Publications by authors named "Hiroyuki Yoshikawa"

232 Publications

[Toxicity of Takifugu exascurusCollected from the Sea of Kumano].

Shokuhin Eiseigaku Zasshi 2021 ;62(1):28-32

Department of Agro-Food Science, Niigata Agro-Food University.

Marine pufferfish Takifugu exascurus is not approved for human consumption due to the lack of information on its toxicity. To clarify the toxicity of T. exascurus, ten live specimens were collected from the Sea of Kumano, Japan, and the toxicity and tetrodotoxin (TTX) concentration were determined using mouse bioassay and high performance liquid chromatography-fluorescence detection (HPLC-FLD), respectively. Toxicity was observed in the skin, liver, and ovaries, but the testes and muscle were non-toxic (<10 MU/g). On the other hand, HPLC-FLD revealed that TTX was detected in the muscle in two of the 10 specimens (1.4 and 1.5 MU/g). Based on the results, TTX is the main toxic component contributing to toxicity in T. exascurus.
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http://dx.doi.org/10.3358/shokueishi.62.28DOI Listing
March 2021

Potentiation of Rocuronium Bromide by Lithium Carbonate: A Case Report.

Anesth Prog 2020 09;67(3):146-150

Division of Dental Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.

Lithium carbonate is a medication used for the management of various mental disorders. The present report describes a case of prolongation of rocuronium bromide in a patient concurrently taking lithium carbonate. A 64-year-old woman was scheduled to undergo cystectomy under general anesthesia. The patient took lithium carbonate (600 mg/d) for treatment of bipolar affective disorder. General anesthesia was induced with propofol, fentanyl, remifentanil, and sevoflurane. After loss of consciousness, rocuronium bromide (50 mg) was administered, and the trachea was intubated. Approximately 1 hour after the administration of rocuronium, the degree of residual muscle relaxant was evaluated using a nerve stimulation device. No muscle contraction occurred with train-of-four (TOF) stimulation. Following administration of sugammadex (200 mg) the TOF ratio increased to 95%. The ionic size of lithium is similar to that of sodium; therefore, lithium is transported into the cell with sodium. The resting membrane potential decreases, leading to a reduction in the height of the action potential. Thus, the effect of the remaining lithium may have been superimposed on the rocuronium neuromuscular blockade. Evaluation with a nerve stimulation device in patients taking lithium is crucial before extubation because of the risk of rocuronium potentiation.
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http://dx.doi.org/10.2344/anpr-66-04-04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530805PMC
September 2020

Production of donor-derived eggs after ovarian germ cell transplantation into the gonads of adult, germ cell-less, triploid hybrid fish†.

Biol Reprod 2020 12;103(6):1289-1299

Noto Center for Fisheries Science and Technology, Faculty of Biological Science and Technology, Kanazawa University, Ishikawa, Japan.

In animals, spermatogonial transplantation in sterile adult males is widely developed; however, despite its utility, ovarian germ cell transplantation is not well developed. We previously showed that the interspecific hybrid offspring of sciaenid was a suitable model for germ cell transplantation studies as they have germ cell-less gonads. However, all these gonads have testis-like characteristics. Here, we tested whether triploidization in hybrid embryos could result in germ cell-less ovary development. Gonadal structure dimorphism and sex-specific gene expression patterns were examined in 6-month-old triploid hybrids (3nHybs). Thirty-one percent of 3nHybs had germ cell-less gonads with an ovarian cavity. cyp19a1a and foxl2, ovarian differentiation-related genes, were expressed in these gonads, whereas dmrt1 and vasa were not expressed, suggesting ovary-like germ cell-less gonad development. Some (26%) 3nHybs had testis-like germ cell-less gonads. Ovarian germ cells collected from homozygous green fluorescent protein (GFP) transgenic blue drum (BD) (Nibea mitsukurii) were transplanted into 6-month-old 3nHybs gonads via the urogenital papilla or oviduct. After 9 months, the recipients were crossed with wild type BD. Among the six 3nHyb recipients that survived, one female and one male produced fertile eggs and motile sperm carrying gfp-specific DNA sequences. Progeny tests revealed that all F1 offspring possessed gfp-specific DNA sequences, suggesting that these recipients produced only donor-derived eggs or sperm. Histological observation confirmed donor-derived gametogenesis in the 3nHyb recipients' gonads. Overall, triploidization reduces male-biased sex differentiation in germ cell-less gonads. We report, for the first time, donor-derived egg production in an animal via direct ovarian germ cell transplantation into a germ cell-less ovary.
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http://dx.doi.org/10.1093/biolre/ioaa168DOI Listing
December 2020

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan.

Cancer Sci 2020 Jul 21;111(7):2546-2557. Epub 2020 May 21.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.
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http://dx.doi.org/10.1111/cas.14445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385338PMC
July 2020

Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial.

Eur J Cancer 2020 05 13;130:114-125. Epub 2020 Mar 13.

Ibaraki Prefectural Central Hospital, Kasama, Japan.

Background: Regarding the comparison between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers, EORTC55971 and CHORUS studies demonstrated noninferiority of NACT. Previously, we reported reduced invasiveness of NACT in JCOG0602. This is a final analysis including the primary endpoint of overall survival (OS).

