Publications by authors named "Satoshi Morita"

582 Publications

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B).

Int J Clin Oncol 2021 Oct 13. Epub 2021 Oct 13.

Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.

Background: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.

Methods: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.

Results: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.

Conclusion: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.
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http://dx.doi.org/10.1007/s10147-021-02043-2DOI Listing
October 2021

Whole-genome sequence analysis of Shiga toxin-producing Escherichia coli O157 strains isolated from wild deer and boar in Japan.

J Vet Med Sci 2021 Oct 8. Epub 2021 Oct 8.

Laboratory of Veterinary Food Hygiene, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University.

The prevalence of Shiga toxin-producing Escherichia coli O157 (STEC O157) strains in wild deer and boar in Japan was investigated. STEC O157 strains were isolated from 1.9% (9/474) of the wild deer and 0.7% (3/426) of the wild boar examined. Pulsed-field gel electrophoresis (PFGE) analysis classified the wild deer and boar strains into four and three PFGE patterns, respectively. The PFGE pattern of one wild boar strain was similar to that of a cattle strain that had been isolated from a farm in the same area the wild boar was caught, suggesting that a STEC O157 strain may have been transmitted between wild boar and cattle. Clade analysis indicated that, although most of the strains were classified in clade 12, two strains were classified in clade 7. Whole-genome sequence (WGS) analysis indicated that all the strains carried mdfA, a drug resistance gene for macrolide antibiotics, and also pathogenicity-related genes similar to those in the Sakai strain. In conclusion, our study emphasized the importance of food hygiene in processing meat from Japanese wild animals for human consumption.
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http://dx.doi.org/10.1292/jvms.21-0454DOI Listing
October 2021

Efficacy and Safety of S-1 Compared With Docetaxel in Elderly Patients With Advanced NSCLC Previously Treated With Platinum-Based Chemotherapy: A Subgroup Analysis of the EAST-LC Trial.

JTO Clin Res Rep 2021 Mar 7;2(3):100142. Epub 2021 Jan 7.

Thoracic Center, St Luke's International Hospital, Tokyo, Japan.

Introduction: Despite recent advances in NSCLC treatment, specific data on the elderly population remain limited. In this post hoc subgroup analysis of the East Asia S-1 Trial in Lung Cancer (EAST-LC) trial, we compared S-1 and docetaxel (DTX) in patients aged 70 years old and above with pretreated advanced NSCLC.

Methods: Patients were randomly assigned (1:1) to receive S-1 (orally, twice daily on d 1-28 of a 6-wk cycle) or DTX (intravenously, on d 1 of a 3-wk cycle). The initial S-1 dose was 80, 100, or 120 mg/day on the basis of body surface area, and the DTX doses were 60 mg/m (Japan) or 75 mg/m (outside Japan). The primary end point was overall survival, and secondary end points included progression-free survival, response rate, quality of life (QOL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30, and safety.

Results: Among 189 patients aged 70 years and above assessed as the full analysis set, baseline characteristics were generally similar between treatment arms. The median overall survival was 14.7 (S-1) versus 12.1 months (DTX); the hazard ratio was equal to 0.76, with a 95% confidence interval (CI) of 0.54-1.07. The median progression-free survival was similar in both arms (both 4.1 mo, hazard ratio = 0.84, 95% CI: 0.60-1.18); and the response rate was 12.9% (S-1) and 14.0% (DTX). The adjusted mean QOL score difference (S-1-DTX until wk 48) was 7.41 (95% CI: 0.37-14.46). Safety profiles were generally consistent with those of the overall EAST-LC population.

Conclusions: S-1 revealed comparable efficacy, safety, and QOL versus DTX in pretreated elderly patients with advanced NSCLC. Results were consistent with the overall EAST-LC data.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474214PMC
March 2021

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With Mutations.

JTO Clin Res Rep 2021 Jan 12;2(1):100107. Epub 2020 Oct 12.

Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.

Patients with NSCLC in East Asia, including Japan, frequently contain mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent -mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring -activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474490PMC
January 2021

Association between tooth loss and longitudinal changes in B-type natriuretic peptide over 5 years in postmenopausal women: the Nagahama Study.

Curr Probl Cardiol 2021 Sep 25:100997. Epub 2021 Sep 25.

