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1.
Takafumi Koyama Toshio Shimizu Satoru Iwasa Yutaka Fujiwara Shunsuke Kondo Shigehisa Kitano Kan Yonemori Akihiko Shimomura Sakura Iizumi Tatsuya Sasaki Junji Furuse Noboru Yamamoto 《Cancer science》2020,111(2):571-579
Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)2‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily. 相似文献
2.
Yamin Qian Xin Wu Yuhki Yokoyama Daisuke Okuzaki Mai Taguchi Haruka Hirose Jiaqi Wang Tsuyoshi Hata Akira Inoue Masayuki Hiraki Masahisa Ohtsuka Hidekazu Takahashi Naotsugu Haraguchi Tsunekazu Mizushima Shinji Tanaka Masaki Mori Hirofumi Yamamoto 《Cancer science》2019,110(11):3520-3532
Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E‐cadherin‐Fc chimera protein (E‐cad‐Fc) enhances cancer stem‐like properties because studies show that soluble E‐cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)‐degron–transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E‐cad‐Fc treatment, we found that E‐cad‐Fc treatment further suppressed proteasome activity and largely enhanced cancer stem‐like properties of ODC‐degron–transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi‐1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5‐fluorouracil (5‐FU) and oxaliplatin (L‐OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E‐cad‐Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E‐cad‐Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E‐cad‐Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation. 相似文献
3.
Mamiko Onuki Koji Matsumoto Takashi Iwata Kasumi Yamamoto Yoichi Aoki Shoji Maenohara Naotake Tsuda Shoji Kamiura Kazuhiro Takehara Koji Horie Nobutaka Tasaka Hideaki Yahata Yuji Takei Yoichi Aoki Hisamori Kato Takeshi Motohara Keiichiro Nakamura Mitsuya Ishikawa Tatsuya Kato Hiroyuki Yoshida Noriomi Matsumura Hidekatsu Nakai Shogo Shigeta Fumiaki Takahashi Kiichiro Noda Nobuo Yaegashi Hiroyuki Yoshikawa 《Cancer science》2020,111(7):2546-2557
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. 相似文献
4.
Kiran Naqvi MD Elias Jabbour MD Jeffrey Skinner BS MHA Kristin Anderson BS Sara Dellasala BS Musa Yilmaz MD Alessandra Ferrajoli MD Prithviraj Bose MD Philip Thompson MBBS Yesid Alvarado MD Nitin Jain MBBS Koichi Takahashi MD Jan Burger MD Zeev Estrov MD Gautam Borthakur MBBS Naveen Pemmaraju MD Shilpa Paul Pharm D Jorge Cortes MD Hagop M. Kantarjian MD 《Cancer》2020,126(1):67-75
5.
6.
Kenji Tamura Kosei Hasegawa Noriyuki Katsumata Koji Matsumoto Hirofumi Mukai Shunji Takahashi Hiroyuki Nomura Hironobu Minami 《Cancer science》2019,110(9):2894-2904
Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death‐1, inhibiting binding to programmed death‐ligand 1 or 2 (PD‐L1 or PD‐L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2‐week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression‐free survival, and safety. PD‐L1 expression and microsatellite‐instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression‐free survival was 5.6, 3.4, and 1.4 months, and 6‐month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD‐L1‐positive (n = 5/15; 33%) versus PD‐L1‐negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI‐high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD‐L1 expression in cervical cancer and MSI‐high in corpus cancer may predict clinical activity of nivolumab in these cancers. 相似文献
7.
Tamami Higuchi Takehiko Yokobori Ryo Takahashi Tomoharu Naito Hiromu Kitahara Takeshi Matsumoto Chihaya Kakinuma Shinji Hagiwara Hiroyuki Kuwano Ken Shirabe Takayuki Asao 《Cancer science》2019,110(9):2933-2940
Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF‐10832 as liposome‐encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF‐10832 with those of gemcitabine. Despite the single intravenous administration, FF‐10832 treatment enabled long‐term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF‐10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome‐encapsulated gemcitabine FF‐10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors. 相似文献
8.
