Publications by authors named "Satoru Miura"

67 Publications

A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non-Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study).

Clin Lung Cancer 2021 Oct 25. Epub 2021 Oct 25.

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

Background: First-line treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death-1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte-associated protein-4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC.

Patients And Methods: Chemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events.

Conclusion: If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2021.10.012DOI Listing
October 2021

Real-world data on NGS using the Oncomine DxTT for detecting genetic alterations in non-small-cell lung cancer: WJOG13019L.

Cancer Sci 2021 Oct 26. Epub 2021 Oct 26.

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

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.
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http://dx.doi.org/10.1111/cas.15176DOI Listing
October 2021

Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global non-interventional study (UpSwinG).

Lung Cancer 2021 Sep 21;162:9-15. Epub 2021 Sep 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. Electronic address:

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.

Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).

Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.009DOI Listing
September 2021

The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events.

Front Oncol 2021 24;11:704475. Epub 2021 Sep 24.

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Objectives: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.

Methods: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.

Results: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) . not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) . not reached (95% CI: 8.4-NE); p = 0.031].

Conclusion: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.
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http://dx.doi.org/10.3389/fonc.2021.704475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498597PMC
September 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

Editorial preface: Radiation contamination of forests and forest products - Consequences and future.

J Environ Radioact 2021 Sep 25:106748. Epub 2021 Sep 25.

Andra, Research and Development Division, France. Electronic address:

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http://dx.doi.org/10.1016/j.jenvrad.2021.106748DOI Listing
September 2021

Dynamics of radiocaesium within forests in Fukushima-results and analysis of a model inter-comparison.

J Environ Radioact 2021 Nov 8;238-239:106721. Epub 2021 Sep 8.

Andra, Research and Development Division, 1-7 Rue Jean-Monnet, 92298, Châtenay-Malabry cedex, France.

Forests cover approximately 70% of the area contaminated by the Fukushima Daiichi Nuclear Power Plant accident in 2011. Following this severe contamination event, radiocaesium (Cs) is anticipated to circulate within these forest ecosystems for several decades. Since the accident, a number of models have been constructed to evaluate the past and future dynamics of Cs in these forests. To explore the performance and uncertainties of these models we conducted a model inter-comparison exercise using Fukushima data. The main scenario addressed an evergreen needleleaf forest (cedar/cypress), which is the most common and commercially important forest type in Japan. We also tested the models with two forest management scenarios (decontamination by removal of soil surface litter and forest regeneration) and, furthermore, a deciduous broadleaf forest (konara oak) scenario as a preliminary modelling study of this type of forest. After appropriate calibration, the models reproduced the observed data reliably and the ranges of calculated trajectories were narrow in the early phase after the fallout. Successful model performances in the early phase were probably attributable to the availability of comprehensive data characterizing radiocaesium partitioning in the early phase. However, the envelope of the calculated model end points enlarged in long-term simulations over 50 years after the fallout. It is essential to continue repetitive verification/validation processes using decadal data for various forest types to improve the models and to update the forecasting capacity of the models.
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http://dx.doi.org/10.1016/j.jenvrad.2021.106721DOI Listing
November 2021

Subsequent systemic therapy for non-small cell lung cancer patients with immune checkpoint inhibitor-related interstitial lung disease.

Transl Lung Cancer Res 2021 Jul;10(7):3132-3143

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD.

Methods: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017.

Results: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) 7.0 months (95% CI: 1-NE); P=0.3154].

Conclusions: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.
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http://dx.doi.org/10.21037/tlcr-21-198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350095PMC
July 2021

A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L).

J Thorac Oncol 2021 Dec 19;16(12):2121-2132. Epub 2021 Aug 19.

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

Objectives: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC.

Methods: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA.

Results: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively.

Conclusions: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
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http://dx.doi.org/10.1016/j.jtho.2021.07.026DOI Listing
December 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

Pembrolizumab plus chemotherapy-induced pneumonitis in chemo-naïve patients with non-squamous non-small cell lung cancer: A multicentre, retrospective cohort study.