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address:

Background: There is disparity between the sexes in cardiovascular diseases including heart failure (HF). This study aimed to investigate the effect of periodontal disease (PD) on plasma B-type natriuretic peptide (BNP) concentration across sex, age, and menopausal status, as well as the interaction effect of MT and diabetes mellitus (DM) on BNP.

Methods: This large-scale prospective cohort study enrolled 7,539 individuals with no myocardial infarctions or angina pectoris at baseline from the general Japanese population. The association between baseline number of missing teeth (MT) and the longitudinal changes in BNP over 5 years (ΔBNP) was evaluated according to sex and menopausal status.

Results: Among 7,539 participants, 3,190 were postmenopausal women with a mean age ± standard deviation of 61.1 ± 7.6 at baseline. Multivariate analysis revealed a positive association between MT and ΔBNP among postmenopausal women even after adjusting for covariates, including traditional HF risk factors (coefficient, 0.210; 95% confidence interval [CI], 0.107 to 0.312; P <0.001), but not in men aged >50. Including an interaction term (MT × DM) in the multivariate model revealed a positive interaction between MT and DM in ΔBNP among postmenopausal women (coefficient for interaction, 1.365; 95% CI, 0.902 to 1.827; P for interaction <0.001).

Conclusions: Our study showed a positive association between MT and ΔBNP, as well as a positive effect of the interactive association between MT and DM, among postmenopausal women. Our results suggest a sex difference of an adverse effect of PD on initial myocardial wall stress in the ventricles.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.100997DOI Listing
September 2021

A phase II study of sequential treatment with anthracycline and taxane followed by eribulin in patients with HER2-negative, locally advanced breast cancer (JBCRG-17).

Breast Cancer Res Treat 2021 Sep 23. Epub 2021 Sep 23.

Department of Surgery, Breast Oncology, NHO Osaka National Hospital, Osaka, Japan.

Purpose: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC.

Methods: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative.

Results: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%).

Conclusion: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.
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http://dx.doi.org/10.1007/s10549-021-06396-0DOI Listing
September 2021

Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka-shi 541-8567, Osaka, Japan.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab-paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m/day on days 1-21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab-paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0-11.8} months) than in group E (4.3 {3.6-6.0} months) (hazard ratio, 0.53; < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.
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http://dx.doi.org/10.3390/cancers13174399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430728PMC
August 2021

Exploration of predictors of benefit from nivolumab monotherapy for patients with pretreated advanced gastric and gastroesophageal junction cancer: post hoc subanalysis from the ATTRACTION-2 study.

Gastric Cancer 2021 Sep 4. Epub 2021 Sep 4.

Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: The phase 3 ATTRACTION-2 study demonstrated that nivolumab monotherapy was superior to placebo for patients with pretreated advanced gastric or gastroesophageal junction cancer, but early progression of tumors in some patients was of concern.

Methods: This post hoc analysis statistically explored the baseline characteristics of the ATTRACTION-2 patients and extracted a single-factor and double-factor combinations associated with early disease progression or early death. In the extracted patient subgroups, the 3-year restricted mean survival times of progression-free survival and overall survival were compared between the nivolumab and placebo arms.

Results: Two single factors (age and peritoneal metastasis) were extracted as independent predictors of early progression, but none of them, as a single factor, stratified patients into two subgroups with significant differences in restricted mean survival time. In contrast, two double-factor combinations (serum sodium level and white blood cell count; serum sodium level and neutrophil-lymphocyte ratio) stratifying patients into two subgroups with significant differences in the restricted mean survival time were extracted. Additional exploratory analysis of a triple-factor combination showed that patients aged < 60 years with peritoneal metastasis and low serum sodium levels (approximately 7% of all patients) might receive less benefit from nivolumab, and patients aged ≥ 60 years with no peritoneal metastasis and normal serum sodium levels might receive higher benefit.

Conclusions: A combination of age, peritoneal metastasis, and serum sodium level might predict benefit from nivolumab as salvage therapy in advanced gastric or gastroesophageal junction cancer patients, especially less benefit for patients having all three risk factors.
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http://dx.doi.org/10.1007/s10120-021-01230-4DOI Listing
September 2021

Impact of prior intravesical bacillus Calmette-Guerin therapy on the effectiveness of pembrolizumab for patients with metastatic urothelial carcinoma.

Urol Oncol 2021 Aug 25. Epub 2021 Aug 25.

Department of Urology, Kagawa University, Kita, Japan.

