Publications by authors named "Masayuki Takeda"

299 Publications

First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small Cell Lung Cancer: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial.

J Thorac Oncol 2021 Oct 11. Epub 2021 Oct 11.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death ligand 1 (PD-L1) ≥1% (primary end point) or <1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up.

Methods: Adults with previously untreated stage IV/recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs).

Results: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 ≥1% (HR 0.76; 95% CI: 0.65-0.90) and PD-L1 <1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred ≤6 months from start of treatment and resolved ≤3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all-randomized population.

Conclusions: At >4 years' minimum follow-up, with all patients off immunotherapy treatment for ≥2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guidelines-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.
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http://dx.doi.org/10.1016/j.jtho.2021.09.010DOI Listing
October 2021

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma.

JTO Clin Res Rep 2021 Jun 29;2(6):100178. Epub 2021 Apr 29.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study.

Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest).

Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths.

Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474437PMC
June 2021

Potential Targets for Overactive Bladder in Older Men Based on Urinary Analysis of Metabolomics.

Urol Int 2021 Sep 16:1-7. Epub 2021 Sep 16.

Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.

Objective: We investigated the association between overactive bladder (OAB) and urinary metabolites in men.

Methods: This prospective observational study included 42 men aged 65-80 years. The 3-day frequency volume chart (FVC), International Prostate Symptom Score (IPSS), and quality of life score were adapted to assess the micturition behavior. Participants with IPSS urgency score ≥2 were included in the OAB group, and those with IPSS urgency score <2 were included in the control group. We performed a comprehensive metabolomic analysis using urine samples. Metabolites were compared between the groups using an unpaired t test and Fisher's exact test in a nonadjusted analysis. Multivariable logistic regression analysis was performed to investigate the association between OAB and the metabolites.

Results: Overall, 23 men were included in the OAB group and 19 in the control group. There were no differences in the background factors except age between the groups. FVC analysis demonstrated that nocturnal urine volume, 24-h micturition frequency, and nocturnal micturition frequency were significantly higher, and the maximum voided volume was significantly lower in the OAB group than in the controls. Metabolomic analysis revealed 14 metabolites that were differentially expressed between the groups. Multivariate analysis indicated that an increase in the levels of 5-iso prostaglandin F2α-VI (5-iPF2a-VI) and 5-methoxyindoleacetic acid was associated with OAB.

Conclusion: Abnormal urinary metabolites, including metabolites in the tryptophan (5-methoxyindoleacetic acid, 3-indoleacetonitrile, and 3-hydroxyanthranilic acid) and arachidonic acid (5-iPF2a-VI) pathways, play a role in the pathogenesis of OAB in older men.
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http://dx.doi.org/10.1159/000518300DOI Listing
September 2021

Mayo Adhesive Probability Score Is Associated with the Operative Time in Laparoscopic Adrenalectomy.

J Laparoendosc Adv Surg Tech A 2021 Sep 3. Epub 2021 Sep 3.

Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.

Laparoscopic adrenalectomy (LA) is the standard treatment for adrenal benign tumors, including primary aldosteronism (PA) or Cushing's syndrome (CS). Several obesity-related factors were associated with prolonged total operative time (OT), but perinephric fat characteristics were not assessed. We investigated whether the Mayo adhesive probability (MAP) score, which evaluates perinephric fat characteristics, was associated with OT for LA. This single-center, retrospective cohort study examined 141 consecutive patients who underwent LA for PA or CS. We reviewed patients' characteristics and OT. MAP scores were recorded using preoperative imaging. The correlation among characteristics data, MAP score, and OT was evaluated. Overall, we assessed 82 women and 59 men. Adrenal tumors were found in 80 PA and 61 CS patients. There were 74 left-sided and 67 right-sided tumors. For all patients, the median age, body mass index, and tumor size were 56 years (interquartile range [IQR] 46-65), 24.1 kg/m (IQR 21.7-26.8), and 19 mm (IQR 13-26), respectively. A total of 91 patients had MAP scores of 0, and 50 had MAP >0. The median OT was 183.5 minutes (IQR: 156-224 minutes) in the MAP >0 group and 162 minutes (IQR: 135-194 minutes) in the MAP = 0 group. In single variable analysis (unadjusted), MAP scores >0 and left-sided tumors were correlated with longer OT. Multivariable regression analysis revealed that this correlation was only significant for MAP scores >0. MAP score may be useful in preoperative planning for PA or CS patients undergoing LA.
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http://dx.doi.org/10.1089/lap.2021.0459DOI Listing
September 2021

Successful treatment of a case of hormone receptor-positive metastatic extramammary Paget disease with tamoxifen.