Eur J Cancer 2021 06 20;150:63-72. Epub 2021 Apr 20.

Internal Medicine III, Wakayama Medical University, Wakayama, 641-8509, Japan.

Introduction: Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings.

Methods: We conducted a 36-centre, retrospective cohort study in patients with chemo-naïve advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019.

Results: The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9-16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6-6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4-10.5) and 9 patients (3.0%, 95% CI 1.4-5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0-6.8) and 7.5 (95% CI 6.5-8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07-3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12-8.20, P = 0.03).

Conclusions: Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy.

Trial Registration Number: UMIN000038084.
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http://dx.doi.org/10.1016/j.ejca.2021.03.016DOI Listing
June 2021

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

Transl Lung Cancer Res 2021 Jan;10(1):252-260

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor () mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity.

Methods: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire.

Results: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively.

Conclusions: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).
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http://dx.doi.org/10.21037/tlcr-20-649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867768PMC
January 2021

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

Eur J Cancer 2021 03 22;145:183-193. Epub 2021 Jan 22.

Respiratory Division, Department of Internal Medicine, Itami City Hospital, 1-100 Koyaike, Itami City, Hyogo, 664-8540, Japan.

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.

Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.

Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).

Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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http://dx.doi.org/10.1016/j.ejca.2020.12.026DOI Listing
March 2021

Calculations for ambient dose equivalent rates in nine forests in eastern Japan from Cs and Cs radioactivity measurements.

J Environ Radioact 2021 Jan 17;226:106456. Epub 2020 Nov 17.

Japan Atomic Energy Agency, Center for Computational Science and e-Systems, 178-4-4 Wakashiba, Kashiwa, Chiba, 277-0871, Japan.

Understanding the relationship between the distribution of radioactive Cs and Cs in forests and ambient dose equivalent rates (H˙(10)) in the air is important for researching forests in eastern Japan affected by the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. This study used a large number of measurements from forest samples, including Cs and Cs radioactivity concentrations, densities and moisture contents, to perform Monte Carlo radiation transport simulations for H˙(10) between 2011 and 2017. Calculated H˙(10) at 0.1 and 1 m above the ground had mean residual errors of 19% and 16%, respectively, from measurements taken with handheld NaI(Tl) scintillator survey meters. Setting aside the contributions from natural background radiation, Cs and Cs in the organic layer and the top 5 cm of forest soil generally made the largest contributions to calculated H˙(10). The contributions from Cs and Cs in the forest canopy were calculated to be largest in the first two years following the accident. Uncertainties were evaluated in the simulation results due to the measurement uncertainties in the model inputs by assuming Gaussian measurement errors. The mean uncertainty (relative standard deviation) of the simulated H˙(10) at 1 m height was 11%. The main contributors to the total uncertainty in the simulation results were the accuracies to which the Cs and Cs radioactivities of the organic layer and top 5 cm of soil, and the vertical distribution of Cs and Cs within the 5 cm soil layers, were known. Radioactive cesium located in the top 5 cm of soil was the main contributor to H˙(10) at 1 m by 2016 or 2017 in the calculation results for all sites. Studies on the Cs distribution within forest soil will therefore help explain radiation levels henceforth in forests affected by the FDNPP accident. The merits of this study are that it modelled multiple forests for a long time period, with the important model inputs being informed by field measurements, and it quantified how the measurement uncertainties in these inputs affected the calculation results.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106456DOI Listing
January 2021

Global Cs fallout inventories of forest soil across Japan and their consequences half a century later.

J Environ Radioact 2020 Dec 5;225:106421. Epub 2020 Oct 5.

