Publications by authors named "Junji Kishimoto"

115 Publications

Efficacy of intensive lipid-lowering therapy with statins stratified by blood pressure levels in patients with type 2 diabetes mellitus and retinopathy: Insight from the EMPATHY study.

Hypertens Res 2021 Sep 15. Epub 2021 Sep 15.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Intensive lipid-lowering therapy is recommended in individuals exhibiting type 2 diabetes mellitus (T2DM) with microvascular complications (as high-risk patients), even without known cardiovascular disease (CVD). However, evidence is insufficient to stratify the patients who would benefit from intensive therapy among them. Hypertension is a major risk factor, and uncontrolled blood pressure (BP) is associated with increased CVD risk. We evaluated the efficacy of intensive vs. standard statin therapy for primary CVD prevention among T2DM patients with retinopathy stratified by BP levels. We used the dataset from the EMPATHY study, which compared intensive statin therapy targeting low-density lipoprotein cholesterol (LDL-C) levels of <70 mg/dL and standard therapy targeting LDL-C levels ranging from ≥100 to <120 mg/dL in T2DM patients with retinopathy without known CVD. A total of 4980 patients were divided into BP ≥ 130/80 mmHg (systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 80 mmHg, n = 3335) and BP < 130/80 mmHg (n = 1645) subgroups by baseline BP levels. During the median follow-up of 36.8 months, 281 CVD events were observed. Consistent with previous studies, CVD events occurred more frequently in the BP ≥ 130/80 mmHg subgroup than in the BP < 130/80 mmHg subgroup (P < 0.001). In the BP ≥ 130/80 mmHg subgroup, intensive statin therapy was associated with lower CVD risk (HR 0.70, P = 0.015) than standard therapy after adjustment. No such association was observed in the BP < 130/80 mmHg subgroup. The interaction between BP subgroup and statin therapy was significant. In conclusion, intensive statin therapy targeting LDL-C < 70 mg/dL provided benefits in primary CVD prevention when compared with standard therapy among T2DM patients with retinopathy and BP ≥ 130/80 mmHg.
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http://dx.doi.org/10.1038/s41440-021-00734-xDOI Listing
September 2021

Kawasaki Disease and Vaccination: Prospective Case-Control and Case-Crossover Studies among Infants in Japan.

Vaccines (Basel) 2021 Jul 30;9(8). Epub 2021 Jul 30.

Kawasaki Disease Center, Fukuoka Children's Hospital, Fukuoka 813-0017, Japan.

The causal effects of vaccines on Kawasaki disease (KD) remain elusive. We aimed to examine the association between vaccines administered during infancy and the development of KD in Japan. We conducted a multicenter prospective case-control study using questionnaires and compared the vaccination status of infants (age: 6 weeks to 9 months) who developed KD (KD group; = 102) and those who did not develop KD (non-KD group; = 139). Next, we performed a case-crossover study of 98 cases in the KD group and compared the status of vaccinations between the case and control periods. We also compared the incidence of KD in children for each 5-year period before and after the addition of new vaccines (2012-2013) using data from the Nationwide Survey of KD. In the case-control study, the vaccination status of the KD and control groups did not differ to a statistically significant extent. Multivariable analysis of the vaccination status and patient backgrounds showed no significant association between vaccination and KD development. In the case-crossover study, the status of vaccinations during the case and control periods did not differ to a statistically significant extent. In the analysis of data from the Nationwide Survey of KD, the incidence of KD in children of ages subject to frequent vaccination showed no significant increases in the latter five years, 2014-2018. Based on these prospective analyses, we confirmed that vaccination in early infancy did not affect the risk of KD.
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http://dx.doi.org/10.3390/vaccines9080839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402330PMC
July 2021

Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure.

ESC Heart Fail 2021 Aug 13. Epub 2021 Aug 13.

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka-shi, Fukuoka, Japan.

Aims: Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy-to-use prediction model with high accuracy using the top predictors identified by the ML algorithm.

Methods And Results: Machine learning-based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow-up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy-to-use prediction model was developed based on these predictors. The c-statistics and Brier scores of the developed ML-based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD-VC) achieved the highest c-statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non-loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART-HF) was established as an easy-to-use prediction model. Compared with the conventional models, SMART-HF achieved a higher c-statistic {ACD-VC: 0.777 [95% confidence interval (CI) 0.751-0.803], SMART-HF: 0.765 [95% CI 0.739-0.791], SHFM: 0.713 [95% CI 0.684-0.742], MAGGIC: 0.726 [95% CI 0.698-0.753]} and better Brier scores (ACD-VC: 0.121, SMART-HF: 0.124, SHFM: 0.139, MAGGIC: 0.130).