Invest New Drugs 2021 Aug 31. Epub 2021 Aug 31.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.
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http://dx.doi.org/10.1007/s10637-021-01168-5DOI Listing
August 2021

Current Status of Next-Generation Sequencing-Based Cancer Genome Profiling Tests in Japan and Prospects for Liquid Biopsy.

Life (Basel) 2021 Aug 6;11(8). Epub 2021 Aug 6.

Department of Cancer Genomics and Medical Oncology, Nara Medical University, Kashihara 634-8521, Japan.

Next-generation sequencing-based comprehensive genome profiling (CGP) testing, OncoGuide NCC Oncopanel System, and FoundationOne CDx Cancer Genomic Profile have been covered by the Japanese national health insurance system since June 2019. Because CGP was initially developed to enroll patients into an early-phase clinical trial for solid tumors, its approved indications have been limited to patients who have completed the standard chemotherapy treatment. Approximately 14,000 cases have been registered with the Center for Cancer Genomics and Advanced Therapeutics as of March 2021. Measuring the drug access rate is not enough due to patients' deteriorating condition during CGP analysis and due to the limited number of ongoing clinical trials available, although tumor-agnostic therapies, such as the use of pembrolizumab in high microsatellite-instable solid tumors and in conditions with a high tumor mutational burden (≥10 mut/Mb) as well as the use of entrectinib and larotrectinib in fusion-positive tumors have been approved in Japan. Moreover, since this analysis is performed using DNA derived from tumor tissue, it is difficult to perform CGP in cases in which an insufficient amount of tissue exists. Thus, noninvasive blood-based assays have been developed, and CGP panels using circulating tumor DNA from blood were approved in March 2021. However, cost, timing, and the number of tests allowed by the health system have not yet been determined. Therefore, in this review, we outline the current status and issues of CGP testing using tumor tissues as well as the expectations and limitations of liquid biopsy for use in Japanese clinical practice.
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http://dx.doi.org/10.3390/life11080796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399872PMC
August 2021

Durable response to EGFR tyrosine kinase inhibitors in a patient with non-small cell lung cancer harboring an EGFR kinase domain duplication.

Thorac Cancer 2021 08 9;12(16):2283-2287. Epub 2021 Jul 9.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

Epidermal growth factor receptor (EGFR) kinase domain duplication (KDD) has been identified as an oncogenic driver in 0.05% to 0.14% of non-small cell lung cancer (NSCLC) patients. However, little is known of the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for such patients. Here, we report the case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18-25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib. As far as we are aware, this is the first report of EGFR-TKI efficacy for carcinomatous meningitis in a NSCLC patient harboring EGFR-KDD.
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http://dx.doi.org/10.1111/1759-7714.14081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365001PMC
August 2021

Successful engraftment of epithelial cells derived from autologous rabbit buccal mucosal tissue, encapsulated in a polymer scaffold in a rabbit model of a urethral stricture, transplanted using the transurethral approach.

Regen Ther 2021 Dec 8;18:127-132. Epub 2021 Jun 8.

Center for Advancing Clinical Research (CACR), University of Yamanashi -Faculty of Medicine, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.

Background: A pilot study reported an autologous buccal mucosal cell transplant in humans through the trans-urethral route using the buccal epithelium expanded and encapsulated in scaffold-hybrid approach to urethral stricture (BEES-HAUS), a minimally invasive approach to treat urethral stricture. Although successful outcomes were achieved in that study, for further validation, it is essential to prove that the transplanted buccal epithelium was engrafted over the urothelium through histological examination of the urethra, harvested post-transplant, which is infeasible in humans. Herein, we report the successful creation of an animal model of urethral stricture and the engraftment of epithelial cells derived from autologous buccal mucosal tissue, encapsulated in a thermo-reversible gelation polymer (TGP) scaffold, transplanted by trans-urethral route.