Shikoku Research Center, Forestry and Forest Products Research Institute, 2-915 Asakuranishi, Kochi, 780-8077, Japan. Electronic address:

Japanese forests were exposed to multiple sources of radioactive contamination. To acquire scientific guidance on forest management planning, it is crucial to understand the long-term radiocesium (Cs) distribution (and redistribution) over time. To obtain robust evidence of the residual global fallout of Cs (Cs-GFO) after a few decades, we determined Cs-GFO inventory in forest soil at 1171 soil pits of 316 plots evenly spaced across Japan from 2006 to 2011, shortly before the Fukushima Dai-ichi Nuclear Power Plant accident. The activity concentration measurements were performed using a NaI well-type scintillation counter. The average (±SD) Cs-GFO in forest soil (0-30 cm from the surface) of the National Forest Soil Carbon Inventory (NFSCI) sampling plots uniformly extracted from the entire country was estimated to be 2.27 ± 1.73 kBq m (n = 316) as of Oct. 1, 2008. A high nationwide spatial variation was found in Cs-GFO, where relatively high Cs-GFO was found along the Sea of Japan compared with the total annual precipitation. We also obtained a reconstructed decay-corrected cumulative Cs-GFO dataset from the fallout observatories as the initial Cs-GFO. The cumulative Cs-GFO of fallout observatories averaged 2.47 ± 0.95 kBq m (n = 39) as of Oct. 1, 2008 and displayed spatial variation similar to that in forest soil. To identify whether Cs-GFO remains in forest soil across Japan, we examined a general linear mixed-effect model comparing Cs-GFO between forest soil and the observatory under normalized annual precipitation and region. The model did not indicate a significant difference, but relatively lesser Cs-GFO was found in forest soil, where the least-squares mean of Cs-GFO in forest soils was 79.1% of that of the observatory. The variation in Cs-GFO in forest soils within NFSCI sampling plots was 1.4 times greater than that among plots. The high spatial variation in Cs-GFO within a 0.1-ha plot strongly suggested the redistribution of Cs-GFO within the forest catchment. The vertical distribution pattern of Cs-GFO across three depth layers indicated that the Cs-GFO redistributions were likely attributed to the movements of sediments and mass. Moreover, when extracting soil pits assumed to have the least soil disturbance from the vertical distribution pattern, no significant difference in Cs-GFO was observed between forest soil and observatory data. These findings provide important insights into the stability of Cs-GFO in the forest ecosystem. Considering the potential hotspot where Cs-GFO can accumulate deeper in the soil (>30 cm in depth), most Cs-GFO has remained in the forest for decades. Our study offers microscale heterogeneous Cs-GFO distribution in forests for ensuring long-term forest management planning necessary for both the long-term migration and local accumulation of Cs in forests.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106421DOI Listing
December 2020

Seasonal changes in radiocesium and potassium concentrations in current-year shoots of saplings of three tree species in Fukushima, Japan.

J Environ Radioact 2020 Nov 10;223-224:106409. Epub 2020 Sep 10.

Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-0032, Japan.

We studied seasonal changes in radiocesium (Cs) activity and potassium concentrations in current-year leaves and branches of Pinus densiflora (naturally regenerated saplings), Cryptomeria japonica (planted saplings) and Quercus serrata (planted saplings and coppice shoots) in Fukushima, Japan. We collected current-year shoots from 10 individuals of each species over two growing seasons at intervals of 1-4 months, between June 2016 and December 2017. For the deciduous species Q. serrata, we also collected dead leaves that remained attached to branches in December to investigate reabsorption of Cs. All collected shoots were divided into leaves and branches, oven-dried, and ground; dry weights of each sample were recorded. Cs activity concentrations were measured using a germanium semiconductor detector. Potassium concentrations were quantified using inductively coupled plasma optical emission spectrometry (ICP-OES). Increases in dry weight were observed in both leaves and branches between May/June and August; growth then slowed considerably and virtually ceased after October. Clear seasonal changes in Cs activity concentrations were observed in both 2016 and 2017, regardless of tree species. Concentrations were higher in young leaves and branches during May and June, then decreased and changed relatively little from August to winter. Reduced Cs activity concentrations in dead leaves of Q. serrata were observed only in December 2017 (approximately 15% lower than in October). This reduction may indicate reabsorption of Cs in leaves prior to shedding. The changes in potassium concentrations were similar to those in Cs in both years. Potassium concentrations were higher in young leaves than in mature leaf and branch samples collected later in the year. A reduction of about 50% in the potassium concentrations in dead leaves of Q. serrata was also observed in December. A positive relationship between Cs and potassium concentrations in leaves and branches was observed in all species, except for planted Q. serrata. This relationship may indicate that Cs moves in tree shoots with potassium. Leaf and branch weight correlated negatively with Cs and potassium concentrations. Reduced concentrations may indicate dilution of these elements as a result of biomass increases over the growing season. Our results imply that irrespective of species, Cs exhibits seasonal variations resulting from dilution; these variations correspond with trends in potassium, with higher levels in young organs and decreased levels in older organs.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106409DOI Listing
November 2020