Objective: The aim of this study was to determine whether a history of treatment for non-muscle invasive bladder cancer (NMIBC), including intravesical bacillus Calmette-Guerin (BCG) therapy, affects the treatment outcomes of pembrolizumab in patients with metastatic, chemo-resistant urothelial carcinoma (UC).

Materials And Methods: The clinicopathological data of 755 patients with metastatic, chemo-resistant UC who received pembrolizumab were retrospectively reviewed. Best overall response and overall survival (OS) from the initiation of pembrolizumab were analyzed with regard to the history of NMIBC treatment and BCG usage using propensity score matching (PSM).

Results: A total of 155 (20.5%) patients had a history of NMIBC treatment, of which 97 (12.8%) had received intravesical BCG therapy. When compared to patients without a NMIBC history (median 10.0 months), the OS from the initiation of pembrolizumab for patients with a NMIBC history (13.3 months, HR [95% CI] 0.79 [0.62-1.02], P = 0.073), those with a NMIBC history and BCG (12.1 months, HR 0.87 [0.64-1.17], P = 0.356), or those with a NMIBC history but not BCG (14.5 months, HR 0.68 [0.45-1.12], P = 0.061) were not significantly different. This tendency was robust after 1:1 or 1:2 PSMs. The objective response rate (ORR, 24.5% vs. 31.0%, P = 0.222) and disease control rate (DCR, 56.1% vs. 52.1%, P = 0.501) of the 155 patients with an NMIBC history did not differ from those of 155 matched patients without an NMIBC history. Among those with an NMIBC history, the prior use of BCG did not affect OS (with vs. without BCG, 12.1 vs. 14.5 months, HR 1.29 [0.80-2.09], P = 0.295), ORR (24.5% vs. 34.0%, P = 0.298) or DCR (57.1% vs. 56.0%, P = 0.908). The ORR in BCG-treated patients was significantly lower than that in those without a NMIBC history (19.8% vs. 33.3%, P = 0.042), whereas DCR between the 2 groups did not differ significantly (55.8% vs. 54.4%, P = 0.855).

Conclusions: Our risk-adjusted analyses revealed that a history of prior NMIBC treatment, including intravesical BCG therapy, did not affect the treatment outcomes of pembrolizumab in metastatic UC patients.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.002DOI Listing
August 2021

Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.

Lancet Respir Med 2021 Aug 26. Epub 2021 Aug 26.

Division of Pulmonary Medicine, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan. Electronic address:

Background: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life.

Methods: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed.

Findings: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47).

Interpretation: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression.

Funding: Chugai Pharmaceutical.
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http://dx.doi.org/10.1016/S2213-2600(21)00166-1DOI Listing
August 2021

Long-Term Outcomes of a Randomized Study of Neoadjuvant Induction Dual HER2 Blockade with Trastuzumab and Lapatinib Followed by Weekly Paclitaxel Plus Dual HER2 Blockade for HER2-Positive Primary Breast Cancer (Neo-Lath Study).

Cancers (Basel) 2021 Aug 9;13(16). Epub 2021 Aug 9.

Breast Cancer Unit, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto-shi 606-8507, Kyoto, Japan.

We conducted the Neo-LaTH study in which patients were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus the anti-HER2 therapy, and in estrogen receptor (ER)-positive patients, with or without concurrent endocrine therapy. The use of endocrine therapy did not affect the response; comprehensive pathological complete response (CpCR) plus ypN0 rate was 57.6% and 30.3% in ER-negative and ER-positive patients, respectively. After surgery, patients received an anthracycline-based regimen based on physician's choice, followed by trastuzumab for 1 year, and in ER-positive patients, endocrine therapy for 5 years. Here, we report the 5-year survival outcomes. Among the followed-up patients ( = 212), the 5-year disease-free survival (DFS), distant DFS, and overall survival rates were 87.8% [95% confidence interval (CI), 82.5-91.6%], 93.7% (95% CI, 89.3-96.3%), and 95.6% (95% CI, 91.7-97.7%), respectively, with no difference between ER-negative and ER-positive patients. The 5-year DFS rate was significantly higher in patients who had a CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%; = 0.0387). The stratified analysis showed better survival outcomes in patients who had CpCRypN0 than in those who did not after neoadjuvant treatment, regardless of use of adjuvant anthracycline therapy.
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http://dx.doi.org/10.3390/cancers13164008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394774PMC
August 2021

Association of Sleep Disordered Breathing and Blood Pressure with Albuminuria: The Nagahama Study.

