 nonsense and splice-site variants were prevalent (n = 30 and 20, respectively), but there were also COL1A1 and COL1A2 triple-helical glycine substitutions (n = 2 and 1, respectively). In the moderate-to-severe group, although COL1A1 and COL1A2 glycine substitutions were common (n = 14 and 18, respectively), other variants were also detected. The single case of type 5 had the characteristic c.-14C>T variant in IFITM5.

Conclusion: These results increase our previous detection rate for COL1A1/2 variants to 99% and provide insight into the genotype-phenotype correlations in OI.
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http://dx.doi.org/10.1002/mgg3.1675DOI Listing
May 2021

Up-regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients With Advanced Ovarian High-grade Serous Carcinoma.

Anticancer Res 2021 Mar;41(3):1647-1654

Department of Pathology, Saitama Medical University International Medical Center, Saitama, Japan;

Background: Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. Our previous study on ovarian clear-cell carcinoma found histone deacetylase 6 (HDAC6) overexpression led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and a therapeutic target for ovarian HGSC.

Patients And Methods: The clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC was immunohistochemically evaluated. In addition, expression of programmed cell death ligand-1 (PD-L1), and hypoxia-inducible factor-1α (HIF1α) were analyzed using clinical samples from 88 patients with ovarian HGSC, and their clinicopathological characteristics were reviewed.

Results: Twenty-three patients had high HDAC6 expression, 10 positive PD-L1 expression, and 33 high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p<0.001), incomplete surgical resection (p=0.002), and frequent occurrence of stable disease/progressive disease according to the Response Evaluation Criteria in Solid Tumors (p=0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with reduced progression-free (p=0.001) and overall (p=0.008) survival. On multivariate analysis, high HDAC6 expression (hazard ratio=1.65, 95% confidence interval 1.03-2.66; p=0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF1α expression positively correlated with that of HDAC6.

Conclusion: HDAC6 may become a potential therapeutic target in patients with ovarian HGSC since its up-regulation is considered to be associated with a poor prognosis in patients with this cancer.
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http://dx.doi.org/10.21873/anticanres.14927DOI Listing
March 2021

Transcriptomic analysis of hormone-sensitive patient-derived endometrial cancer spheroid culture defines Efp as a proliferation modulator.

Biochem Biophys Res Commun 2021 Apr 26;548:204-210. Epub 2021 Feb 26.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, 350-1241, Japan; Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, 173-0015, Japan. Electronic address:

Estrogen-responsive endometrial cancer (EC) is prevalent in uterine cancer. Its precise molecular mechanisms remain to be elucidated partly because of limited availability of estrogen-sensitive EC models recapitulating clinical pathophysiology. We previously established EC patient-derived cancer cell (EC-PDC) spheroid culture with high expression of estrogen receptor α (ERα). Using this EC-PDC, we study the transcriptional regulation and function of estrogen-responsive finger protein (Efp), a prototypic tripartite motif (TRIM) protein that modulates protein degradation and RNA processing. Intense estrogen-dependent EFP mRNA induction and high ERα occupancy to EFP estrogen responsive element (ERE) were observed in EC-PDC. Luciferase reporter gene assay showed that the ERE facilitates EFP transcriptional activity estrogen-dependently. siRNA-mediated Efp silencing in EC-PDC resulted in suppressed spheroid proliferation and altered gene expression profile, featuring downregulation of genes related to cell cycle (e.g., CDK6) and inflammation/immune responses (e.g., IL10RA, IL26, and IL6ST) while unaffected expression of cancer stemness-related markers. Taken together, EC-PDC spheroid culture is a powerful EC tool that enables to dissect Efp-mediated ERα signaling pathways as an estrogen-sensitive EC model. This study provides an insight into alternative EC therapeutic strategies targeting ERα-Efp axis.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.066DOI Listing
April 2021

Preclinical diagnosis and identification of the chimeric CYP11B1/CYP11B2 gene in two pediatric cases of a Japanese family with glucocorticoid-remediable aldosteronism.

Hypertens Res 2021 Mar 1. Epub 2021 Mar 1.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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http://dx.doi.org/10.1038/s41440-021-00633-1DOI Listing
March 2021

[Ⅰ. Secondary Cytoreductive Surgery for Platinum-Sensitive Recurrent Ovarian Cancer -Review and Consideration from Recent International Phase Ⅲ Trials].