Conclusions: The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART-HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART-HF model has the clear merit of easy operability even by non-healthcare providers with a user-friendly online interface (https://hfriskcalculator.herokuapp.com/). Risk models developed using SMART-HF may provide a novel modality for risk stratification of patients with HF.
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http://dx.doi.org/10.1002/ehf2.13556DOI Listing
August 2021

Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity.

BMJ Open 2021 07 27;11(7):e047003. Epub 2021 Jul 27.

Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Introduction: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP.

Methods And Analysis: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints.

Ethics And Dissemination: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals.

Trial Registration Numbers: NCT04621136 and jRCT2071200047.
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http://dx.doi.org/10.1136/bmjopen-2020-047003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317081PMC
July 2021

Development of Quality of Life Questionnaire for Patients with Parkinson's Disease Undergoing STN-DBS.

Neurol Med Chir (Tokyo) 2021 Aug 21;61(8):475-483. Epub 2021 Jun 21.

National Cerebral and Cardiovascular Center.

In device-aided therapy (DAT) for Parkinson's disease (PD), factors such as device-related adverse effects, psychological and lifestyle changes, and specific disease progression can affect the quality of life (QoL) of patients with advanced PD. However, there is no existing QoL scale that includes the effects of therapeutic devices. From a semi-structured interview with patients with PD undergoing deep brain stimulation (DBS), we extracted the content of utterances that were thought to affect the QoL and created a draft questionnaire consisting of 113 items. This questionnaire was administered to 54 other patients undergoing DBS, whose data were examined for reliability and validity by factor analysis, and finally, a 24-item PD QoL questionnaire for patients on DAT (PDQ-DAT) was developed. Presently, the PDQ-DAT is the only scale that can assess the QoL of patients on DAT, including the influence treatment devices have on them. In the future, it might be used to help in shared decision-making in medicine by incorporating the patient's sense of burden and values in the selection of treatment methods.
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http://dx.doi.org/10.2176/nmc.oa.2020-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365237PMC
August 2021

An open-label phase Ⅰ/Ⅱ a clinical trial of 11β-HSD1 inhibitor for Cushing's syndrome and autonomous cortisol secretion.

J Clin Endocrinol Metab 2021 Jun 18. Epub 2021 Jun 18.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.

Context: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate anti-metabolic and anti-sarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients.

Objective: To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients.

Design: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database.

Setting: Kyushu University Hospital, Kurume University Hospital, and related facilities.

Patients: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance.

Intervention: Oral administration of 200-mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200-mg BID) was administered for the residual 12 weeks.

Main Outcome Measures: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75 g-oral glucose tolerance test at 24 weeks.

Results: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% (SD, 14.8 [90% CI: -14.8- -1.0], P=0.033) and -2.7% (14.5 [-10.2-3.4], P=0.18) at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% (1.7 [-3.3- -1.8], P<0.001), and body muscle percentage increased by 2.4% (1.6 [1.7-3.1], P<0.001).

Conclusions: S-707106 is an effective insulin sensitizer and anti-sarcopenic and anti-obesity medication for these patients.
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http://dx.doi.org/10.1210/clinem/dgab450DOI Listing
June 2021

Effects of Medications and Subthalamic Nucleus-Deep Brain Stimulation on the Cutaneous Silent Period in Patients With Parkinson's Disease.

Neuromodulation 2021 May 21. Epub 2021 May 21.

Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan.

Objectives: We sought to evaluate whether the cutaneous silent period (CSP) could be an electrophysiological indicator reflective of the effects of therapy for Parkinson's disease (PD), including anti-PD medications or deep brain stimulation (DBS).

Material And Methods: We recorded the CSP in 43 patients with PD prior to and following the administration of medication during a pre-DBS evaluation (30 cases) and the "on" and "off" states of subthalamic nucleus DBS (13 cases). The CSP was elicited from the abductor pollicis brevis muscle by an electrical stimulation of the index finger that was 2, 4, and 15 times stronger than the sensory threshold (ST). We measured changes in latencies, including the onset, duration, and end of CSP, and waveform scores from 0 to 3. The correlation between the CSP score and unified PD rating score part III (UPDRS-III) also was assessed.