Methods: Patients were randomised to PDS (PDS followed by 8x paclitaxel and carboplatin, i.e. TC regimen) or NACT (4x TC, interval debulking surgery [IDS], 4x TC). The primary endpoint was OS. The noninferiority hazard ratio (HR) margin for NACT compared with PDS was 1·161. The planned sample size was 300.

Findings: Between 2006 and 2011, 301 patients were randomised, 149 to PDS and 152 to NACT. The median OS was 49·0 and 44·3 months in the PDS and NACT. HR for NACT was 1·052 [90·8% confidence interval (CI) 0·835-1·326], and one-sided noninferiority p-value was 0·24. Median progression-free survival was 15·1 and 16·4 months in the PDS and NACT (HR: 0·96 [95%CI 0·75-1·23]). In the PDS arm, 147/149 underwent PDS and 49/147 underwent IDS. In the NACT arm 130/152 underwent IDS. Complete resection was achieved in 12% (17/147) of PDS and 31% (45/147) of PDS ± IDS in the PDS arm and in 64% (83/130) of IDS in the NACT arm. Optimal surgery (residual tumour <1 cm) was achieved in 37% (55/147), 63% (92/147), and 82% (107/130 respectively. In the NACT, PS 2/3, serum albumin ≤2·5, CA125 > 2000 an institution with low study activity was advantageous, whereas clear/mucinous histology was disadvantageous for OS.

Interpretation: The noninferiority of NACT was not confirmed. NACT may not always be a substitute for PDS. However, as our study had smaller numbers, the noninferiority of the previous studies cannot be denied.

Funding: Ministry of Health, Labour and Welfare, Japan and the National Cancer Center, Japan.

Clinical Trial Information: UMIN000000523.
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http://dx.doi.org/10.1016/j.ejca.2020.02.020DOI Listing
May 2020

Single Cell Analysis of Neutrophils NETs by Microscopic LSPR Imaging System.

Micromachines (Basel) 2019 Dec 31;11(1). Epub 2019 Dec 31.

Department of Applied Physics, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan.

A simple microengraving cell monitoring method for neutrophil extracellular traps (NETs) released from single neutrophils has been realized using a polydimethylsiloxane (PDMS) microwell array (MWA) sheet on a plasmon chip platform. An imbalance between NETs formation and the succeeding degradation (NETosis) are considered associated with autoimmune disease and its pathogenesis. Thus, an alternative platform that can conduct monitoring of this activity on single cell level at minimum cost but with great sensitivity is greatly desired. The developed MWA plasmon chips allow single cell isolation of neutrophils from 150 µL suspension (6.0 × 10 cells/mL) with an efficiency of 36.3%; 105 microwells with single cell condition. To demonstrate the utility of the chip, trapped cells were incubated between 2 to 4 h after introducing with 100 nM phorbol 12-myristate 13-acetate (PMA) before measurement. Under observation using a hyperspectral imaging system that allows high-throughput screening, the neutrophils stimulated by PMA solution show a significant release of fibrils and NETs after 4 h, with observed maximum areas between 314-758 µm. An average absorption peak wavelength shows a redshift of Δλ = 1.5 nm as neutrophils release NETs.
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http://dx.doi.org/10.3390/mi11010052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019790PMC
December 2019

A Microfluidic Platform for Single Cell Fluorometric Granzyme B Profiling.

Theranostics 2020 1;10(1):123-132. Epub 2020 Jan 1.

Graduate School of Engineering, Osaka University, Suita, Osaka, 565-0871, JAPAN.

Granzyme B (GrB) is an essential cytotoxic effector in cancer immunotherapy as it can be a potential biomarker to predict the efficacy of immunotherapies including checkpoint inhibitors. Monitoring the Granzyme B activity in cells would help determine a patient's clinical response to treatment and lead to better treatment strategies by preventing administration of ineffective therapies and avoid adverse events resulting in a delay in subsequent treatment. : A microfluidic device with hydrodynamic traps and pneumatic valving system was fabricated using photo and soft lithography. Single cell Granzyme B (GrB) activity was detected and measured fluorometrically using a commercial assay kit with a peptide substrate containing GrB recognition sequence (Ac-IEPD-AFC) and AFC (7-Amino-4-trifluoromethylcoumarin) label. Fluorescence was observed and measured using a confocal microscope with CSU-W1 scanner unit and CCD camera as well as an inverted microscope with photodetector. Model cells (NK-92, GrB-transduced Jurkat, and THP1 cells) and human PBMCs from healthy donor and lung cancer patients including an anti-PD-1 antibody treated patient were profiled of its GrB activity as proof of concept. : GrB expression from the model cells was found to be markedly different. NK-92 cells were found to have higher GrB activity than the GrB-transduced Jurkat cells. THP-1 was found to have relatively no significant activity. A marked increase in GrB expression was also observed in anti-PD-1 treated lung cancer patient sample in comparison to PBMC from a healthy donor. TCR+ Ig-G4+ PBMC cells were found to have high activity which signifies a clear response to PD-1 blockade. : As proof of concept, we have shown the capability of a microfluidic platform to measure GrB production through a single cell enzymatic activity assay. Our platform might be a promising tool for evaluating the sensitivity of immunotherapies and identifying specific T cell subset responsible for the anti-tumor response.
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http://dx.doi.org/10.7150/thno.37728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929635PMC
April 2021

Four cases of Mayer-Rokitansky-Küster-Hauser syndrome treated via non-surgical vaginal reconstruction using uterine cervical dilators.