Gan To Kagaku Ryoho 2021 Feb;48(2):191-194

Dept. of Gynecologic Oncology, Saitama Medical University International Medical Center.

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February 2021

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer.

J Gynecol Oncol 2021 Mar 6;32(2):e21. Epub 2021 Jan 6.

Department of Gynecology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Objective: The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting.

Methods: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs).

Results: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease).

Conclusion: The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib.

Trial Registration: ClinicalTrials.gov Identifier: NCT03759587.
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http://dx.doi.org/10.3802/jgo.2021.32.e21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930455PMC
March 2021

[Cancer Risk in Lynch Syndrome-Associated Endometrial Cancer Patients and Their Relatives].

Gan To Kagaku Ryoho 2020 Dec;47(13):2257-2259

Dept. of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University.

Endometrial cancer(EC)is often the sentinel cancer in women with Lynch syndrome(LS), but the actual incidence of EC as the sentinel cancer in patients with LS is not well-known in Japan. We investigated the history of malignancies and incidence of sentinel cancers in patients with LS-associated EC and their relatives. We examined 8 patients with LS-associated EC between 2005 and 2019. Five of them(63%)had suffered from a cancer other than EC, while 5(63%)had developed a cancer after EC. Seven patients(88%)had EC as the sentinel cancer, while 1(13%)developed colorectal cancer before EC. Among first-degree relatives(15 men and 23 women), 15(40%)had a history of cancer, of whom 7 were women (30%). Five women(22%)had EC, all sentinel. Among second-degree relatives(40 men, 44 women, 14 unknown), 16 (16%)had cancer. Four women(9%)had a history of cancer, of whom 2(5%)had EC, all sentinel. Although we only investigated a few LS cases, the importance of EC as the sentinel cancer was highlighted in Japanese women with LS.
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December 2020

Histopathological features of HER2 overexpression in uterine carcinosarcoma: proposal for requirements in HER2 testing for targeted therapy.

Virchows Arch 2021 Jun 9;478(6):1161-1171. Epub 2021 Jan 9.

Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Uterine carcinosarcoma (UCS) is an uncommon and highly aggressive tumor. There is no HER2 testing protocol for UCS despite the development of HER2 antibody conjugates. We aimed to elucidate histopathological HER2 expression details in UCS, to compare HER2 scores between ASCO/CAP criteria for gastric and breast cancer, and to propose requirements for HER2 testing for UCS. Eighty-nine specimens from 84 patients with metastatic/recurrent UCS were prospectively collected from May 2018 to July 2020. We performed HER2 immunohistochemistry (IHC) for 89 specimens and FISH for 44 specimens. HER2 expression details and HER2 score were evaluated according to the latest ASCO/CAP criteria for gastric (2016) and breast cancer (2018). HER2 IHC scores according to the gastric cancer criteria were 0 in 31 cases (35%), 1+ in 26 (29%), 2+ in 22 (25%), and 3+ in 10 cases (11%) of the 89 specimens. A lateral/basolateral membranous staining pattern was observed in 28/32 (88%) specimens with HER2 scores of 2+/3+. HER2 intratumoral heterogeneity was identified in 28/32 (88%) of the specimens with HER2 scores of 2+/3+. The overall concordance rate of HER2 score was 70% between the gastric and breast criteria. FISH revealed HER2 gene amplification in 10/44 (23%) specimens containing only lateral/basolateral membranous staining pattern. Based on the histopathological features of HER2 expression in UCS, a scoring system that accepts lateral/basolateral staining patterns should be applied. Furthermore, we proposed specific requirements for UCS testing, including specimen selection, scoring system, and calculating the proportion of HER2-positive cells.
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http://dx.doi.org/10.1007/s00428-021-03017-5DOI Listing
June 2021

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer.

J Gynecol Oncol 2021 Mar 10;32(2):e16. Epub 2020 Dec 10.

Department of Obstetrics and Gynecology, St. Mary Hospital, Fukuoka, Japan.

Objective: To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer.

Methods: This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs.

Results: Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%.

Conclusion: Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified.