Results: The onset latency and duration of CSP were significantly different between high (15ST) and low-strength stimulations (2ST and 4ST). However, there were no significant latency changes (onset, duration, end of CSP) before and after receiving medication, or during the on and off state of the DBS. Anti-PD medications substantially increased the CSP waveform score only in the 4ST state. However, the waveform score significantly increased in all stimuli states during the DBS-on state. Both medication and the DBS-on state decreased the UPDRS-III. Nevertheless, there was no statistically significant correlation between the UPDRS-III and CSP waveform scores.

Conclusion: Different onset latencies and the duration of CSP between low- and high-strength stimuli support the hypotheses proposing two different reflex pathways. Despite being independent from the UPDRS-III, the CSP may be an electrophysiological indicator reflective of the changes in inhibitory activity to the spinal α-motoneuron in response to anti-PD medications and DBS.
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http://dx.doi.org/10.1111/ner.13454DOI Listing
May 2021

Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability.

J Hypertens 2021 Jul;39(7):1435-1443

Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University.

Background: Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability.

Methods: The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months.

Results: In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45-0.90) and 1.21 (95% CI 0.82-1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results.

Conclusion: Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.
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http://dx.doi.org/10.1097/HJH.0000000000002823DOI Listing
July 2021

Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC.

J Thorac Oncol 2021 09 27;16(9):1523-1532. Epub 2021 Apr 27.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Introduction: We aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC.

Methods: In this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m) on day 1 or nab-paclitaxel (100 mg/m) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis.

Results: Between May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4-19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9-16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68-1.07). Median progression-free survival was 4.2 months (95% CI: 3.9-5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9-4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63-0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0-36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9-20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively).

Conclusions: Nab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2021.03.027DOI Listing
September 2021

Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan.

JAMA Netw Open 2021 04 1;4(4):e214475. Epub 2021 Apr 1.

Kawasaki Disease Center, Fukuoka Children's Hospital, Kashiiteriha, Higashi-ku, Fukuoka, Japan.

Importance: The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD.

Objective: To assess the role of droplet or contact transmission in the etiopathogenesis of KD.

Design, Setting, And Participants: This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children's Hospital and 5 adjacent general hospitals. The number of admissions for KD and infectious diseases were analyzed. Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases.

Exposures: Quarantine and isolation owing to the COVID-19 state of emergency.

Main Outcomes And Measures: The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020. A Poisson regression model was used to analyze them.

Results: The study participants included 1649 patients with KD (median [interquartile range] age, 25 [13-43] months; 901 boys [54.6%]) and 15 586 patients with infectious disease (data on age and sex were not available for these patients). The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean [SD], 24.8 [5.6] vs 18.0 [4.0] admissions per month; 27.4% decrease; adjusted incidence rate ratio [aIRR], 0.73; 95% CI, 0.48-1.10; P = .12). However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean [SD], 157.6 [14.4] vs 39.0 [15.0] admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean [SD], 43.8 [12.9] vs 6.0 [2.0] admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections). Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001).

Conclusions And Relevance: In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.4475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025113PMC
April 2021

Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: An open-label, randomised phase 2 clinical trial.

Eur J Cancer 2021 May 1;149:14-22. Epub 2021 Apr 1.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Background: Osimertinib is now a standard treatment for patients with previously untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC). We here investigated whether the combination of osimertinib with cytotoxic chemotherapy might hold additive efficacy, as well as tolerability.

Patients And Methods: We conducted an open-label randomised phase 2 study to evaluate osimertinib and carboplatin-pemetrexed combination in comparison with osimertinib monotherapy in EGFR mutation-positive NSCLC patients who experienced disease progression associated with the emergence of the T790M resistance mutation of EGFR during first-line EGFR-TKI therapy. The primary endpoint was PFS, with secondary endpoints, including OS, response, and safety. Given that osimertinib was approved as a first-line treatment during the study, patient accrual was discontinued, and a final analysis was performed for the 62 enrolled patients.

Results: Median PFS was 15.8 months for the osimertinib monotherapy group and 14.6 months for the combination therapy group (hazard ratio of 1.09, with a 95% confidence interval of 0.51-2.32; P = .83). Median OS was not reached in either group. The overall response rate was 71.4% in the osimertinib monotherapy group and 53.6% in the combination group. The frequency or severity of known adverse events in the combination group was comparable to those with carboplatin and pemetrexed previously reported, and novel adverse events were not observed in this study.