Methods: An animal model of urethral stricture was created in Japanese white male rabbits using electro-coagulation. Buccal tissue was harvested from the rabbits and subjected to enzyme digestion, followed by 5-7 days of in vitro culture in conventional two-dimensional (2D) culture and in a 3D platform of thermo-reversible gelation polymer (3D-TGP) culture. The cells harvested from the groups were mixed and encapsulated and transplanted with TGP, by transurethral catheterization. Fourteen days later, the urethra was harvested and subjected to histological examination. The buccal biopsy tissue, cells after digestion and cells post-culture were also subjected to histological examination. Urethrogram and endoscopy images were recorded at different time points.

Results: The stricture was successfully created, with the coagulated area markedly stenosed. Histological staining of the cells after in vitro processing showed that the cells grew with native epithelial and rounded cell morphology in 3D-TGP while they differentiated into fibroblast like-cells in 2D culture. Histological staining of the urethral tissue after transplantation revealed the engraftment of the transplanted buccal mucosal cells, with stratified squamous epithelium over the specialized stratified urothelium in the urethrotomy site.

Conclusion: We used histology to prove the successful engraftment of TGP-encapsulated buccal mucosal epithelial cells in an animal model of urethral injury with healing of the injured tissue. The model of urethral stricture and cell therapy, using a transurethral approach, recapitulates the previously reported BEES-HAUS approach and lays the foundation for larger multi-centric translational clinical studies.
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http://dx.doi.org/10.1016/j.reth.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203727PMC
December 2021

Cardiovascular safety of vibegron, a new β3-adrenoceptor agonist, in older patients with overactive bladder: Post-hoc analysis of a randomized, placebo-controlled, double-blind comparative phase 3 study.

Neurourol Urodyn 2021 08 17;40(6):1651-1660. Epub 2021 Jun 17.

Medical Affairs, Kyorin Pharmaceutical Co., Ltd., Toyko, Japan.

Aims: To examine the safety and efficacy of vibegron, a new β3-adrenoceptor agonist, in patients aged ≥65 years, with a focus on the effects on cardiovascular system and overactive bladder (OAB) symptoms.

Methods: A post-hoc subgroup analysis was performed of a randomized, placebo-controlled, double-blind comparative phase 3 study of vibegron, including those assigned to receive either vibegron 50 mg (V50), vibegron 100 mg (V100), or placebo for 12 weeks. Subjects were stratified into two subgroups based on age: a <65-year subgroup and a ≥65-year subgroup. Safety (changes in systolic and diastolic blood pressure, pulse rate, and residual urine volume) and efficacy (changes in the numbers of micturitions, urgency episodes, urgency urinary incontinence [UUI] episodes, and the voided volume/micturition) were assessed in the subgroups treated with vibegron vs. placebo.

Results: There were no significant differences in the cardiovascular outcomes (blood pressure and pulse rate), nor in the changes in residual urine volume, between the V50/100 and placebo groups in the <65-year or ≥65-year subgroup after 12-week treatment. Adverse events were slightly increased in the ≥65-year subgroup. In the efficacy analysis, V50/100 demonstrated similar efficacy in the <65-year and ≥65-year subgroups; an increasing trend in the voided volume/micturition was observed in subjects aged ≥65 years compared to subjects aged <65 years.

Conclusions: Vibegron was suggested to be similarly effective in patients ≥65 and <65 years and to have minimal influence on cardiovascular parameters.
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http://dx.doi.org/10.1002/nau.24732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362047PMC
August 2021

Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA.

Cancer Sci 2021 Sep 12;112(9):3911-3917. Epub 2021 Jul 12.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue-based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer-related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.
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http://dx.doi.org/10.1111/cas.15022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409307PMC
September 2021

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

Int J Clin Oncol 2021 Sep 11;26(9):1628-1639. Epub 2021 Jun 11.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC).