Ann Am Thorac Soc 2021 Aug 4. Epub 2021 Aug 4.

Graduate School of Medicine, Kyoto University, Respiratory Care and Sleep Control Medicine, Kyoto, Japan;

Rationale: Although sleep disordered breathing (SDB) may increase urinary albumin excretion (UAE) by raising nocturnal blood pressure (BP) in addition to diurnal BP, the correlation has not been investigated in a general population.

Objectives: To evaluate the relationships among UAE, SDB and BP during sleep in a large population cohort.

Methods: Among 9,850 community residents, UAE was assessed by the urinary albumin creatinine ratio (UACR) in spot urine. Sleep duration and SDB were evaluated by a wearable actigraph and pulse oximeter, respectively. We calculated the actigraphy-modified 3% oxygen desaturation index (Acti-3%ODI) by correcting the time measured by pulse oximetry according to sleep duration obtained by actigraphy. Further, participants were instructed to measure morning and sleep BP at home by a timer-equipped oscillometric device.

Results: Measurements of sleep parameters, UAE and office BP were completed in 6,568 participants. The multivariate analysis that included confounders showed a significant association of Acti-3%ODI with UACR. (β=0.06, p<0.001) Further, a positive interaction between office systolic BP (SBP) and Acti-3%ODI for UACR was found. (β=0.06, p<0.001) Among the 6,568 persons enrolled in the analysis, 5,313 completed measurements of BP at home. In this cohort, the association of Acti-3%ODI with UACR remained significant (β=0.06, p<0.001) even after morning and sleep SBP were included in the analysis. Further, mediation analysis revealed that 28.3% (95% confidence interval: 14.9-41.7%, p<0.001) of the association of Acti-3%ODI with UACR was explained by the mediation of morning and sleep SBP metrics.

Conclusions: SDB and office SBP were independently and synergistically associated with UAE, which is considered as a risk factor for chronic kidney disease and cardiovascular events. SDB may raise UAE not only by increasing BP but involving other pathologic pathways.
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http://dx.doi.org/10.1513/AnnalsATS.202105-528OCDOI Listing
August 2021

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer.

Cancer Sci 2021 Jul 30. Epub 2021 Jul 30.

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

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.
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http://dx.doi.org/10.1111/cas.15092DOI Listing
July 2021

Combination therapy of bevacizumab with either S-1 and irinotecan or mFOLFOX6/CapeOX as first-line treatment of metastatic colorectal cancer (TRICOLORE): Exploratory analysis of RAS status and primary tumour location in a randomised, open-label, phase III, non-inferiority trial.

Eur J Cancer 2021 Sep 22;154:296-306. Epub 2021 Jul 22.

Department of Internal Medicine, Division of Medical Oncology, Showa University Koto Toyosu Hospital, Tokyo, Japan.

Aim: The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis.

Methods: In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017.

Results: With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028).

Conclusion: S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC.

Trial Registration: UMIN-CTR: 000007834.
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http://dx.doi.org/10.1016/j.ejca.2021.06.013DOI Listing
September 2021

Prognostic Impact of Lateral Pelvic Node Dissection on the Survival of Patients in Low Rectal Cancer Subgroups Based on Lymph Node Size.

Ann Surg Oncol 2021 Oct 13;28(11):6179-6188. Epub 2021 Jul 13.

Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background: Lateral pelvic node (LPN) dissection (LPND) is considered a promising technique for treating low rectal cancer; however, there is insufficient evidence of its prognostic value. Using centrally reviewed preoperative pelvic magnetic resonance (MR) images, this study aimed to find the patient population who has benefited from LPND.

Patients And Methods: MR images of patients from 69 institutes with stage II-III low rectal cancer were reviewed by experienced radiologists. Recurrence-free survival (RFS), overall survival (OS), and short-term outcomes were measured.

Results: In total, 731 preoperative MR images were reviewed (excluding patients with short-axis LPN ≥ 10 mm). Of these, 322 underwent total mesorectum excision (TME) without LPND (non-LPND group), and 409 underwent TME with LPND (LPND group). Preoperative treatment was performed for 40% and 25% of patients in the non-LPND and LPND groups, respectively. The incidence of postoperative complications was higher in the LPND group (44.5%) than in the non-LPND group (33.2%; P = 0.002). Among patients with LPNs < 5 mm, OS and RFS curves were not significantly different between the groups. Among patients with LPNs ≥ 5 mm, the LPND group had significantly higher 5-year OS and RFS than the non-LPND group (OS: 81.9% versus 67.3%; RFS: 69.4% versus 51.6%). On multivariate analysis of LPN ≥ 5 mm cases, LPND was independently associated with RFS.