J Obstet Gynaecol Res 2020 Mar 19;46(3):542-546. Epub 2019 Dec 19.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Vaginal creation is the standard treatment for Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Although non-surgical method is recommended as a first-line treatment in the American College of Obstetricians and Gynecologists guidelines for gynecological practice, it is not commonly performed in Japan. At our hospital, vaginal dilation using uterine cervical dilators (Hegar's dilator) is performed for patients with MRKH syndrome. We report four cases successfully treated with vaginal dilation. After the examination, patients were instructed to practice daily self-dilation at home. The initiation size was No. 13 with 10.5-mm diameter. After the vaginal cavity was dilated to a depth of 6 cm, the size of dilators was gradually increased until No. 30 with 25-mm diameter in a tip and 28-mm diameter in a trunk. The duration required to achieve the outcome was 5-22 months. All cases were successfully treated without any severe complication.
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http://dx.doi.org/10.1111/jog.14180DOI Listing
March 2020

Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program.

Cancer Sci 2019 Dec 4;110(12):3811-3820. Epub 2019 Nov 4.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, P  < .0001) and CIN2-3/AIS (83.3% to 45.0%, P  = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch-up vaccination (P = .04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government's suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.
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http://dx.doi.org/10.1111/cas.14212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890435PMC
December 2019

Contrasting Toxin Selectivity between the Marine Pufferfish and the Freshwater Pufferfish .

Toxins (Basel) 2019 08 10;11(8). Epub 2019 Aug 10.

Graduate School of Fisheries and Environmental Sciences, Nagasaki University. 1-14, Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan.

To clarify the differences in toxin selectivity between marine and freshwater pufferfish, we conducted experiments in artificially reared nontoxic specimens of (marine) and (freshwater) using tetrodotoxin (TTX) and paralytic shellfish poison (PSP; decarbamoylsaxitoxin (dcSTX) or saxitoxin (STX)). specimens were administered feed homogenate containing TTX or dcSTX (dose of toxin, 55.2 nmol/fish) and specimens were administered feed homogenate containing TTX + STX (dose of each toxin, 19.2 nmol/fish) by oral gavage. The toxin content in the intestine, muscle, skin, liver, and gonads was quantified after 24 and 48 or 72 h. In , TTX administered into the intestine was absorbed into the body and transferred and retained mainly in the skin and liver, while dcSTX was hardly retained in the body, although it partly remained in the intestine. In strong contrast, in , little TTX remained in the body, whereas STX was absorbed into the body and was transferred and retained in the ovary and skin. The findings revealed that TTX/PSP selectivity differs between the marine species and the freshwater species . , which naturally harbors TTX, selectively accumulates TTX, and , which naturally harbors PSP, selectively accumulates PSP.
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http://dx.doi.org/10.3390/toxins11080470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722796PMC
August 2019

Germ cell-less hybrid fish: ideal recipient for spermatogonial transplantation for the rapid production of donor-derived sperm†.

Biol Reprod 2019 08;101(2):492-500

Division of Fisheries Resource Sciences, Faculty of Fisheries, Kagoshima University, Shimoarata 4-50-20, Kagoshima City, Japan.

An interspecific hybrid marine fish that developed a testis-like gonad without any germ cells, i.e., a germ cell-less gonad, was produced by hybridizing a female blue drum Nibea mitsukurii with a male white croaker Pennahia argentata. In this study, we evaluated the suitability of the germ cell-less fish as a recipient by transplanting donor testicular cells directly into the gonads through the urogenital papilla. The donor testicular cells were collected from hemizygous transgenic, green fluorescent protein (gfp) (+/-) blue drum, and transplanted into the germ cell-less gonads of the 6-month-old adult hybrid croakers. Fluorescent and histological observations showed the colonization, proliferation, and differentiation of transplanted spermatogonial cells in the gonads of hybrid croakers. The earliest production of spermatozoa in a hybrid recipient was observed at 7 weeks post-transplantation (pt), and 10% of the transplanted recipients produced donor-derived gfp-positive spermatozoa by 25 weeks pt. Sperm from the hybrid recipients were used to fertilize eggs from wild-type blue drums, and approximately 50% of the resulting offspring were gfp-positive, suggesting that all offspring originated from donor-derived sperm that were produced in the transplanted gfp (+/-) germ cells. To the best of our knowledge, this is the first report of successful spermatogonial transplantation using a germ cell-less adult fish as a recipient. This transplantation system has considerable advantages, such as the use of comparatively simple equipment and procedures, and rapid generation of donor-derived spermatogenesis and offspring, and presents numerous applications in commercial aquaculture.
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http://dx.doi.org/10.1093/biolre/ioz045DOI Listing
August 2019

Endotracheal Intubation Complicated by a Palatal Tooth in a Patient With Treacher Collins Syndrome.

Anesth Prog 2019 ;66(1):42-43

Division of Dental Anesthesiology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan.