Conclusion: This is the first randomised study to investigate the efficacy and safety of the combination of osimertinib and cytotoxic chemotherapy for EGFR-mutated NSCLC. The addition of chemotherapy to osimertinib as a second-line treatment did not prolong survival, while it was found to be generally tolerable. This combination strategy will be further validated in the first-line setting.

Trial Registration: Japan Registry of Clinical Trials (jRCT) identifier: jRCTs071180062.
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http://dx.doi.org/10.1016/j.ejca.2021.02.019DOI Listing
May 2021

Clinical Trial of a Cancer Vaccine Targeting VEGF and KIF20A in Advanced Biliary Tract Cancer.

Anticancer Res 2021 Mar;41(3):1485-1496

Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan;

Background: As the prognosis of biliary tract cancer (BTC) is extremely poor and treatment options are limited, new treatment modalities are urgently needed. We designed a phase II clinical trial to investigate the immune responses and clinical benefits of OCV-C01, an HLA-A*24:02-restricted three-peptide cancer vaccine targeting VEGFR1, VEGFR2, and KIF20A.

Patients And Methods: Participants were patients with advanced BTC who had unresectable tumours and were refractory to standard chemotherapy. OCV-C01 was injected weekly until the discontinuance criteria were met.

Results: Six participants, including four patients positive for HLA-A*24:02, were enrolled in this study for assessment of efficacy. Four out of six patients exhibited vaccine-specific T-cell responses to one or more of three antigens. Log-rank tests revealed that vaccine-specific T cell responses contributed significantly to overall survival.

Conclusion: The cancer vaccine had positive effects on survival, indicating that this approach warrants further clinical studies.
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http://dx.doi.org/10.21873/anticanres.14907DOI Listing
March 2021

Effects of intensive exercise combined with dapagliflozin on body composition in patients with type 2 diabetes: a randomized controlled trial.

Endocr J 2021 Mar 26;68(3):329-343. Epub 2020 Dec 26.

Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

This study was aimed to evaluate the effects of intensive exercise in addition to the administration of sodium-glucose cotransporter 2 inhibitor dapagliflozin (DAPA) on body composition, including fat-free mass, in type 2 diabetes. We randomly assigned 146 patients to 24 weeks of treatment with intensive exercise, including resistance training, plus 5 mg (up to 10 mg) of DAPA daily (IT group) or DAPA alone (CT group). The primary endpoint was the difference in the change in fat-free mass from baseline to 24 weeks between the groups. The skeletal muscle mass index (SMI); metabolic profile, including HbA1c; and regional fat mass were also determined. ANCOVA was used for the group comparison, with least squares mean (LSM) differences and 95% confidence interval (CI). There was no significant difference in the change in fat-free mass (LSM difference -0.1 kg (95% CI: -0.5 to 0.4) and SMI (LSM difference -0.1 kg (95% CI: -0.2 to 0.1) between the groups. In contrast, the reduction of trunk fat mass was significantly higher in the IT group than in the CT group ((LSM difference -0.5 kg [95% CI -0.9 to -0.1]). Higher adherence to the resistance training tended to be associated with changes in HbA1c and high-sensitivity CRP levels. Our study suggests that intensive exercise do not prevent the reduction of fat-free mass after administration of SGLT2 inhibitors but can increase the reduction in abdominal fat, presumably leading to further improvements of hyperglycemia and chronic inflammation than DAPA alone in type 2 diabetes patients.
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http://dx.doi.org/10.1507/endocrj.EJ20-0599DOI Listing
March 2021

Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial.

Jpn J Ophthalmol 2020 Sep 18;64(5):455-461. Epub 2020 Aug 18.

Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Purpose: To evaluate the safety and efficacy of BBG (Brilliant Blue G250) for lens capsular staining during cataract surgery with continuous curvilinear capsulorhexis.

Study Design: Prospective clinical study.

Methods: This clinical trial enrolled 30 eyes of 30 patients who underwent cataract surgery with BBG (0.25 mg/mL Brilliant Blue G250) for capsular staining. Visualization of the lens capsule and the ease of capsulorhexis with BBG staining were evaluated in five grades (grade 0 to 4) by the Independent Data Monitoring Committee and the surgeons. The safety of BBG was also evaluated in terms of ocular and systemic tolerance for 7 days after surgery.