Conclusions: Despite the high incidence of postoperative complications, this study showed the prognostic impact of LPND on low rectal cancer patients with LPNs (≥ 5 mm, < 10 mm short axis) measured by experienced radiologists. Trial registration UMIN-ID: UMIN000013919.
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http://dx.doi.org/10.1245/s10434-021-10312-7DOI Listing
October 2021

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching.

J Geriatr Oncol 2021 Jul 5. Epub 2021 Jul 5.

Department of Urology, Faculty of Medicine, University of Toyama, Toyama, Japan.

Background: We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC).

Methods: A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients <75 and ≥75 years old were compared.

Results: The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged <75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the <75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age <75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the <75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651).

Conclusions: The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.
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http://dx.doi.org/10.1016/j.jgo.2021.07.002DOI Listing
July 2021

Repurposing bromocriptine for Aβ metabolism in Alzheimer's disease (REBRAnD) study: randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer's disease with presenilin 1 (PSEN1) mutations.

BMJ Open 2021 06 30;11(6):e051343. Epub 2021 Jun 30.

Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Introduction: Alzheimer's disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD.

Methods And Analysis: This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted.

Ethics And Dissemination: The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process.

Trial Registration Number: jRCT2041200008, NCT04413344.
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http://dx.doi.org/10.1136/bmjopen-2021-051343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246358PMC
June 2021

Femoral head collapse rate among Japanese patients with pre-collapse osteonecrosis of the femoral head.

J Int Med Res 2021 Jun;49(6):3000605211023336

Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, Gifu, Japan.

Objective: In this study, we aimed to elucidate the relationship between the duration from diagnosis to femoral head collapse and the collapse rate among patients with pre-collapse osteonecrosis of the femoral head (ONFH).

Methods: In this retrospective, observational, multicenter study, we analyzed 268 patients diagnosed with ONFH and classified them using the Japanese Investigation Committee classification. The primary endpoint was duration from the time of diagnosis to femoral head collapse for each type of ONFH.

Results: The 12-, 24-, and 36-month collapse rates among participants were 0%, 0%, and 0% for type A, respectively; 0%, 2.0%, and 10.8% for type B, respectively; 25.5%, 40.8%, and 48.5% for type C-1, respectively; and 57.4%, 70.3%, and 76.7% for type C-2 ONFH, respectively. A comparison of unilateral and bilateral ONFH, using Kaplan-Meier survival curves demonstrated similar collapse rates.

Conclusions: The lowest collapse rate was observed for ONFH type A, followed by types B, C-1, and C-2. Additionally, a direct association was observed between the collapse rate and location of the osteonecrotic lesion on the weight-bearing surface.
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http://dx.doi.org/10.1177/03000605211023336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258762PMC
June 2021

Markers of cardiovascular disease risk in sleep-disordered breathing with or without comorbidities: the Nagahama Study.

J Clin Sleep Med 2021 Jun 21. Epub 2021 Jun 21.

Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Study Objectives: Whether the association between sleep-disordered breathing (SDB) and cardiovascular disease (CVD) is independent of comorbid risk factors for CVD is controversial. The objective of this study is to elucidate whether the association between SDB severity and the surrogate markers of CVD evets differs in relation to the number of comorbidities.

Methods: This cross-sectional study included 7731 participants. Severity of SDB was determined by the oxygen desaturation index adjusted by actigraph-measured objective sleep time. Participants were stratified according to SDB severity and the number of comorbidities (hypertension, diabetes, dyslipidemia and obesity), and the associations between the maximum value of intima-media thickness of the common carotid artery (CCA-IMT-max), brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) were evaluated.

Results: Among participants with no risk factor, CCA-IMT-max increased according to SDB severity (n = 1022, <0.0001). Even after the matching of background, the median CCA-IMT-max value was 14% higher in moderate-severe SDB cases than those without SDB (n=45 in each group, =0.020). The difference was not significant for baPWV and CAVI. On the other hand, a significant difference in CCA-IMT-max was not found in those with multiple comorbidities. Consistently, multiple regression analysis revealed an independent association between CCA-IMT-max and moderate-severe SDB for all study participants (β: 0.0222 (95% confidence interval: 0.0039-0.0405), =0.017), but the association was not significant for stratified participants with multiple comorbidities.