We report a case of difficult endotracheal intubation in a patient with Treacher Collins syndrome. A sixteen-year-old female patient scheduled for general anesthesia had a displaced palatal tooth that interfered with laryngoscope insertion into the pharyngeal space. To address this problem, we successfully performed endotracheal intubation using a fiberscope while elevating the epiglottic vallecula using a King Vision™ video laryngoscope. A later operation was performed after tooth extraction without difficult laryngoscopy. Our experience stresses the importance of removing obstructions to laryngoscopic inspection prior to general anesthesia.
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http://dx.doi.org/10.2344/anpr-66-02-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424163PMC
January 2020

Human papillomavirus genotype and prognosis of cervical cancer: Favorable survival of patients with HPV16-positive tumors.

Papillomavirus Res 2018 12 19;6:41-45. Epub 2018 Oct 19.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Ibaraki Prefectural Central Hospital, Kasama, Ibaraki 309-1793, Japan.

The prognostic impact of human papillomavirus (HPV) type on invasive cervical cancer (ICC) was analyzed for 137 women treated for ICC at a single institution between 1999 and 2007. The study subjects were divided into three groups according to HPV genotype: HPV16-positive (n = 59), HPV18-positive (n = 33), and HPV16/18-negative ICC (non-HPV16/18, n = 45). The median follow-up time was 102.5 months (range, 5-179). The 10-year overall survival (10y-OS) rates in women with FIGO stage I/II disease were similar among HPV genotypes: 94.7% for HPV16 (n = 39), 95.2% for HPV18 (n = 26), and 96.4% for non-HPV16/18 (n = 29). However, the 10y-OS rates in women with FIGO stage III/IV tumors were 73.7% for HPV16 (n = 20), 45.7% for HPV18 (n = 7), and 35.7% for other types (n = 16), with significantly higher survival in HPV16-positive compared with HPV16-negative ICC (10y-OS; 73.7% vs. 39.5%, P = 0.04). This difference in FIGO stage III/IV tumors remained significant after adjusting for age and histology (hazard ratio 0.30, 95% confidence interval 0.09-0.86, P = 0.02). These results suggest that detection of HPV16 DNA may be associated with a favorable prognosis in patients with FIGO stage III/IV ICC. Given that most women with FIGO stage III/IV tumors received concurrent chemoradiotherapy, this finding may imply that HPV16-positive tumors are more chemoradiosensitive.
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http://dx.doi.org/10.1016/j.pvr.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218653PMC
December 2018

Prognostic significance of PIK3CA mutation in stage IIB to IVA cervical cancers treated by concurrent chemoradiotherapy with weekly cisplatin.

Medicine (Baltimore) 2018 Aug;97(31):e11392

Department of Obstetrics and Gynecology, Faculty of Medicine Doctoral Program in Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba Ibaraki Prefectural Central Hospital, Ibaraki, Japan.

The standard treatment for locally advanced cervical cancer is cisplatin-based concurrent chemoradiotherapy (CCRT). Although the activated PI3-kinase/Akt pathway is known to be involved in both cisplatin-resistance and radioresistance, to date, only a few studies have reported significant associations between PIK3CA gene mutational status and outcome by CCRT in the disease. The aim of this study was to clarify the prognostic significance of PIK3CA mutational status in cervical cancers treated by CCRT.We analyzed PIK3CA mutation in 59 patients with stage IIB to IVA cervical carcinomas primarily treated by CCRT with weekly cisplatin using formalin-fixed paraffin-embedded biopsy specimens before treatment. Fifty-seven of 59 patients (97%) had locally advanced cancers with stage IIIA to IVA. Clinicopathologic data and patient survival were retrospectively compared according to PIK3CA mutational status.PIK3CA mutation was found in 7 of 59 patients (12%). No significant differences in clinicopathologic characteristics were observed according to PIK3CA mutational status. Patients with wild-type PIK3CA showed significantly improved cancer-specific survival as compared with mutated patients (P = .044). Subsequent survival analyses revealed that PIK3CA mutation was a significant prognostic factor for poor overall survival [multivariate adjusted hazard ratio (HR), 3.9; 95% confidence interval (95% CI), 1.3-11.8; P = .017] and cancer-specific survival (multivariate adjusted HR, 3.6; 95% CI, 1.2-11.0; P = .024).Together with previous published findings, the current study further supports the clinical significance of PIK3CA mutation in cervical cancer. Our observations suggest that molecular inhibitors targeting the PI3-kinase/Akt pathway may improve the outcome by CCRT in cervical cancers harboring PIK3CA mutation, providing significant implications for novel treatment strategy based on precision medicine in the disease.
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http://dx.doi.org/10.1097/MD.0000000000011392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081058PMC
August 2018

Chemically Regulated ROS Generation from Gold Nanoparticles for Enzyme-Free Electrochemiluminescent Immunosensing.

Anal Chem 2018 05 17;90(9):5773-5780. Epub 2018 Apr 17.

Department of Applied Physics , Osaka University , 2-1 Yamadaoka , Suita , Osaka 565-0871 Japan.