Methods: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance.

Results: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib.

Conclusions: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
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http://dx.doi.org/10.1007/s10147-021-01947-3DOI Listing
September 2021

Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice.

Life Sci 2021 Aug 27;278:119555. Epub 2021 Apr 27.

Department of Urology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.

Objectives: Nocturia is a major problem in geriatric patients. Clock genes regulate circadian bladder function and Piezo type mechanosensitive ion channel component 1 (Piezo1) that senses bladder fullness. We utilized WT and Clock mutant (Clock: nocturia phenotype) mice to determine if the effects of GsMTx4, a Piezo1 inhibitor, is dependent on circadian Piezo1 expression in the bladder.

Methods: We compared voiding behavior in mice after the administration of vehicle, low dose, or high dose of GsMTx4. Intraperitoneal injections (IP) were performed at Zeitgeber time (ZT) 0, lower Piezo1 expression phase (ZT0-IP) and ZT12, higher Piezo1 expression phase (ZT12-IP). Urine volume (Uvol), voiding frequency (VF), and urine volume per void (Uvol/v) were measured using metabolic cages.

Results: VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in Clock mice. VF decreased significantly at ZT0-IP in WT mice after both doses, but only decreased after high dose in Clock mice. Uvol/v increased in WT mice at ZT0-IP after both doses and at ZT12-IP after high dose. Uvol/v increased in Clock mice only at ZT0-IP after high dose. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP.

Conclusions: The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level. The maximum effect occurred during sleep phase in WT. These results may lead to new therapeutic strategies against nocturia.
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http://dx.doi.org/10.1016/j.lfs.2021.119555DOI Listing
August 2021

Implementation of clinical sequencing for molecular profiling in patients with advanced cancer.

Cancer Biomark 2021 ;31(2):119-126

Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.

Background: The advancement of cancer genomics has allowed for multiplex gene assays using next-generation sequencing (NGS) to be practically implemented, however, a clinical practice system remains to be established.

Objective: We evaluated the feasibility of clinical sequencing using NGS-based multiplex gene assays between cooperating medical institutions in patients with advanced cancers.

Methods: In this observational study, DNA and RNA samples prepared from existing tumor tissues were subjected to comprehensive genomic profiling using targeted sequencing.

Results: From January 2017 to March 2019, 36 samples from 33 patients were assessed. Of all patients, 27 (82%) had lung cancer, with the median age of 50 years (range 38-83). Multiplex gene panel tests were successfully carried out on 35/36 (97%) samples. Potentially actionable gene alterations were identified in 10/30 (33%) samples (3 HER2, 2 KRAS, 2 ALK, 1 PIK3CA, 1 RET, and 1 CDKN2A). In the 6 samples examined for resistant mechanisms, ALK I1171N mutation and MET copy number gain were detected in 2 patients with ALK rearrangement-positive lung cancer.

Conclusions: Clinical sequencing using NGS-based multiplex gene assays between collaborating domestic medical institutions was feasible, with a success rate of > 97%. Overall, clinical sequencing benefits therapeutic decision-making in patients with advanced cancer.
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http://dx.doi.org/10.3233/CBM-200781DOI Listing
January 2021

A 3D Polymer Scaffold Platform for Enhanced Culture of Human & Rabbit Buccal Epithelial Cells for Cell Therapies.

Tokai J Exp Clin Med 2021 Apr 20;46(1):1-6. Epub 2021 Apr 20.

II Department of Surgery & Center for Advancing Clinical Research (CACR), University of Yamanashi, Faculty of Medicine, 1110, Shimokato, Chuo, Yamanashi 409-3898, Japan.

Background: Buccal mucosal epithelial cells show promising application for various regenerative medicine approaches. In this study, we examined the feasibility of culturing rabbit and human buccal mucosal epithelial cells in a novel thermoreversible gelation polymer (TGP) scaffold, without feeder layers or other foreign proteins.