Conclusions: SDB severity is associated with the CCA-IMT-max level, but the independent association becomes weaker for those with multiple comorbidities.
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http://dx.doi.org/10.5664/jcsm.9460DOI Listing
June 2021

Lymph node dissection in thymic carcinomas and neuroendocrine carcinomas.

Interact Cardiovasc Thorac Surg 2021 07;33(2):242-249

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.

Objectives: Although lymph node (LN) metastases are not uncommon in thymic carcinomas, preoperative LN evaluation, intraoperative lymph node dissection (LND) and postoperative outcomes remain unknown. The aim of this study was to elucidate the characteristics of and outcomes in patients with thymic carcinomas and thymic neuroendocrine carcinomas undergoing LND.

Methods: A retrospective chart review was performed using our multi-institutional database to identify patients who underwent resection and LND for thymic carcinoma or thymic neuroendocrine carcinoma between 1991 and 2018. An enlarged mediastinal LN was defined as having a short-axis diameter >1 cm. We assessed survival outcomes using the Kaplan-Meier analysis.

Results: N1-level LND was performed in 41 patients (54.6%), N2-level LND in 14 patients (18.7%) and both-level LND in 16 patients (21.3%). Pathological LN metastasis was detected in 20 patients (26.7%) among the 75 patients undergoing LND. There was a significant difference in the number of LN stations (P = 0.015) and metastasis factor (P = 0.0042) between pathologically LN-positive and pathologically LN-negative patients. The sensitivity of enlarged LNs on preoperative computed tomography was 18.2%. There was a tendency towards worse overall survival of pathologically N2-positive patients, although the difference was not statistically significant (P = 0.15).

Conclusions: Preoperative CT appears to play a limited role in detecting pathological LN metastases. Our findings suggest that the significance of N1- and N2-level LND should be evaluated in prospective studies to optimize the postoperative management of patients with thymic carcinomas and neuroendocrine carcinomas.
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http://dx.doi.org/10.1093/icvts/ivab079DOI Listing
July 2021

Impact of histological variants on outcomes in patients with urothelial carcinoma treated with pembrolizumab: a propensity score matching analysis.

BJU Int 2021 Jun 10. Epub 2021 Jun 10.

Department of Urology, University of Toyama, Toyama, Japan.

Objectives: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo-resistant urothelial carcinoma (UC).

Patients And Methods: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM).

Results: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68-1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non-squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15-0.90; P = 0.023) compared to patients with PUC.

Conclusions: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo-resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.
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http://dx.doi.org/10.1111/bju.15510DOI Listing
June 2021

Recombinant human FGF-2 for the treatment of early-stage osteonecrosis of the femoral head: TRION, a single-arm, multicenter, Phase II trial.

Regen Med 2021 06 2;16(6):535-548. Epub 2021 Jun 2.

Department of Orthopedic Surgery, Gifu University, Gifu, 501-1194, Japan.

This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.
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http://dx.doi.org/10.2217/rme-2021-0049DOI Listing
June 2021

4-step, 2-h carboplatin desensitization in Japanese patients with ovarian cancer: a prospective study.

Int J Clin Oncol 2021 Aug 26;26(8):1553-1560. Epub 2021 May 26.

Department of Medical Oncology, Hyogo Cancer Center, 13-70, Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan.

Background: Carboplatin is a key drug for ovarian cancer. However, it sometimes induces hypersensitivity reactions (HSRs) that result in the discontinuation of the treatment. Although various desensitization protocols have been reported in previous retrospective studies, a limited number of prospective studies have analyzed these protocols.

Methods: Patients with platinum-sensitive relapsed ovarian cancer who experienced carboplatin-induced HSRs were treated with diluted solutions of 1/1000, 1/100, 1/10 and an undiluted solution of carboplatin over a 1-h period. If no HSRs occurred within the first two cycles, a short protocol regimen over a 30-min period per solution was followed. The primary endpoint was treatment completion rate.