In the present work, we report on an enzyme-free electrochemiluminescent (ECL) immunosensing scheme utilizing the catalytic generation of reactive oxygen species (ROS) from gold nanoparticles (AuNPs) (diameter ≥5 nm) dispersed in aqueous solutions of trishydroxymethylaminomethane (Tris). First, to examine this catalytic pathway in detail, the effects of various factors such as the AuNP size and concentration, dispersant type and concentration, and dissolved oxygen were investigated using the electrochemiluminescence (ECL) of luminol. It was found that the catalytic generation of ROS from AuNPs can be regulated chemically by altering conditions such as the type, concentration, and pH of the solution that the AuNPs are dispersed in. Under the best conditions studied in this work, the AuNPs displayed high catalytic activity toward ROS generation, with an estimated apparent turnover number per AuNP of 0.1 s, comparable to those of several common peroxide-producing enzymes. Following these studies, this phenomenon was applied to develop a one-step enzyme-free ECL immunosensor based on sandwiching the target analyte using antibody-conjugated magnetic beads (MB) and AuNPs. Using IgA as a model analyte, the developed immunosensor was able to detect the target in the range of 1 ng/mL to 10 μg/mL, with the lower detection limit being comparable to those of commercial assays for the same target. Altering the antibodies used to modify the MB and AuNPs could further improve the detection limit as well as expand the applicability of this immunoassay to the detection of other analytes.
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http://dx.doi.org/10.1021/acs.analchem.8b00118DOI Listing
May 2018

Hybrid Sterility in Fish Caused by Mitotic Arrest of Primordial Germ Cells.

Genetics 2018 06 2;209(2):507-521. Epub 2018 Apr 2.

Research Center for Advanced Science and Technology, Tokyo University of Marine Science and Technology, Tateyama, Chiba 294-0308, Japan

Sterility in hybrid animals is widely known to be due to a cytological mechanism of aberrant homologous chromosome pairing during meiosis in hybrid germ cells. In this study, the gametes of four marine fish species belonging to the Sciaenid family were artificially fertilized, and germ cell development was examined at the cellular and molecular levels. One of the intergeneric hybrids had gonads that were testis-like in structure, small in size, and lacked germ cells. Specification of primordial germ cells (PGCs) and their migration toward genital ridges occurred normally in hybrid embryos, but these PGCs did not proliferate in the hybrid gonads. By germ cell transplantation assay, we showed that the gonadal microenvironment in hybrid recipients produced functional donor-derived gametes, suggesting that the germ cell-less phenotype was caused by cell autonomous proliferative defects of hybrid PGCs. This is the first evidence of mitotic arrest of germ cells causing hybrid sterility in animals.
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http://dx.doi.org/10.1534/genetics.118.300777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972423PMC
June 2018

Malignant triton tumor of the duodenum: report of a case.

Int Cancer Conf J 2018 Apr 13;7(2):52-58. Epub 2018 Mar 13.

Department of Gastroenterological Surgery, Japan Community Health Care Organization Sapporo Hokushin Hospital, Atsubetsu-ku, Chuoh 2-jo, 6-2-1, Sapporo, 004-8618 Japan.

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.
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http://dx.doi.org/10.1007/s13691-018-0320-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498344PMC
April 2018

Separate analysis of human papillomavirus E6 and E7 messenger RNAs to predict cervical neoplasia progression.

PLoS One 2018 21;13(2):e0193061. Epub 2018 Feb 21.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

A few studies previously suggested that human papillomavirus (HPV) E6 messenger RNA (mRNA) may exist uniformly in all grades of cervical intraepithelial neoplasia (CIN), whereas the detection rate of E7 mRNA may increase with disease progression from low-grade CIN to invasive carcinoma. The aim of this study was to clarify the different roles of E6 and E7 mRNAs in cervical carcinogenesis. The presence of each E6 and E7 mRNA was analyzed in 171 patients with pathologically-diagnosed CIN or cervical carcinoma. We utilized a RT-PCR assay based on consensus primers which could detect E6 mRNA (full-length E6/E7 transcript) and E7 mRNAs (spliced E6*/E7 transcripts) separately for various HPV types. E7 mRNAs were detected in 6% of CIN1, 12% of CIN2, 24% of CIN3, and 54% of cervical carcinoma. The presence of E7 mRNAs was significantly associated with progression from low-grade CIN to invasive carcinoma in contrast with E6 mRNA or high-risk HPV (HR-HPV) DNA (p = 0.00011, 0.80 and 0.54). The presence of both E6 and E7 mRNAs was significantly associated with HPV16/18 DNA but not with HR-HPV DNA (p = 0.0079 and 0.21), while the presence of E6 mRNA was significantly associated with HR-HPV DNA but not with HPV16/18 DNA (p = 0.036 and 0.089). The presence of both E6 and E7 mRNAs showed high specificity and low sensitivity (100% and 19%) for detecting CIN2+ by contrast with the positivity for HR-HPV DNA showing low specificity and high sensitivity (19% and 89%). The positive predictive value for detecting CIN2+ was even higher by the presence of both E6 and E7 mRNAs than by the positivity for HR-HPV DNA (100% vs. 91%). In 31 patients followed up for CIN1-2, the presence of both E6 and E7 mRNAs showed significant association with the occurrence of upgraded abnormal cytology in contrast with E6 mRNA, HR-HPV DNA, or HPV16/18 DNA (p = 0.034, 0.73, 0.53, and 0.72). Our findings support previous studies according to which E7 mRNA is more closely involved in cervical carcinogenesis than E6 mRNA. Moreover, the separate analysis of E6 and E7 mRNAs may be more useful than HR-HPV DNA test for detecting CIN2+ precisely and predicting disease progression. Further accumulation of evidence is warranted to validate our findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821364PMC
May 2018

[HPV Vaccination Program - The History and Recent Progress].