Methods & Results: The results of this 28-day culture, u sing the conventional technique (2D) and TGP (3D) showed that the epithelial cell morphology could be maintained only in the TGP group while cells in the 2D group de-differentiated to fibroblast morphology in both human and rabbit samples. CK3 expression, a marker for epithelial differentiation was higher in 3D-TGP cultured cells than 2D.

Conclusion: TGP based cell culture is a prospective methodology to culture buccal mucosal epithelial cells efficiently without using foreign biological components for tissue engineering applications.
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April 2021

A Phase II Study to Assess the Efficacy of Osimertinib in Patients With EGFR Mutation-positive NSCLC Who Developed Isolated CNS Progression (T790M-negative or Unknown) During First- or Second-generation EGFR-TKI or Systemic Disease Progression (T790M-negative) After Treatment With First- or Second-generation EGFR-TKI and Platinum-based Chemotherapy (WJOG12819L).

Clin Lung Cancer 2021 07 25;22(4):376-380. Epub 2021 Jan 25.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.
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http://dx.doi.org/10.1016/j.cllc.2020.12.009DOI Listing
July 2021

Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study.

Cancer Sci 2021 Apr 24;112(4):1556-1566. Epub 2021 Feb 24.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan.

MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non-small-cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono-1, NCT02414139) in patients with advanced METΔex14-mutated/MET-amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14-mutated or MET-amplified) and line of therapy (first- [1L] or second-/third-line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14-mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%-69.2%), median DOR was not evaluable, and progression-free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET-amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment-related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET-amplified NSCLC, consistent with the overall population.
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http://dx.doi.org/10.1111/cas.14826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019204PMC
April 2021

[EVALUATING THE RELATIONSHIP BETWEEN LOWER URINARY TRACT SYMPTOMS AND ENDOTHELIAL FUNCTION USING FLOW-MEDIATED DILATION, AND THE EFFECTS OF TADALAFIL].

Nihon Hinyokika Gakkai Zasshi 2020 ;111(1):1-8

Department of Urology, Nagakubo Hospital.

(Objective) Recently, lower urinary tract symptoms (LUTS) were reported to be associated with endothelial dysfunction. Endothelial function is non-invasively measured by flow-mediated dilation (FMD). As tadalafil has the potential to improve atherosclerosis, we evaluated the relationship between LUTS and endothelial function using FMD, and the effects of tadalafil. (Patients and methods) We conducted FMD examinations for a total of 122 males, and analyzed its association with IPSS, OABSS, and cardiovascular risks. Furthermore, 21 BPH patients received 5 mg of tadalafil per day for one year. We defined the Low FMD group as FMD < 3.9% and the Control group as other values, and compared the effects of tadalafil between groups. (Results) In the 122 male patients, FMD was negatively correlated with nocturia and OABSS. Patients with hypertension or coronary artery disease had a lower FMD than those without.In the tadalafil administration study, the Low FMD group achieved greater improvement of IPSS, OABSS and FMD than the Control group. (Conclusion) FMD examination revealed that endothelial dysfunction is closely associated with LUTS in males, and that tadalafil is effective for patients with endothelial dysfunction.
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http://dx.doi.org/10.5980/jpnjurol.111.1DOI Listing
February 2021

Corrigendum: Blockade of Acid-Sensing Ion Channels Increases Urinary Bladder Capacity With or Without Intravesical Irritation in Mice.

Front Physiol 2020 15;11:624382. Epub 2020 Dec 15.

Department of Urology, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.

[This corrects the article DOI: 10.3389/fphys.2020.592867.].
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http://dx.doi.org/10.3389/fphys.2020.624382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770126PMC
December 2020

Interstitial lung disease associated with capmatinib therapy in a patient with non-small cell lung cancer harboring a skipping mutation of MET exon 14.