Results: The use of BBG improved visualization of the lens capsule and complete capsulorhexis was performed in all patients. The major endpoint (Independent Data Monitoring Committee evaluation) showed that use of BBG improved visualization of the lens capsule and the ease of capsulorhexis (grades 2 to 4); the committee's grading results were similar to those of the surgeons. Frequent complications observed in more than two eyes were conjunctival injection, corneal edema and intraocular pressure elevation. No severe complications were observed in ocular and systemic evaluations.

Conclusion: BBG staining contributed to improved visualization of the lens capsule and aided in the completion of capsulorhexis during cataract surgery. The use of BBG for capsular staining also exhibited favorable safety results.
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http://dx.doi.org/10.1007/s10384-020-00763-yDOI Listing
September 2020

Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies.

Int J Hematol 2020 Oct 12;112(4):510-523. Epub 2020 Jul 12.

Department of Hematology, Karatsu Higashimatsuura Medical Association, Saga, Japan.

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.
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http://dx.doi.org/10.1007/s12185-020-02941-7DOI Listing
October 2020

Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G).

Eur J Cancer 2020 08 8;135:11-21. Epub 2020 Jun 8.

Cancer Chemotherapy Center, Osaka Medical College, Osaka, Japan.

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study.

Patients And Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety.

Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%).

Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.
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http://dx.doi.org/10.1016/j.ejca.2020.04.014DOI Listing
August 2020

Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 10;21(5):472-476. Epub 2020 Apr 10.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Background: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC.

Patients And Methods: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival.

Conclusion: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.03.010DOI Listing
September 2020

An Observational Study of Team Management Approach for CapeOX Therapy in Patients with Advanced and Recurrent Colorectal Cancer: SMILE Study (The Study of Metastatic colorectal cancer to investigate the Impact of Learning Effect).

J Anus Rectum Colon 2020 28;4(2):79-84. Epub 2020 Apr 28.

Fujita Health University Hospital International Medical center, Toyoake, Japan.

Objectives: In recent years, CapeOX therapy for patients with colorectal cancer is widely used. We previously reported that a multidisciplinary approach decreases the worsening of adverse events and increases patient satisfaction. In this study, we conducted a multicenter, prospective, observational study to evaluate the incidence of adverse events, health-related quality of life (HRQOL) of the patient, and efficacy of a management (intervention) according to the support system (SMILE study).

Methods: As the interventional method, the following more than one method was carried out in each institute, 1: support with telephone, 2: dosing instruction by a pharmacist, 3: skin care instruction by a nurse, and 4: patient instruction by a doctor. The primary endpoint was the incidence of hand-foot syndrome (HFS) of more than grade 2. The secondary endpoint was the HRQOL evaluation and efficacy. The questionnaire (HADS) was administered before the start of the chemotherapy and in 1, 2, 4, 5, and 8 courses to evaluate quality of life (QOL).

Results: From April 2011 to September 2012, 80 patients were enrolled from 14 sites, and all patients were the subjects of analysis. The demographic background was as follows: man/woman: 46/34, age median: 63 (36-75), and management interventional method 1/2/3/4: 36/68/73/78. The overall percentage of HFS that exceeded grade 2 within 6 months was 16.3%. It was 11.1% with the telephone support group and 20.5% without the telephone support group (p = 0.26).

Conclusions: A multi-professional telephone support may reduce the deterioration of HFS. Further study which includes larger cohort is needed in the future.
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http://dx.doi.org/10.23922/jarc.2019-020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186009PMC
April 2020

Mallampati test with phonation, tongue protrusion and supine position is most correlated with Cormack-Lehane test.

Odontology 2020 Oct 10;108(4):617-625. Epub 2020 Feb 10.

Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Many modified Mallampati tests have been developed to date. Samsoon's modified Mallampati test (standard Mallampati test) is currently widely used. We newly designed seven types of assessment protocol of Mallampati test, in addition to standard Mallampati test. In this study, we studied the correlation between eight types of protocol (standard and seven alternative protocols) of Mallampati test and Cormack-Lehane test. We newly designed assessment protocols as new Mallampati test. These are different protocols depending on the presence or absence of phonation, those of protrusion of tongue, and sitting position or supine position. The oropharyngeal structures visualized by these eight types of Mallampati test for total of 145 patients undergoing dental oral surgery were evaluated. The scores derived via eight types of Mallampati test were recorded. The influence of phonation, tongue protrusion and body position on Mallampati test score was analyzed, respectively. The relationships between eight types of Mallampati test and Cormack-Lehane test were analyzed. Tongue protrusion, phonation and sitting position tended to lower the score of Mallampati test (p < 0.001, respectively). The standard Mallampati test was not correlated with Cormack-Lehane test. In the new Mallampati tests, assessment protocol with tongue protrusion, phonation and sitting position, that with tongue protrusion and supine position, or that with tongue protrusion, phonation and supine position were significantly correlated with Cormack-Lehane test, respectively. (p = 0.020, p = 0.007 and p = 0.004, respectively). The standard Mallampati test did not correlate with Cormack-Lehane test. Mallampati test with phonation, tongue protrusion and supine position were most correlated with Cormack-Lehane test.
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http://dx.doi.org/10.1007/s10266-020-00490-3DOI Listing
October 2020

Rationale and design of a phase II trial of osimertinib as first-line treatment for elderly patients with epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (SPIRAL-0 study).

Transl Lung Cancer Res 2019 Dec;8(6):1086-1090

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has a potent inhibitory effect against both T790M resistance mutations and EGFR-TKI sensitizing in EGFR, with a relatively low affinity for wild-type EGFR. Osimertinib has been approved as a therapeutic agent for patients with T790M-mutation positive advanced non-small cell lung cancer. As a first-line treatment, osimertinib may significantly prolong progression-free survival (PFS) in comparison with the earlier generation first-line standard treatment. Osimertinib has been reported to provide survival benefits to EGFR mutation-positive patients. However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remains to be established.

Methods: In this single arm, prospective, open-label, multicenter, phase II trial, 40 subjects aged ≥75 years with EGFR mutation-positive advanced non-small-cell-lung cancer will be recruited. Patients will be treated with osimertinib 80 mg/day until disease progresses or until the patient meets a discontinuation criterion. The primary endpoint is 1-year PFS. Secondary endpoints are overall response rate, PFS, overall survival, and safety. Thirty-seven patients are required for the present study, as calculated based on normal approximation with a one-sided α level of 5% and 80% power, assuming that the expected 1-year PFS is 70% and the 1-year PFS threshold is 50%.

Discussion: We are conducting an intervention study to investigate the safety and efficacy of osimertinib as a first-line treatment agent for EGFR mutation-positive NSCLC in patients aged ≥75 years.

Trial Registration Number: jRCTs071180007.
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http://dx.doi.org/10.21037/tlcr.2019.11.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976354PMC
December 2019

Rationale and design of a phase II trial of osimertinib as first-line treatment for elderly patients with epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (SPIRAL-0 study).

Transl Lung Cancer Res 2019 Dec;8(6):1086-1090

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has a potent inhibitory effect against both T790M resistance mutations and EGFR-TKI sensitizing in EGFR, with a relatively low affinity for wild-type EGFR. Osimertinib has been approved as a therapeutic agent for patients with T790M-mutation positive advanced non-small cell lung cancer. As a first-line treatment, osimertinib may significantly prolong progression-free survival (PFS) in comparison with the earlier generation first-line standard treatment. Osimertinib has been reported to provide survival benefits to EGFR mutation-positive patients. However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remains to be established.

Methods: In this single arm, prospective, open-label, multicenter, phase II trial, 40 subjects aged ≥75 years with EGFR mutation-positive advanced non-small-cell-lung cancer will be recruited. Patients will be treated with osimertinib 80 mg/day until disease progresses or until the patient meets a discontinuation criterion. The primary endpoint is 1-year PFS. Secondary endpoints are overall response rate, PFS, overall survival, and safety. Thirty-seven patients are required for the present study, as calculated based on normal approximation with a one-sided α level of 5% and 80% power, assuming that the expected 1-year PFS is 70% and the 1-year PFS threshold is 50%.

Discussion: We are conducting an intervention study to investigate the safety and efficacy of osimertinib as a first-line treatment agent for EGFR mutation-positive NSCLC in patients aged ≥75 years.

Trial Registration Number: jRCTs071180007.
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http://dx.doi.org/10.21037/tlcr.2019.11.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976354PMC
December 2019

Microaneurysm Imaging Using Multiple En Face OCT Angiography Image Averaging: Morphology and Visualization.

Ophthalmol Retina 2020 02 27;4(2):175-186. Epub 2019 Sep 27.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Purpose: In diabetic retinopathy (DR), OCT angiography (OCTA) could not image all fluorescein angiography (FA)-detected microaneurysms. We investigated whether multiple image averaging could enhance the microaneurysm detection capability of OCTA in patients with DR.