Gan To Kagaku Ryoho 2017 Sep;44(9):713-716

Ibaraki Prefectural Central Hospital.

Four years have passed since HPV vaccination "crisis" occurred in June 2013. In Japan,a publicly funded HPV vaccination program for adolescent females aged 12-16 years began in December 2010. However,the Japanese government withdrew its recommendation for HPV vaccination in June, 2013 because news reports on potential adverse effects of HPV vaccines without any medical evidence appeared repeatedly. The vaccination coverage among adolescent females decreased quickly from around 70%in females born between 1994 and 1999 to only 1%in females born since 2001 over the country. The suspension of recommendation for vaccination has continued to the present,though there is no scientific or epidemiologic evidence to demonstrate the causal linkage between post-vaccination symptoms and the HPV vaccines. Very recently,an ecological investigation reported that similar symptoms also occur in unvaccinated adolescents in Japan. Medical organizations in Japan are also calling for a resumption of the HPV vaccination program. Now,the resumption of the recommendation needs a political judgment.
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September 2017

Early impact of the Japanese immunization program implemented before the HPV vaccination crisis.

Int J Cancer 2017 10 12;141(8):1704-1706. Epub 2017 Jul 12.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1002/ijc.30855DOI Listing
October 2017

Sensitive Detection of Glycated Albumin in Human Serum Albumin Using Electrochemiluminescence.

Anal Chem 2017 06 16;89(11):5909-5915. Epub 2017 May 16.

Department of Applied Physics, Graduate School of Engineering, Osaka University , 2-1, Yamadaoka, Suita, Osaka 565-0871, Japan.

Monitoring of blood glucose content is vital for diabetes patients. The conventional widely used method involves an invasive procedure for blood sampling. In addition, blood glucose measured by this way is affected by immediate food consumption and it does not show accurate baseline blood glucose measurement. Thus, monitoring blood glucose by a noninvasive method that accurately reflects baseline blood glucose content is important. Glycated albumin (GA), a biomarker for diabetes indicating the average blood glucose over 2 weeks, can be used for semilong-term blood glucose monitoring. Detection of GA in saliva is a noninvasive method that alleviates the use of needles for diabetic patients; however, its content in saliva is in the nanomolar range. Therefore, the GA enzymatic detection method was combined with the ECL method for a highly sensitive detection of GA in human serum albumin and in the saliva sample. Here, the standard curve was constructed using model substrate, FZK, between 0.1 and 2 μM, and GA in human serum albumin was measured in this range. Also, we successfully demonstrated the detection limit of 0.1 μM GA in human serum albumin sample using ECL, which has seen improvement of about 70 times more than the colorimetric methods. The detection of GA in real saliva sample suggested that sample dilution of 5 times may be necessary to suppress the ECL quenching effect by impurities.
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http://dx.doi.org/10.1021/acs.analchem.7b00280DOI Listing
June 2017

Locally Produced BDNF Promotes Sclerotic Change in Alveolar Bone after Nerve Injury.

PLoS One 2017 10;12(1):e0169201. Epub 2017 Jan 10.

Division of Dental Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Gakkocho-dori, Chuo-ku, Niigata, Japan.

Brain-derived neurotrophic factor (BDNF), which is released due to nerve injury, is known to promote the natural healing of injured nerves. It is often observed that damage of mandibular canal induces local sclerotic changes in alveolar bone. We reported that peripheral nerve injury promotes the local production of BDNF; therefore, it was possible to hypothesize that peripheral nerve injury affects sclerotic changes in the alveolar bone. This study aimed to evaluate the effect of BDNF on osteogenesis using in vitro osteoblast-lineage cell culture and an in vivo rat osteotomy model. MC3T3-E1 cells were cultured with BDNF and were examined for cell proliferative activity, chemotaxis and mRNA expression levels of osteoblast differentiation markers. For in vivo study, inferior alveolar nerve (IAN) injury experiments and mandibular cortical osteotomy were performed using a rat model. In the osteotomy model, exogenous BDNF was applied to bone surfaces after corticotomy of the mandible, and we morphologically analyzed the new bone formation. As a result, mRNA expression of osteoblast differentiation marker, osteocalcin, was significantly increased by BDNF, although cell proliferation and migration were not affected. In the in vivo study, osteopontin-positive new bone formation was significantly accelerated in the BDNF-grafted groups, and active bone remodeling, involving trkB-positive osteoblasts and osteocytes, continued after 28 days. In conclusion, BDNF stimulated the differentiation of MC3T3-E1 cells and it promoted new bone formation and maturation. These results suggested that local BDNF produced by peripheral nerve injury contributes to accelerating sclerotic changes in the alveolar bone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224970PMC
August 2017

Peripheral Brain-Derived Neurotrophic Factor Modulates Regeneration Following Inferior Alveolar Nerve Injury in Rats.

J Oral Facial Pain Headache 2016 Fall;30(4):346-354

Aims: To examine the effects of local brain-derived neurotrophic factor (BDNF) produced after nerve injury on the functional regeneration of the damaged nerve.