Trial Registration: ClinicalTrials.gov Identifier: NCT03759600.
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http://dx.doi.org/10.3802/jgo.2021.32.e16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930437PMC
March 2021

Immunogenomic landscape of gynecologic carcinosarcoma.

Gynecol Oncol 2021 Feb 6;160(2):547-556. Epub 2020 Dec 6.

Project for Development of Innovative Research on Cancer Therapeutics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan. Electronic address:

Objective: Carcinosarcoma (CS) of the uterus or ovary is a rare, biphasic tumor comprising epithelial and mesenchymal elements, and exhibits more aggressive clinical features than its carcinoma counterpart. Four molecular subtypes of CS were recently established based on genomic aberration profiles (POLE, MSI, CNH, and CNL) and shown to be associated with multiple clinicopathological parameters, including patient outcomes. However, the role of the immune microenvironment in CS remains unclear. Here, we investigated the influence of the immune cells that infiltrate CS to better understand the immunological status of gynecological CS.

Methods: Tumor immune microenvironmental analyses on CS samples were performed using immune cell profiling with RNA-seq, transcriptomic subtyping with microenvironmental genes, and T-cell receptor repertoire assay. Carcinoma and sarcoma elements from CS samples were also assessed separately.

Results: Relying on estimations of tumor-infiltrating cell types from RNA-seq data, POLE and MSI (hypermutator) tumors showed an enrichment of M1 macrophages, plasma cells and CD8 T cells, whereas CNH and CNL (non-hypermutator) tumors had high levels of M2 macrophages. Further subclassification by immune-related, non-cancer genes identified a fraction of tumors with distinct patient outcomes, particularly those with the CNH genomic aberration subtype. T-cell heterogeneity was independently correlated with prolonged progression-free survival. Differential analysis of carcinoma and sarcoma elements identified many shared mutations but there was little overlap in the T-cell receptor repertoire between the two elements.

Conclusions: Tumor immune microenvironmental analyses could offer potential clinical utility in the stratification of gynecological CS above classification by genomic aberration subtype alone.
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http://dx.doi.org/10.1016/j.ygyno.2020.11.030DOI Listing
February 2021

Identification of serum cytokine clusters associated with outcomes in ovarian clear cell carcinoma.

Sci Rep 2020 10 28;10(1):18503. Epub 2020 Oct 28.

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1298, Japan.

Serum cytokine and chemokine networks may reflect the complex systemic immunological interactions in cancer patients. Studying groups of cytokines and their networks may help to understand their clinical biology. A total of 178 cases of ovarian cancer were analyzed in this study, including 73 high-grade serous (HGSC), 66 clear cell (CCC) and 39 endometrioid carcinomas. Suspension cytokine arrays were performed with the patients' sera taken before the primary surgery. Associations between each cytokine and clinicopathological factors were analyzed in all patients using multivariate linear regression models, and cluster analyses were performed for each histotype. In the multivariate analyses, twelve of 27 cytokines were correlated with histotypes. Cluster analyses in each histotype revealed 2 cytokine signatures S1 and S2 in HGSC, and similarly C1 and C2 in CCC. Twenty-two of 27 cytokines were commonly clustered in HGSC and CCC. Signature S1 and C1 included IL-2,6,8,15, chemokines and angiogenic factors, whereas signature S2 and C2 included IL-4,5,9,10,13, TNF-α and G-CSF. Four subgroups based on a high or low level for each signature were identified, and this cluster-based classification demonstrated significantly different progression-free and overall survivals for CCC patients (P = 0.00097 and P = 0.017).
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http://dx.doi.org/10.1038/s41598-020-75536-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595156PMC
October 2020

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

J Gynecol Oncol 2020 Nov;31(6):e93

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan.

Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines.

Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition.

Results: mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages.

Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
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http://dx.doi.org/10.3802/jgo.2020.31.e93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593222PMC
November 2020

Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6-dependent Epilepsy Than Pyridoxal 5'-Phosphate.

Pediatr Neurol 2020 12 2;113:33-41. Epub 2020 Sep 2.

Department of Child Neurology, Okayama University Hospital, Okayama, Japan; Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid.

Methods: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations.

Results: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain.

Conclusions: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.08.020DOI Listing
December 2020

Tumor-related mutations in cell-free DNA in pre-operative plasma as a prognostic indicator of recurrence in endometrial cancer.