Design: Prospective and cross-sectional observational study.

Participants: Consecutive 31 patients (n = 62 eyes) with DR.

Methods: All eyes underwent FA and 3 × 3 mm fovea-centered OCTA images were obtained using 2 devices: RTVue XR Avanti (Optovue Inc, Fremont, CA) and OCT HS-100 (Canon Inc, Toyko, Japan). OCTA imaging (HS-100) was performed 10 consecutive times. Microaneurysm detection capability was compared among 5 OCTA images (single image, ×3, ×5, and ×10 averaged images and single scan image with the RTVue XR Avanti device).

Main Outcome Measures: Microaneurysm detection capability and the correlation between microaneurysm clinical characteristics or morphology and the extent of image averaging required for OCTA detection.

Results: A total of 415 microaneurysms could be analyzed in 31 eyes from 25 patients. Microaneurysms detected on single image, ×3, ×5, and ×10 averaged OCTA images were 144 (34.7%), 227 (54.7%), 285 (68.7%), and 306 (73.7%), respectively. Microaneurysm detection capability was significantly increased with increased image averaging. Microaneurysm detection with OCTA was not correlated with retinal thickness, FA leakiness, and indocyanine green angiogram detection or the number of averaged images, whereas there was significant correlation between microaneurysm morphology and microaneurysm visibility by the image-averaging process for 4 morphologies, particular the focal bulge types (P < 0.01).

Conclusions: In DR, multiple image averaging is useful for increasing the microaneurysm detection capability of OCTA, especially for focal bulge-type microaneurysms.
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http://dx.doi.org/10.1016/j.oret.2019.09.010DOI Listing
February 2020

Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Oncologist 2020 06 24;25(6):475-e891. Epub 2019 Oct 24.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen.

Background: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC).

Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS).

Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period.

Conclusion: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2019-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288639PMC
June 2020

Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors.

Cancer 2020 01 10;126(1):219-227. Epub 2019 Sep 10.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment.

Methods: Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing.

Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P < .001) for EGFR-TKI-naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04).

Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.
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http://dx.doi.org/10.1002/cncr.32481DOI Listing
January 2020

Promoting Patient Care Through Communication Training in a Pre-clerkship Pharmacy Education Course in Japan.

Am J Pharm Educ 2019 06;83(5):6745

Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

The purpose of this study was to teach communication skills for patient care to pre-clerkship students and observe changes in student perspectives towards communication from pre- to post-training. Two cohorts of fourth-year pharmacy students completed an eight-week pre-clerkship training course designed to improve their communication skills. The course involved class discussions and in-class research of medications, practicing communication skills, learning to give science-based responses, and developing an awareness of patient education for lifestyle, self-medication, quality of life, and medication adherence. A comparison of students' pre- and post-training responses to a questionnaire were used to assess changes in students' ability and confidence in communicating with patients. An exploratory factor analysis was used to analyze and compare the data results. Students' mean post-training scores for perceived ability to make small talk and confidence to communicate with patients increased compared to pre-training scores. Based on the results of the exploratory factor analysis, the greatest increase in students' scores was in the area of patient education skills. The pre-clerkship communication training improved student understanding of the pharmacy communication skills needed to conduct effective patient education and pharmacist-patient interaction beyond dispensing, affirming the theory that specialized communication training before students' begin a clerkship may be essential.
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http://dx.doi.org/10.5688/ajpe6745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630866PMC
June 2019

Randomized phase II study of pemetrexed or pemetrexed plus bevacizumab for elderly patients with previously untreated non-squamous non-small cell lung cancer: Results of the Lung Oncology Group in Kyushu (LOGIK1201).

Lung Cancer 2019 06 5;132:1-8. Epub 2019 Apr 5.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Lung Oncology Group in Kyushu (LOGiK), Fukuoka, Japan.

Objectives: To evaluate the efficacy and safety, we conducted a randomized phase II study of pemetrexed (Pem) versus Pem + bevacizumab (Bev) for elderly patients with non-squamous non-small cell lung cancer (NSqNSCLC).

Patients And Methods: The eligibility criteria were as follows: NSqNSCLC, no prior therapy, stage IIIB/IV disease or postoperative recurrence, age: ≥75 years, performance status (PS): 0-1, and adequate bone marrow function. The patients were randomly assigned (1:1 ratio) to receive Pem or Pem + Bev. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the response rate, OS, toxicities, and cost-effectiveness.