Methods: The inferior alveolar nerve was transected in adult male rats and 1 μg or 10 μg of BDNF antibody was administered at the injury site; a third group of rats received saline and a fourth group underwent nerve ligation. BDNF mRNA was quantified in the transected tissue and trigeminal ganglion by using real-time polymerase chain reaction (PCR). Head withdrawal thresholds following mechanical (tactile) stimulation (with von Frey filaments) of the mental region were measured for 3 weeks postoperatively. Electromyographic activity of the jaw opening reflex (JOR) was recorded from the anterior belly of the digastric muscle.

Results: Within 24 hours, transection induced significant elevation of BDNF mRNA expression in the injured tissue (unpaired t test, P < .01). The head withdrawal threshold to mechanical stimulation increased at 1 day after transection and then decreased (two-way repeated measures analysis of variance [ANOVA], P < .001). At 2 weeks after surgery, the head withdrawal threshold was higher than before surgery in the group that received a higher dose of BDNF antibody (ANOVA, P < .001), but not in the group that received a smaller dose (ANOVA, P > .05). No significant differences were observed in the latency or threshold of the JOR between saline- and antibody-treated rats (unpaired t test, P > .05).

Conclusion: These results suggest that locally administered BDNF antibody neutralizes nerve injury-induced BDNF at the injury site and thus influences sensorimotor recovery.
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http://dx.doi.org/10.11607/ofph.1651DOI Listing
August 2017

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

Int J Gynecol Cancer 2017 01;27(1):37-43

Faculty of Medicine, Departments of *Obstetrics and Gynecology and †Clinical Trial and Clinical Epidemiology, and ‡Department of Pathology, Tsukuba Human Tissue Diagnostic Center, University of Tsukuba, Tsukuba, Japan.

Objectives: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort.

Methods: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens.

Results: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021).

Conclusions: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.
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http://dx.doi.org/10.1097/IGC.0000000000000848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181121PMC
January 2017

Radiological diagnosis of gas gangrene in a fetus at term.

Taiwan J Obstet Gynecol 2016 Aug;55(4):582-4

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Objective: To report a case of gas gangrene in a fetus at term, which was diagnosed by antenatal computed tomography (CT) imaging.

Case Report: A 23-year-old primiparous woman, who did not undergo any prenatal health checks until term, developed hypertension, proteinuria, and clouding of consciousness, and experienced intrauterine fetal death. A single, mature fetus with voluminous gas bubbles was observed on CT, which was consistent with a diagnosis of fetal gas gangrene. Following the induction of labor, a dead, malodorous infant was delivered, along with foul-smelling and frothy amniotic fluid. The patient's condition deteriorated, and intensive care support was required to treat the patient for septic shock and disseminated intravascular coagulation during the postpartum period. She died on the 2(nd) postpartum day.

Conclusion: Fetal gas gangrene is a very rare and potentially lethal event in pregnant women. To our knowledge, this is the first report on the antenatal diagnosis of fetal gas gangrene in a term pregnancy through CT. CT was useful for evaluating the extent of emphysematous change in the fetal and maternal organs.
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http://dx.doi.org/10.1016/j.tjog.2016.06.006DOI Listing
August 2016

Versatile Micropatterning of Plasmonic Nanostructures by Visible Light Induced Electroless Silver Plating on Gold Nanoseeds.

ACS Appl Mater Interfaces 2016 Sep 1;8(36):23932-40. Epub 2016 Sep 1.

Department of Applied Physics, Osaka University , 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

A versatile fabrication technique for plasmonic silver (Ag) nanostructures that uses visible light exposure for micropatterning and plasmon resonance tuning is presented. The surface of a glass substrate modified with gold (Au) nanoseeds by a thermal dewetting process was used as a Ag plating platform. When a solution containing silver nitrate and sodium citrate was dropped on the Au nanoseeds under visible light exposure, the plasmon-mediated reduction of Ag ions was induced on the Au nanoseeds to form Ag nanostructures. The plasmon resonance spectra of Ag nanostructures were examined by an absorption spectral measurement and a finite-difference time-domain (FDTD) simulation. Some examples of Ag nanostructure patterning were demonstrated by means of light exposure through a photomask, direct writing with a focused laser beam, and the interference between two laser beams. Surface enhanced Raman spectroscopy (SERS) of 4-aminothiophenol (4-ATP) was conducted with fabricated Ag nanostructures.
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http://dx.doi.org/10.1021/acsami.6b07661DOI Listing
September 2016

Prognostic factors from a randomized phase III trial of paclitaxel and carboplatin versus paclitaxel and cisplatin in metastatic or recurrent cervical cancer: Japan Clinical Oncology Group (JCOG) trial: JCOG0505-S1.

Cancer Chemother Pharmacol 2016 Oct 23;78(4):785-90. Epub 2016 Aug 23.

Department of Obstetrics and Gynecology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Purpose: The Japan Clinical Oncology Group (JCOG) trial JCOG0505 demonstrated the statistically significant non-inferiority of paclitaxel plus carboplatin (TC) to paclitaxel plus cisplatin (TP) in terms of overall survival (OS) in metastatic or recurrent cervical cancer. In that trial, patients were randomly assigned, adjusting for institution and known prognostic factors. The objective of this ancillary study was to evaluate the appropriateness of the adjustment factors used to have randomly assigned treatments and to investigate new potentially useful prognostic factors of paclitaxel plus platinum for future randomized trials in metastatic or recurrent cervical cancer.