Int J Gynecol Cancer 2020 09 21;30(9):1340-1346. Epub 2020 Jul 21.

Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan

Objectives: Circulating tumor DNA (ctDNA) has potential as a basis for understanding the molecular features of a tumor non-invasively and for use as a diagnostic, prognostic, and disease-monitoring marker. The aim of this study was to evaluate the clinical roles of ctDNA in patients with endometrial cancer.

Methods: Since and are among the most common mutated genes in endometrial cancer, somatic mutations of these genes were investigated in tumor specimens and plasma collected before surgery, using droplet digital polymerase chain reaction (ddPCR). ctDNA was defined as positive when the corresponding mutation between somatic and plasma was also detected in plasma cell-free DNA (cfDNA). Relationships of the presence of ctDNA with clinicopathological features were examined.

Results: Somatic and/or mutations were found in 68 (34%) of 199 patients with endometrial cancer. Ten (14.7%) of 68 patients had similar mutations in cfDNA. ctDNA detected in pre-operative plasma was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.008), histology (p=0.028), and lymphovascular space invasion (p=0.002), and with shorter recurrence-free and overall survival (p=0.004 and p=0.010, respectively, by log-rank test).

Conclusion: Tumor-related ctDNA detected in plasma before surgery was associated with poorer oncologic outcome on univariate analysis in patients with endometrial cancer harboring or mutations.
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http://dx.doi.org/10.1136/ijgc-2019-001053DOI Listing
September 2020

Evaluation of Circulating Tumor DNA in Patients with Ovarian Cancer Harboring Somatic PIK3CA or KRAS Mutations.

Cancer Res Treat 2020 Oct 6;52(4):1219-1228. Epub 2020 May 6.

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan.

Purpose: Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA.

Materials And Methods: We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the corresponding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma.

Results: The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis.

Conclusion: The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.
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http://dx.doi.org/10.4143/crt.2019.688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577815PMC
October 2020

Current and future strategies for treatment of ovarian clear cell carcinoma.

J Obstet Gynaecol Res 2020 Sep 23;46(9):1678-1689. Epub 2020 Jun 23.

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan.

Ovarian clear cell carcinoma (OCCC) is one of the five histological types of epithelial ovarian cancer (EOC). OCCC comprises 23% of all EOC cases in Japan, whereas the rate of OCCC in North America and Europe is much lower. OCCC is generally categorized as a rare gynecologic malignancy, and there is limited evidence for specific treatment. The clinical basis for treatment of OCCC is mostly based on retrospective studies, many of which were performed in Japan. Until recently, most randomized clinical trials for EOC have included OCCC; therefore, current treatment for OCCC is basically the same as that for other histologic types of EOC. However, the clinical characteristics of OCCC differ from those of high-grade serous carcinoma, particularly for chemosensitivity, and there is a need to develop new treatment for OCCC. The molecular background of OCCC has unique features: tumors are usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, whereas p53 mutations are common in high-grade serous or endometrioid carcinomas. These features may help in development of new treatment for OCCC. In this review, we described the current evidence for treatment of OCCC, including surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, and we discuss ongoing clinical trials and preclinical studies of new treatment approaches for OCCC.
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http://dx.doi.org/10.1111/jog.14350DOI Listing
September 2020

Treatment Outcome of Second-Line Chemotherapy for Gynecologic Carcinosarcoma.

Oncology 2020 11;98(10):699-705. Epub 2020 Jun 11.

Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Introduction: Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy.

Objective: To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma.

Methods: We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated.

Results: Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8-107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2-7.5) months and 12.9 (95% CI, 7.8-16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1-10.5) months in the <180 days group and 16.4 (95% CI, 13.1-130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10-0.66), respectively.

Conclusion: The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval.
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http://dx.doi.org/10.1159/000507333DOI Listing
October 2020

Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma.

J Immunother Cancer 2020 05;8(1)

Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.

Background: There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.

Methods: A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine and promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.

Results: As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAgHLA) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAgHLA) in HR-deficient HGSC.

Conclusions: Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.
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http://dx.doi.org/10.1136/jitc-2019-000375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254153PMC
May 2020

A case of pyridoxine-dependent epilepsy with novel mutations.