Results: Between May 2015 and September 2018, 21 patients were enrolled from two institutions. One patient experienced platinum-sensitive recurrence after the desensitization protocol; thus, 22 sessions were analyzed. Epinephrine use, treatment-related death, and intensive care unit (ICU) admissions did not occur. The median number of desensitization cycles was 6 (range 1-6). Two sessions were discontinued early because of grade 2 dysgeusia and grade 2 malaise. Treatment in two (9.1%) patients was discontinued because of HSR development. The treatment completion rate was 90.9%. Six (27.3%) sessions met the criteria for transition to the short protocol regimen. In 14 (63.6%) sessions, HSRs were observed during infusion of the undiluted solution. The median progression-free survival and overall survival were 14.8 and 23.8 months, respectively.

Conclusion: This 4-step, 2-h carboplatin desensitization protocol is safe and feasible. Patients require careful monitoring with a rapid response to HSRs, especially during the administration of undiluted solutions.
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http://dx.doi.org/10.1007/s10147-021-01935-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286943PMC
August 2021

Safety of Silk-elastin Sponges in Patients with Chronic Skin Ulcers: A Phase I/II, Single-center, Open-label, Single-arm Clinical Trial.

Plast Reconstr Surg Glob Open 2021 Apr 28;9(4):e3556. Epub 2021 Apr 28.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Although traditional wound dressings such as collagen scaffolds promote granulation tissue formation, the efficacy of these dressings in chronic wounds is limited because of high susceptibility to bacterial growth. Biomaterials that can be applied to chronic wounds should have an anti-bacterial function. We previously reported that administering a silk-elastin solution that forms moisturizing hydrogels to wound surfaces of diabetic mice reduced bacterial growth and promoted granulation tissue formation compared with control or carboxymethyl cellulose hydrogels. We hypothesized that silk-elastin promotes wound healing in human chronic wounds by suppressing bacterial growth.

Methods: An open-label, clinical case series was conducted with a prospective, single-arm design at Kyoto University Hospital in Kyoto, Japan. In this study, 6 patients with chronic skin ulcers of any origin (2 < ulcer area (cm) < 25) on their lower extremities were included; patients with critical ischemia were excluded. Silk-elastin sponges were applied and covered with a polyurethane film without changing the dressing for 14 days. Inflammation triggered treatment discontinuation due to fear of infection. The primary study endpoint was adverse events, including inflammation and infection.

Results: Poor hydrogel formation, possibly due to continuous exudation, was observed. No serious adverse events were noted. Two patients discontinued treatment on day 6 and day 7, respectively, due to inflammation, but they were not infected. The other 4 patients completed the 14-day silk-elastin sponge treatment without infection.

Conclusion: Silk-elastin sponge is safe for chronic skin ulcers, and its ability to promote wound healing should be determined by confirmatory clinical trials.
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http://dx.doi.org/10.1097/GOX.0000000000003556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081464PMC
April 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

Validation Study of the International Association for the Study of Lung Cancer Histologic Grading System of Invasive Lung Adenocarcinoma.

J Thorac Oncol 2021 Oct 24;16(10):1753-1758. Epub 2021 Apr 24.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Introduction: A histologic grading system for invasive lung adenocarcinoma (ADC) has been proposed by the International Association for the Study of Lung Cancer (IASLC) Pathology Committee in June 2020. This study evaluated the prognostic value of the IASLC histologic grading system (the IASLC system) in a large Japanese cohort.

Methods: We performed comprehensive histologic subtyping using the semiquantitative estimation of five major patterns and complex glandular patterns in patients with a completely resected lung ADC and determined the histologic grade using the IASLC system. Concordance index and receiver-operating characteristic curves were used to evaluate the clinical utility of the IASLC system for recurrence and death; the comparison was performed with the architectural-pattern system (the Arch system) and the grading system on the basis of the two most predominant patterns (the Sica's system).

Results: Of 1002 patients with invasive ADC, 235 had recurrent disease and 166 died of lung cancer. The concordance index and area under the curve of the IASLC system were 0.777 and 0.807 for recurrence and 0.767 and 0.776 for death, respectively. These were similar to those of the Arch system (0.763 and 0.796 for recurrence, 0.743 and 0.755 for death) and the Sica's system (0.786 and 0.814 for recurrence, 0.762 and 0.773 for death).

Conclusions: We reported that the IASLC system for invasive lung ADC has prognostic significance by evaluating a large Japanese cohort. We believe that the IASLC grading system will provide physicians with better information for postsurgery treatment.
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http://dx.doi.org/10.1016/j.jtho.2021.04.008DOI Listing
October 2021

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19).