Temporal changes in the spatial patterns of air dose rate from 2012 to 2016 at forest floors in Fukushima, Japan.

J Environ Radioact 2020 Oct 24;222:106377. Epub 2020 Aug 24.

Kansai Research Center, Forestry and Forest Products Research Institute, 68 Nagaikyutaroh, Momoyama, Fushimi, Kyoto, Kyoto, 612-0855, Japan.

This study investigates temporal changes in the distribution of air dose rates at forest floors from 2012 to 2016 by measuring air dose rates at a height of 10 cm. The study was conducted at four different topography forest sites in Fukushima Prefecture, Japan. At each forest site, the air dose rate was found to have decreased by 7%-22% over time from 2012 to 2016 owing to the movement of radiocesium from organic layers to mineral soil layers in the forest site. However, the spatial distribution patterns of air dose rates did not change at these forest sites over five years. Besides, high correlations between air dose rates and organic plus surface mineral soil inventories were found at these forest sites during most of study years. Therefore, little changes in the spatial distribution of air dose rates could be caused by radiocesium retention at the same location in these forest sites. No statistical correlation between air dose rates and slope gradients was found in the two hilly forest sites with steep slopes above 35°. Accordingly, this study shows that the distribution patterns of air dose rates in the forest floors remained stable depending on the spatial distribution of radiocesium, which formed in the early phase after the Fukushima Daiichi Nuclear Power Plant accident.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106377DOI Listing
October 2020

Assessment of vertical radiocesium transfer in soil via roots.

J Environ Radioact 2020 Oct 12;222:106369. Epub 2020 Aug 12.

Kansai Research Center, FFPRI, 68 Nagaikyutaroh, Momoyama, Fushimi, Kyoto, 612-0855, Japan.

Several years after the Fukushima Daiichi Nuclear Power Plant accident, the surface mineral soil layer is believed to be the main reservoir of radiocesium (Cs) in forest ecosystems in Japan. Dissolved Cs combines with clay minerals in the soil, and hence, it is not expected to easily infiltrate over time. However, previous studies have indicated that Cs derived from the older global fallout migrated deeper than that of the Chernobyl accident, and this cannot be explained by only the dissolved Cs vertical migration in the soil. Considering the carbon and nutrient dynamics in the forest floor, the Cs transfer process in soil via roots may alter its vertical distribution on a decadal scale. Therefore, in this study, we investigated the Cs activity concentrations in both roots and soil matrix, by considering four (0-20 cm) or six (0-30 cm) mineral soil layers taken at every 5 cm at seven study sites dominated by one of the six plant species (three coniferous forests, one deciduous forest, two deciduous forests covered by Sasa, and one bamboo forest) in eastern Japan in 2013. Comparing the results of Cs activity concentrations between roots and soil matrix taken at the same soil layer, roots at the surface (0-5 cm) layer often showed lower values than the soil matrix. However, roots deeper than 5 cm had higher activity concentrations than the soil matrix, conversely. The Cs inventories ratio of roots to soil matrix are about 1% at the 0-5 and 5-10 cm soil layer, and about 2% at the soil layers deeper than 10 cm. These results suggest that decomposition of root litter little affect the short-term vertical migration of Cs in the forest soil. However, it indicates that continuous production and mortality of roots with relatively high Cs activity concentrations have an important role for changing the vertical distribution of Cs on time scale of decades, particularly at deeper soil layers.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106369DOI Listing
October 2020

Chemical sequential extraction of O horizon samples from Fukushima forests: Assessment for degradability and radiocesium retention capacity of organic matters.