Masataka Yamazaki Akihiro Yoshitake Tatsuo Takahashi Tsutomu Ito Naritaka Kimura Hideyuki Shimizu 《Journal of cardiac surgery》2019,34(8):728-731
Minimally invasive mitral valve surgery (MIMVS), despite its challenges, is not a rare procedure. However, MIMVS via a right small thoracotomy must be performed using long‐shafted surgical instruments and thoracotomy instruments specialized for minimally invasive cardiac surgeries. We have performed 12 cases of MIMVS via right small thoracotomy using the superior trans‐septal approach and secured a surgical visual field that easily allows a finger to reach the mitral valve annulus without using special instruments for minimally invasive cardiac surgery. We named this technique the “drawer‐case technique.” In conclusion, MIMVS via right thoracotomy using the superior trans‐septal approach can be performed easily and safely, similar to mitral valve surgery performed via median sternotomy. 相似文献
9.
Masashi Uehara Jun Takahashi Shota Ikegami Ryosuke Tokida Hikaru Nishimura Noriko Sakai Hiroyuki Kato 《The spine journal》2019,19(2):349-356
BACKGROUND CONTEXT
It is widely recognized that sagittal spinal alignment changes with age. However, there are presently no clear benchmarks for such values or those for the cervical spine in the general population. Quality epidemiological studies are needed to establish standards for spinal alignment deviation.OBJECTIVES
In this study of an aged Japanese population, we employed random sampling from the basic resident registry of a rural town for subject selection to determine reference values of sagittal spinal alignment including the cervical spine.STUDY DESIGN
Japanese resident cohort study based on a municipal registry.PATIENT SAMPLE
A total of 413 aged people randomly sampled from the resident registry of a rural Japanese town.OUTCOME MEASURES
All subjects underwent a whole spine lateral radiograph for measurement of sagittal spinal alignment parameters.METHODS
Registered citizens of 50 to 89 years old were targeted for this survey. We established eight groups based on age (50s, 60s, 70s, and 80s) and gender (male and female) after random sampling from the resident registry of Obuse town in 2014. A total of 413 people (203 males and 210 females) were enrolled. Radiographic parameters of sagittal spinal alignment of the cohort were measured and analyzed. Funding for this study was provided by the Japan Orthopaedics and Traumatology Research Foundation (10,000 USD), the Japanese Orthopaedic Association (5,000 USD), the Japanese Society for Musculoskeletal Medicine (40,000 USD), and the Nakatomi Foundation (15,000 USD).RESULTS
Global spinal alignments became more misaligned with age for both genders. Sagittal vertical axis (SVA) forward shift was significantly more frequent in 80s males and 70s females, and SVA in 80s females was a mean of 66 mm forward of that of 50s females. Cervical protrusion was markedly greater in 60s males onwards. In women, lumbar lordosis and posterior pelvic inclination were noticeable from a younger age than in men. The amount of pelvic tilt misalignment in female subjects was approximately 10 years earlier than their male counterparts.CONCLUSIONS
This first resident cohort of Japanese individuals determined average spinal alignment parameters by age and gender. Spinal balance generally shifts forward as age increases. A forward shift in the upper cervical spine occurs first in men, whereas lumbopelvic alignment shift occurs first in women. 相似文献10.
Kazuto Tsukita Haruhi Sakamaki‐Tsukita Kanta Tanaka Toshihiko Suenaga Ryosuke Takahashi 《Movement disorders》2019,34(10):1452-1463
Previous studies that have investigated the potential of in vivo abnormal α‐synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α‐synuclein deposits in PD through a systematic review and meta‐analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case‐control studies that examined in vivo tissue samples using anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibody in PD patients and controls. Using a univariate random‐effects model, pooled sensitivity and specificity (95% confidence interval) of anti‐native α‐synuclein antibody were 0.54 (0.49‐0.60) and 0.72 (0.68‐0.76) for the gastrointestinal tract and 0.76 (0.60‐0.89) and 0.60 (0.43‐0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti‐phosphorylated α‐synuclein antibody were 0.43 (0.37‐0.48) and 0.82 (0.78‐0.86) for the gastrointestinal tract, 0.76 (0.69‐0.82) and 1.00 (0.98‐1.00) for the skin, 0.42 (0.26‐0.59) and 0.94 (0.84‐0.99) for the minor salivary glands, and 0.66 (0.51‐0.79) and 0.96 (0.86‐1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α‐synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti‐phosphorylated α‐synuclein antibody consistently has higher specificity than anti‐native α‐synuclein antibody; and (3) skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society 相似文献