Int J Clin Oncol 2021 Jul 23;26(7):1229-1236. Epub 2021 Apr 23.

Breast Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Anthracycline (A) or taxane T-based regimens are the standard early-line chemotherapy for metastatic breast cancer (BC). A previous study has shown a survival benefit of eribulin in heavily pretreated advanced/recurrent BC patients. The present study aimed to compare the benefit of eribulin with treatment of physician's choice (TPC) as first- or second-line chemotherapy for recurrent HER2-negative BC.

Methods: Patients with recurrent HER2-negative BC previously receiving anthracycline and taxane AT-based chemotherapy in the adjuvant or first-line setting were eligible for this open-label, randomized, parallel-group study. Patients were randomized 1:1 by the minimization method to receive either eribulin (1.4 mg/m on day one and eight of each 21-day cycle) or TPC (paclitaxel, docetaxel, nab-paclitaxel or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure (TTF), overall response rate (ORR), duration of response, and safety (UMIN000009886).

Results: Between May 2013 and January 2017, 58 patients were randomized, 57 of whom (26 eribulin and 31 TPC) were analyzed for efficacy. The median PFS was 6.6 months with eribulin versus 4.2 months with TPC (hazard ratio: 0.72 [95% confidence interval (CI), 0.40-1.30], p = 0.276). Median TTF was 6.0 months with eribulin versus 3.6 months with TPC (hazard ratio: 0.66 [95% CI, 0.39-1.14], p = 0.136). Other endpoints were also similar between groups. The most common grade ≥ 3 adverse event was neutropenia (22.2% with eribulin versus 16.1% with TPC).

Conclusions: Eribulin seemed to improve PFS or TTF compared with TPC without statistical significance. Further validation studies are needed.
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http://dx.doi.org/10.1007/s10147-021-01920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213561PMC
July 2021

Multiparametric magnetic resonance imaging facilitates the selection of patients prior to fertility-sparing management of endometrial cancer.

Abdom Radiol (NY) 2021 09 7;46(9):4410-4419. Epub 2021 Apr 7.

Department of Diagnostic Radiology and Nuclear Medicine, Kyoto University Hospital, Kyoto, Japan.

Purpose: To compare the diagnostic performance of biparametric magnetic resonance imaging (bpMRI) versus multiparametric MRI (mpMRI) for the staging of well-differentiated endometrioid endometrial cancer (EC) in potential candidates for fertility-sparing management.

Methods: This multi-center retrospective study included 48 potential candidates for fertility-sparing management (age <46 years, grade 1 endometroid EC) who did not wish to undergo fertility-sparing management and thus underwent definitive surgery. Two readers (R1, R2) independently reviewed bpMRI (T1, T2, and diffusion-weighted imaging) and mpMRI (bpMRI and dynamic contrast-enhanced imaging, DCE) during two separate sessions spaced one month apart for the presence of myometrial invasion (MI), cervical stromal involvement (CSI), malignant adnexal disease (mAD), and pelvic lymphadenopathy (pLNM). Each reader also recorded maximum tumor diameter, tumor volume, and tumor-to-uterine volume ratio (TVR) on T2-weighted imaging. The diagnostic performance of bpMRI and mpMRI was determined for each reader with surgical pathology serving as a gold standard.

Results: The area under the receiver operating curve (AUC) for bpMRI versus mpMRI was 0.76/0.78 (R1/R2) versus 0.84/0.83 for MI, 0.79/0.76 versus 0.99/0.80 for CSI, 0.84/0.84 versus 0.84/0.80 for mAD, and 0.82/0.82 for pLMN. The sensitivity and specificity of MRI for detecting tumor spread beyond the endometrium were 71%/77% and 71%/65% for bpMRI (R1/R2) vs. 84%/90% and 71%/65% for mpMRI (R1/R2), respectively. The AUC of maximum tumor diameter, tumor volume, and TVR for MI was 0.71/0.61, 0.73/0.75, and 0.75/0.77 for R1/R2, respectively.

Conclusion: MRI had moderate diagnostic performance across potential candidates for fertility-sparing treatment of EC. mpMRI outperformed bpMRI for detecting EC spreading beyond the endometrium.
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http://dx.doi.org/10.1007/s00261-021-03050-7DOI Listing
September 2021
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