Results: Forty-one patients were enrolled and 40 (20 from each group) were assessable. Their characteristics were as follows: male/female = 23/17; median age (range) = 78 (75-83); stage IIIB/IV/postoperative recurrence = 1/30/9; PS 0/1 = 11/29. All cases involved adenocarcinoma. There was no significant intergroup difference in PFS and the median PFS (95% confidence interval) values of the Pem and Pem + Bev groups were 5.4 (3.0-7.4) and 5.5 (3.6-9.9) months, respectively (p = 0.66). The response rate was significantly higher in the Pem + Bev group (15% vs. 55%, p = 0.0146), and there was no significant difference in OS (median: 16.0 vs. 16.4 months, p = 0.58). Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia were seen in 10 and 30, 20 and 55, and 5 and 5 cases, respectively. Drug costs were higher in the Pem + Bev group (median: 1,522,008 vs. 3,368,428 JPY, p = 0.01). No treatment-related deaths occurred.

Conclusions: Adding Bev to Pem did not result in improved survival in the elderly NSqNSCLC patients. Compared with Pem + Bev, Pem monotherapy had similar effects on survival, a more favorable toxicity profile, and was more cost-effective in elderly NSqNSCLC patients. Pem monotherapy might be one of the optional regimen for NSqNSCLC patients aged ≥75 years.
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http://dx.doi.org/10.1016/j.lungcan.2019.01.008DOI Listing
June 2019

T-bet lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer.

Breast Cancer Res Treat 2019 Aug 8;176(3):569-577. Epub 2019 May 8.

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells.

Methods: This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10 mm.

Results: Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet tumors had longer overall survival (OS) compared with patients with T-bet tumors (p = 0.047). The combination of CD8 and T-bet was associated with a better recurrence-free survival (RFS) and OS compared to CD8/T-bet tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12-0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07-0.95, p = 0.039 for OS).

Conclusions: OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC.
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http://dx.doi.org/10.1007/s10549-019-05256-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586701PMC
August 2019

Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.

Lung Cancer 2018 11 18;125:136-141. Epub 2018 Sep 18.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address:

Objectives: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC).

Patients And Methods: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation.

Results: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached.

Conclusion: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.014DOI Listing
November 2018

Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing.

Cancer Sci 2018 Dec 13;109(12):3921-3933. Epub 2018 Nov 13.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance-conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non-small-cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M-including copy number gain of NRAS or MET-were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression-free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR-TKI treatment.
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http://dx.doi.org/10.1111/cas.13820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272092PMC
December 2018

Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy.

Graefes Arch Clin Exp Ophthalmol 2018 Dec 6;256(12):2275-2282. Epub 2018 Sep 6.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.

Purpose: Fluorescein angiography (FA) has been conventionally used for detection of retinal nonperfused area (NPA) in diabetic retinopathy (DR) in spite of its qualitative evaluation. Optical coherence tomography angiography (OCTA) has been recently reported to be useful for the quantification of retinal vascular disorder in DR. In this study, we examined whether retinal flow density (FD) measurement in OCTA was useful for NPA detection in DR.

Methods: The study included 41 eyes from 29 patients with DR who underwent FA and OCTA. Regions surrounded by arteries or veins were extracted in the OCTA image, and the FDs in each region were measured by Image J. Furthermore, each region was classified as NPA or perfused area (PA) in FA. The receiver operating characteristic (ROC) curve was prepared by logistic regression analysis of the FD. The AUC (area under the ROC curve) and cutoff value of FD were also calculated.

Results: Two hundred fifty-two regions were analyzed and classified into 38 NPA regions and 214 PA regions using FA. FD of each capillary plexus in NPA was significantly smaller than in PA (p < 0.0001). The AUC of total capillary plexus layers (TCP), superficial capillary plexus layer (SCP), and deep capillary plexus layer (DCP) was 0.975, 0.974, and 0.971, respectively. All areas, where the FD was more than the cutoff value (0.07 in TCP), were diagnosed with PA. Three areas with intraretinal microvascular abnormalities (IRMA) were diagnosed as PA despite being below the cutoff value.

Conclusions: FD measurement in OCTA is useful for NPA detection in DR.
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http://dx.doi.org/10.1007/s00417-018-4122-6DOI Listing
December 2018
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