J Environ Radioact 2020 Sep 5;220-221:106306. Epub 2020 Jun 5.

Center for Forest Restoration and Radioecology, Forestry and Forest Products Research Institute, 1 Matsunosato, Tsukuba, Ibaraki, 305-8687, Japan.

To investigate how radiocesium (Cs) is retained in the O horizon via interactions with organic matter, we collected O horizon samples in Japanese cedar (Cryptomeria japonica) and konara oak (Quercus serrata) forest sites in Fukushima during the 8 years following the Fukushima Dai-ichi Nuclear Power Plant accident. To assess degradability and Cs retention capacity of organic matter, we conducted chemical sequential extraction with organic solvent and sulfuric acid, collecting the following fractions: organic solvent extractives (Fraction 1), acid-soluble carbohydrates (Fraction 3), and acid-insoluble residue (Fraction 4). In all samples, across sampling years and sites, Cs content in Fractions 1, 3, and 4, as a proportion of the total Cs content, was 0.0-23.6%, 18.4-42.9%, and 44.8-76.0%, respectively. Generally, Cs is considered to be electrostatically bound to organic matter and relatively mobile, making it easily extractable by sulfuric acid treatment. However, we observed a relatively high proportion of Cs in Fraction 4, suggesting strong retention of Cs and their immobility in the O horizon. Complex organic matter such as lignin or tannin may contribute this retention. We also noted that some part of Cs may be also retained by clay minerals in the O horizon. Although organic matter in Fractions 1 and 3 is considered to decompose faster than that in Fraction 4, over the observation period the Cs proportion and net rate of decrease in Cs content (in total and in each fraction) remained nearly constant. This result implies that decomposition of organic matter and the consequent release of bound Cs may be partly compensated by additional input of Cs from the canopy and Cs recycling by soil microorganisms. Our study highlights the potential role of organic matter in the O horizon as a temporary reservoir of Cs and a driver of the Cs cycle in forest ecosystems.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106306DOI Listing
September 2020

Treatment Rationale and Design of a Phase III Study of Afatinib or Chemotherapy in Patients with Non-small-cell Lung Cancer Harboring Sensitizing Uncommon Epidermal Growth Factor Receptor Mutations (ACHILLES/TORG1834).

Clin Lung Cancer 2020 11 21;21(6):e592-e596. Epub 2020 May 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.

We describe the treatment rationale and design of our randomized phase III study, the ACHILLES trial (Japan Registry of Clinical Trials: jRCTs031180175). The aim of this study is to investigate the superiority of afatinib over chemotherapy as first-line treatment in patients with advanced nonsquamous non-small-cell lung cancer with sensitizing uncommon or compound epidermal growth factor receptor (EGFR) mutations, with the exception of de novo T790M mutations and exon 20 insertions. Eligible patients will be randomized at a 1:2 ratio to receive either chemotherapy or afatinib until disease progression or unacceptable toxicity. Patients in the chemotherapy arm will receive pemetrexed 500 mg/m + cisplatin 75 mg/m or carboplatin area under the curve (AUC) 5 or 6 every 3 weeks × 4 cycles, followed by pemetrexed 500 mg/m every 3 weeks. In the afatinib arm, investigators will choose the starting dose of afatinib (30 mg or 40 mg orally daily). The primary endpoint is progression-free survival. A total of 106 patients will be enrolled in this trial over a 30-month registration period with a 15-month follow-up. Enrollment began in March 2019. The results of this trial will establish the superiority of afatinib over chemotherapy in a cohort with a large variety of EGFR mutations.
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http://dx.doi.org/10.1016/j.cllc.2020.05.011DOI Listing
November 2020

Relationship between the activity concentration of Cs in the growing shoots of Quercus serrata and soil Cs, exchangeable cations, and pH in Fukushima, Japan.