Oxf Med Case Reports 2020 Mar 6;2020(3):omaa008. Epub 2020 May 6.

Department of Neurology, Gunma Children's Medical Centre, Shibukawa, Gunma, Japan.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in that included NM_001182.4:[c.1196G > T] and [c.1200 + 1G > A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.
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http://dx.doi.org/10.1093/omcr/omaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202051PMC
March 2020

[Ⅲ.The Current Status and Future Perspective of Chemotherapy, Targeted Therapy and Immunotherapy for Cervical Cancer].

Gan To Kagaku Ryoho 2020 Feb;47(2):242-246

Dept. of Gynecologic Oncology, Saitama Medical University International Medical Center.

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February 2020

Clinical Practice Guidelines for Achondroplasia.

Clin Pediatr Endocrinol 2020 9;29(1):25-42. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Achondroplasia (ACH) is a skeletal dysplasia that presents with limb shortening, short stature, and characteristic facial configuration. ACH is caused by mutations of the gene, leading to constantly activated FGFR3 and activation of its downstream intracellular signaling pathway. This results in the suppression of chondrocyte differentiation and proliferation, which in turn impairs endochondral ossification and causes short-limb short stature. ACH also causes characteristic clinical symptoms, including foramen magnum narrowing, ventricular enlargement, sleep apnea, upper airway stenosis, otitis media, a narrow thorax, spinal canal stenosis, spinal kyphosis, and deformities of the lower extremities. Although outside Japan, papers on health supervision are available, they are based on reports and questionnaire survey results. Considering the scarcity of high levels of evidence and clinical guidelines for patients with ACH, clinical practical guidelines have been developed to assist both healthcare professionals and patients in making appropriate decisions in specific clinical situations. Eleven clinical questions were established and a systematic literature search was conducted using PubMed/MEDLINE. Evidence-based recommendations were developed, and the guidelines describe the recommendations related to the clinical management of ACH. We anticipate that these clinical practice guidelines for ACH will be useful for healthcare professionals and patients alike.
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http://dx.doi.org/10.1297/cpe.29.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958518PMC
January 2020

Clinical Practice Guidelines for Hypophosphatasia.

Clin Pediatr Endocrinol 2020 9;29(1):9-24. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.
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http://dx.doi.org/10.1297/cpe.29.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958520PMC
January 2020

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE-100.

Cancer Sci 2020 Apr 28;111(4):1324-1332. Epub 2020 Feb 28.

Kurume University School of Medicine, Kurume, Japan.

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.
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http://dx.doi.org/10.1111/cas.14340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156846PMC
April 2020

A phase 2 study of intraperitoneal carboplatin plus intravenous dose-dense paclitaxel in front-line treatment of suboptimal residual ovarian cancer.

Br J Cancer 2020 03 31;122(6):766-770. Epub 2020 Jan 31.

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, 350-1298, Japan.

Background: We evaluated the efficacy of intraperitoneal (IP) carboplatin in combination with dose-dense paclitaxel (ddTCip) for suboptimal residual ovarian cancer.

Methods: This was a phase 2 study to evaluate ddTCip. Patients with stage II-IV ovarian carcinoma, who underwent primary cytoreductive surgery and had radiologically evaluable disease after surgery, were eligible to participate in this study. IP carboplatin (AUC = 6) was administered on day 1, and intravenous paclitaxel (80 mg/m) was administered on days 1, 8 and 15. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Interval- debulking surgery followed by the same regimen was allowed when indicated.

Results: A total of 117 patients were considered eligible for this study prior to surgery and temporarily registered. Of the 117 patients, 76 patients met the inclusion criteria and were enrolled in this study. Fifty-nine (83.1%) patients had objective clinical responses. Median PFS and OS were 18.3 and 55.5 months, respectively. Sixty-four (84.2%) patients had grade 3/4 neutropenia, 43 (56.5%) patients had anaemia and 17 (22.4%) patients had thrombocytopenia. Port-related adverse events occurred in nine (11.8%) patients.

Conclusions: Front-line chemotherapy with ddTCip therapy appears safe and effective, even for patients with suboptimal residual ovarian cancer.