Thorac Cancer 2021 02 21;12(4):549-552. Epub 2020 Dec 21.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Capmatinib is a MET tyrosine kinase inhibitor (TKI) that has recently been approved for the treatment of advanced non-small cell lung cancer (NSCLC) positive for skipping mutations of MET exon 14 (METex14). Drug-induced interstitial lung disease (ILD) is a relatively rare, but potentially serious, side effect of TKIs administered for lung cancer treatment. Here we report a case of capmatinib-induced ILD in a patient with NSCLC harboring a METex14 skipping mutation. Capmatinib should be immediately discontinued if ILD is suspected, and treatment with corticosteroid should be considered.
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http://dx.doi.org/10.1111/1759-7714.13790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882388PMC
February 2021

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

Oncologist 2021 04 6;26(4):e588-e596. Epub 2021 Jan 6.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.

Materials And Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan.

Results: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy.

Conclusion: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs.

Implications For Practice: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
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http://dx.doi.org/10.1002/onco.13639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018334PMC
April 2021

Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.

Br J Cancer 2021 03 10;124(5):914-924. Epub 2020 Dec 10.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects.

Methods: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB).

Results: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8 T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8 T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice.

Conclusions: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8 T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
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http://dx.doi.org/10.1038/s41416-020-01201-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921555PMC
March 2021

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1).

Int J Clin Oncol 2021 Feb 29;26(2):233-283. Epub 2020 Nov 29.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published "Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment" in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made.

Methods: A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020.

Results: The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines.

Conclusion: We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
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http://dx.doi.org/10.1007/s10147-020-01831-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819967PMC
February 2021

Blockade of Acid-Sensing Ion Channels Increases Urinary Bladder Capacity With or Without Intravesical Irritation in Mice.

Front Physiol 2020 26;11:592867. Epub 2020 Oct 26.

Department of Urology, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.

We conducted this study to examine whether acid-sensing ion channels (ASICs) are involved in the modulation of urinary bladder activity with or without intravesical irritation induced by acetic acid. All evaluations were conducted during continuous infusion cystometry in decerebrated unanesthetized female mice. During cystometry with a pH 6.3 saline infusion, an i.p. injection of 30 μmol/kg A-317567 (a potent, non-amiloride ASIC blocker) increased the intercontraction interval (ICI) by 30% ( < 0.001), whereas vehicle injection had no effect. An intravesical acetic acid (pH 3.0) infusion induced bladder hyperactivity, with reductions in ICI and maximal voiding pressure (MVP) by 79% ( < 0.0001) and 29% ( < 0.001), respectively. A-317567 (30 μmol/kg i.p.) alleviated hyperreflexia by increasing the acid-shortened ICI by 76% ( < 0.001). This dose produced no effect on MVP under either intravesical pH condition. Further analysis in comparison with vehicle showed that the increase in ICI (or bladder capacity) by the drug was not dependent on bladder compliance. Meanwhile, intravesical perfusion of A-317567 (100 μM) had no effect on bladder activity during pH 6.0 saline infusion cystometry, and drug perfusion at neither 100 μM nor 1 mM produced any effects on bladder hyperreflexia during pH 3.0 acetic acid infusion cystometry. A-317567 has been suggested to display extremely poor penetrability into the central nervous system and thus to be a peripherally active blocker. Taken together, our results suggest that blockade of ASIC signal transduction increases bladder capacity under normal intravesical pH conditions and alleviates bladder hyperreflexia induced by intravesical acidification and that the site responsible for this action is likely to be the dorsal root ganglia.
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http://dx.doi.org/10.3389/fphys.2020.592867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649782PMC
October 2020

Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: Update summary of the 2015  Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis.

Int J Clin Oncol 2021 Jan 8;26(1):1-17. Epub 2020 Nov 8.

Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido, Japan.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).
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http://dx.doi.org/10.1007/s10147-020-01818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788035PMC
January 2021

Predicting osimertinib-treatment outcomes through EGFR mutant-fraction monitoring in the circulating tumor DNA of EGFR T790M-positive patients with non-small cell lung cancer (WJOG8815L).

Mol Oncol 2021 01 17;15(1):126-137. Epub 2020 Nov 17.

Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan.

The WJOG8815L phase II clinical study involves patients with non-small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third-generation EGFR-TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR-TKI-sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing-and T790M-EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation-positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression-free survival were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
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http://dx.doi.org/10.1002/1878-0261.12841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782093PMC
January 2021

A case of urethral metastasis of castration-resistant prostate cancer successfully cured with CyberKnife radiosurgery.