Methods: The study subjects comprised 244 eligible patients in the JCOG0505 who were merged to have received either TC or TP. The effects of the following factors on OS were investigated using a Cox regression model taking into consideration the adjustment factors used in randomization in this trial (e.g., performance status [PS]) and other baseline factors, including platinum-free interval (PFI), pretreatment hemoglobin levels (PHLs), and pretreatment platelet counts (PPCs).

Results: The median follow-up was 17.6 months, and median OS was 18.0 months. The hazard ratio was 1.83 in patients with a PS of 1 or 2 (vs. 0; P = 0.0004; 95 % confidence interval [CI] 1.31-2.55), 2.92 in patients with a PFI of <6 months (vs. PFI of ≥12 months; P < 0.0001; 95 % CI 1.73-4.91), 2.09 in patients with a PFI of <12 months (vs. PFI of ≥12 months; P = 0.0034; 95 % CI 1.28-3.44), and 0.69 in patients with PHL higher than or equal to the median value (vs. less than the median; P = 0.016; 95 % CI 0.51-0.93). No significant differences were obtained for PPC or the other known factors.

Conclusions: In addition to the known prognostic factor of PS, which was used as an adjusting factor, a PFI of <12 months and lower PHL were newly demonstrated to be associated with poor outcomes in patients with metastatic or recurrent cervical cancer. These new prognostic factors should be validated in future prospective trials.

Clinical Trial Information: UMIN-CTR[ http://www.umin.ac.jp/ctr/ ] ID: C000000335.
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http://dx.doi.org/10.1007/s00280-016-3133-4DOI Listing
October 2016

Randomized Phase III Trial of Irinotecan Plus Cisplatin Compared With Paclitaxel Plus Carboplatin As First-Line Chemotherapy for Ovarian Clear Cell Carcinoma: JGOG3017/GCIG Trial.

J Clin Oncol 2016 08 11;34(24):2881-7. Epub 2016 Jul 11.

Toru Sugiyama, Iwate Medical University, Iwate; Aikou Okamoto, Hiroshi Tanabe, and Seiji Isonishi, The Jikei University School of Medicine; Tetsutaro Hamano, Kitasato University; Yasuhisa Terao, Juntendo University; Mikio Mikami, Tokai University; Hiroyuki Nomura and Daisuke Aoki, Keio University; Fumitoshi Terauchi, Tokyo Medical University, Tokyo; Takayuki Enomoto and Koji Nishino, Niigata University, Niigata; Eriko Aotani, Kanagawa Academy of Science and Technology; Nao Suzuki, St Marianna University, Kanagawa; Nobuo Yaegashi, Tohoku University, Miyagi; Kiyoko Kato, Kyushu University, Fukuoka; Hiroyuki Yoshikawa, University of Tsukuba, Ibaraki; Yoshihito Yokoyama, Hirosaki University, Aomori; Keiichi Fujiwara, Saitama Medical University International Medical Center, Saitama, Japan; Jae-Weon Kim, Seoul National University; Byoung-Gie Kim, Sungkyunkwan University, Seoul, South Korea; Sandro Pignata, Istituto Nazionale Tumori di Napoli, Naples, Italy; Jerome Alexandre, Hôpital Hôtel-Dieu, Montreal, Quebec, Canada; and John Green, University of Liverpool, Liverpool, United Kingdom.

Purpose: Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC.

Patients And Methods: Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events.

Results: Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC.

Conclusion: No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC.
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http://dx.doi.org/10.1200/JCO.2016.66.9010DOI Listing
August 2016

Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan Clinical Oncology Group Study JCOG0602.

Eur J Cancer 2016 09 17;64:22-31. Epub 2016 Jun 17.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Japan.

Background: We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS.

Methods: Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523).

Results: Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively).

Conclusion: Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017.
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http://dx.doi.org/10.1016/j.ejca.2016.05.017DOI Listing
September 2016

Fertility-sparing surgery for early stage epithelial ovarian cancer.

Jpn J Clin Oncol 2016 Aug 9;46(8):703-10. Epub 2016 Jun 9.

Ibaraki Prefectural Central Hospital, Kasama, Ibaraki, Japan.

Discussion of fertility-sparing treatment is an important part of pretreatment counseling for young patients with early epithelial ovarian cancer. As a result of late childbearing nowadays, fertility preservation has become a major issue in ovarian cancer patients. The purpose of this review is to update current knowledge on fertility-sparing treatment for early stage epithelial ovarian cancer, which may be useful for pretreatment counseling for reproductive-age patients. The multicenter study data on the fertility-sparing treatment published by Japan Clinical Oncology Group in 2010 confirmed that fertility-sparing surgery is a safe treatment for Stage IA patients with non-clear cell histology and Grade 1 or 2 and suggested that Stage IA patients with clear cell histology and Stage IC patients with non-clear cell histology and Grade 1 or 2 can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy. In the current review, we added the recent case series and review, and discussed the fertility-sparing treatment on young patients with early epithelial ovarian cancer. We need not to change the proposal by the Japan Clinical Oncology Group study, but we should wait for the results of an ongoing prospective study to strongly recommend the proposal of the Japan Clinical Oncology Group study.
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http://dx.doi.org/10.1093/jjco/hyw069DOI Listing
August 2016
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