Trial Registration: UMIN Clinical Trials Registry (ID: UMIN000001713) on February 16th, 2009.
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http://dx.doi.org/10.1038/s41416-020-0734-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078205PMC
March 2020

Landscape of systemic therapy for ovarian cancer in 2019: Primary therapy.

Cancer 2019 Dec;125 Suppl 24:4582-4586

Department of Gynecology, Hyogo Cancer Center, Hyogo, Japan.

According to the statement from the 5th Ovarian Cancer Consensus Conference in 2015, the primary systemic chemotherapy for advanced ovarian cancer is a combination of paclitaxel plus carboplatin administered every 3 weeks (PCq3w). Optional alternatives include weekly dose-dense paclitaxel, in combination and maintenance therapy with bevacizumab, and intraperitoneal chemotherapy. Since then, in addition to the PCq3w strategy, there has been emerging new evidence, especially for poly(adenosine diphosphate-ribose) polymerase inhibitors. Moreover, there are multiple randomized, phase 3 trials testing the addition of antiangiogenic and/or immune checkpoint inhibitors in this patient population. In this article, current and future perspectives of systemic chemotherapy for advanced ovarian cancer are discussed.
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http://dx.doi.org/10.1002/cncr.32475DOI Listing
December 2019

Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions.

Pediatr Int 2020 May;62(5):587-592

Department of Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.

Background: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified.

Methods: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography.

Results: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions.

Conclusions: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.
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http://dx.doi.org/10.1111/ped.14158DOI Listing
May 2020

X-linked Hypophosphatemia (XLH) Mimicking Rheumatic Disease.

Intern Med 2020 05 17;59(9):1233-1234. Epub 2020 Jan 17.

Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

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http://dx.doi.org/10.2169/internalmedicine.4029-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270752PMC
May 2020

Identification of novel mutations of ovarian cancer-related genes from RNA-sequencing data for Japanese epithelial ovarian cancer patients.

Endocr J 2020 Feb 19;67(2):219-229. Epub 2019 Nov 19.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan.

Ovarian cancer has the highest mortality rate among gynecological cancers. Gene mutations are involved in the carcinogenesis, metastasis, and therapeutic response in ovarian cancer. However, the variety and proportion of gene mutation is not fully analyzed in Japanese ovarian cancer patients, especially, in those with recurrent tumors. In the present study, RNA-sequencing was performed for 32 clinical ovarian specimens obtained from 24 Japanese patients (24 primary cancer specimens and 8 recurrent specimens paired with corresponding primary cancer specimens). Mutations in 24 primary specimens were analyzed by comparing the sequence data mapped on RefSeq genes with those in the public online databases BRCA Exchange, COSMIC, ClinVar, and cBioportal. Mutations were observed in TP53 in 16 specimens (67%), BRCA1 in 9 (38%), BRCA2 in 13 (54%), ARID1A in 3 (13%), PIK3CA in 2 (8%), KRAS in 1 (4%), PTEN in 1 (4%), and CTNNB1 in 1 (4%), excluding synonymous mutations. Among those identified muations, 13 of 14 mutations in TP53, 10 of 11 mutations of BRCA1, 10 of 23 mutation positions of BRCA2, none of 7 mutations of ARID1A, 1 mutation of PIK3CA, and 1 mutation of CTNNB1 were consistent with those reported in the public online databases; however, the other mutations identified were novel. Comparison between matched-paired specimens of primary and recurrent tumors revealed the changes of mutational status in expressed RNAs. RNA-sequencing-based mutation analysis will be useful to reveal ethnic differences of gene mutations in ovarian cancer and to understand the contribution of gene mutations to recurrence.
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http://dx.doi.org/10.1507/endocrj.EJ19-0283DOI Listing
February 2020

Clinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma.

Nat Commun 2019 10 31;10(1):4965. Epub 2019 Oct 31.

Project for Development of Innovative Research on Cancer Therapeutics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan.

Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. Previous genomic studies have identified the driver genes and genomic properties associated with CS. However, there is still no molecular subtyping scheme with clinical relevance for this disease. Here, we sequence 109 CS samples, focusing on 596 genes. We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Multi-regional comparative sequencing reveals genomic alteration-independent CS cell differentiation. Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development.
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http://dx.doi.org/10.1038/s41467-019-12985-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823358PMC
October 2019