Urol Case Rep 2020 Nov 13;33:101346. Epub 2020 Jul 13.

Department of Urology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.

Distant urethral metastasis of the castration-resistant prostate cancer (CRPC) is very rare. In this case report, we present a 69-year-old man who was first diagnosed prostate cancer from the sessile papillary tumor in the prostatic urethra which recurred after surgery and androgen deprivation therapy and finally treated with CyberKnife radiosurgery. There has been no recurrence for 50 months. To the best of our knowledge, there is no case of urethral metastasis of the CRPC successfully controlled with CyberKnife radiosurgery in the literature.
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http://dx.doi.org/10.1016/j.eucr.2020.101346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573952PMC
November 2020

Cine magnetic resonance imaging provides novel predictors of early continence recovery after radical prostatectomy: Assessment of the dynamics of pelvic floor muscles.

Neurourol Urodyn 2021 01 16;40(1):256-264. Epub 2020 Oct 16.

Department of Urology, University of Yamanashi Graduate School of Medical Sciences, Chuo, Japan.

Aims: Postprostatectomy incontinence is a major complication of prostatectomy. Although pelvic floor muscle training can successfully treat postprostatectomy incontinence, evidence for how muscle movement affects continence recovery is lacking. We evaluated dynamic factors of prostatectomy patients using cine magnetic resonance imaging to identify risk factors for postprostatectomy incontinence and reveal the contribution of pelvic floor muscles to continence recovery.

Methods: A total of 128 prostate cancer patients who underwent robot-assisted laparoscopic surgery were enrolled. Cine magnetic resonance imaging was performed preoperatively and 6 months after surgery. Continence was defined as pad-free or use of safety pads. We defined the bladder neck elevation distance during pelvic floor muscle training as the bladder elevation distance. Patients with continence recovery within 1 month comprised the continence group (n = 48); other patients comprised the incontinence group (n = 80).

Results: The preoperative bladder elevation distance was significantly longer in the continence group than in the incontinence group (10.4 vs. 8.2 mm; p < .001). The postoperative bladder elevation distance of the continence group tended to be longer (9.9 vs. 8.9 mm; p = .057). Multivariate analysis showed that the preoperative bladder elevation distance significantly contributed to continence recovery (p = .016). Patients with a longer preoperative bladder elevation distance (>8.5 mm) experienced continence recovery significantly faster than patients with a shorter distance (<8.5mm) (p = .038).

Conclusions: Bladder elevation distance, a novel dynamic parameter, was strongly associated with early continence recovery. Cine magnetic resonance imaging can assess a patient's risk of postprostatectomy incontinence and guide pelvic floor muscle training.
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http://dx.doi.org/10.1002/nau.24544DOI Listing
January 2021

BRCA2 Reversion Mutation Identified by Liquid Biopsy After Durable Response to FOLFIRINOX in BRCA2-Associated Pancreatic Cancer.

Pancreas 2020 Nov/Dec;49(10):e101-e103

Department of Therapeutic Oncology Graduate School of Medicine Kyoto University Kyoto, Japan Clinical Genetics Unit Kyoto University Hospital Kyoto, Japan Department of Diagnostic Pathology Kyoto University Hospital Kyoto, Japan Department of Medical Oncology Kindai University Faculty of Medicine Osaka, Japan Department of Genome Biology Kindai University Faculty of Medicine Osaka, Japan Department of Therapeutic Oncology Graduate School of Medicine Kyoto University Kyoto, Japan.

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http://dx.doi.org/10.1097/MPA.0000000000001672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598072PMC
September 2021

Simultaneous targeting of MET overexpression in mutation-positive non-small cell lung cancer can increase the benefit of EGFR-TKI therapy?

Transl Lung Cancer Res 2020 Aug;9(4):1617-1622

Department of Medical Oncology, Kindai University, Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.

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http://dx.doi.org/10.21037/tlcr-20-707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481636PMC
August 2020
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