J Environ Radioact 2020 Sep 31;220-221:106276. Epub 2020 May 31.

Hokkaido Research Center, Forestry and Forest Products Research Institute, 7 Hitsujigaoka, Toyohira, Sapporo, Hokkaido, 062-8516, Japan.

Incorporation of radiocesium by plants via root uptake appears to be affected by some of the exchangeable cations in the soil and/or pH of the soil. However, few studies have examined the relationship between Cs in trees and soil properties in the area surrounding the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) after the accident in March 2011. To elucidate the relationships between the root uptake of Cs by deciduous broadleaved trees and soil properties, we measured the activity concentration of Cs in the growing shoots of coppiced konara oak (Quercus serrata) grown after the FDNPP accident and the amounts of total Cs; exchangeable (ex-) Cs, ex-K, ex-Mg, and ex-Ca; and pH (HO) in soils collected from 34 forest stands in Fukushima between December 2016 and May 2017. Ex-Cs showed a positive linear relationship with the activity concentration of Cs in the growing konara oak shoots, whereas ln-transformed ex-K, ex-Mg, ex-Ca, and pH (HO) showed negative linear relationships with ln-transformed Cs activity concentrations in the growing shoots. However, only ex-Cs and ex-K were identified as significant factors determining the activity concentration of Cs in konara oak according to multiple regression methods and a model selection using Akaike information criterion; ex-K had a stronger influence on the activity concentration of Cs in konara oak than ex-Cs. In the present study, we demonstrated that soil ex-K negatively and non-linearly alters Cs activity concentration in deciduous broadleaved trees. We also noted that the relationship between Cs in deciduous broadleaved trees and soil ex-K in forests without K fertilization was similar to the relationships between Cs in other plants and ex-K in K-fertilized lands reported in previous studies of the FDNPP accident.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106276DOI Listing
September 2020

A randomized phase 3 study of maintenance therapy with S-1 plus best supportive care versus best supportive care after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell carcinoma of the lung (WJOG7512L).

Cancer 2020 08 2;126(16):3648-3656. Epub 2020 Jun 2.

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

Background: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC).

Methods: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival.

Results: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe.

Conclusions: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.
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http://dx.doi.org/10.1002/cncr.32987DOI Listing
August 2020

A phase II study of Osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer: treatment rationale and protocol design of the OCEAN study (LOGIK 1603/WJOG 9116L).

BMC Cancer 2020 May 1;20(1):370. Epub 2020 May 1.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

Background: Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15-30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear.

Methods: In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing.

Discussion: Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis.

Trial Registration: UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019).
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http://dx.doi.org/10.1186/s12885-020-06874-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195707PMC
May 2020

Prognostic significance of the radiologic features of pneumonitis induced by anti-PD-1 therapy.

Cancer Med 2020 05 9;9(9):3070-3077. Epub 2020 Mar 9.

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Interstitial lung disease (ILD) induced by anti-programmed-cell death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) is potentially life-threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune-related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti-PD-1/PD-L1 therapies, the association between radiologic features and clinical outcomes remains unclear.

Methods: Patients with advanced non-small-cell lung cancer who were treated with 1st to 3rd line anti-PD-1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD.

Results: A total of 231 patients who received anti-PD-1 therapy were enrolled. Thirty-one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2-NE) versus not reached (95% CI: 13.2-NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival.

Conclusions: This study demonstrated that patients who developed GGO exhibited worse outcomes among non-small-cell lung cancer patients receiving anti-PD-1 therapies.
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http://dx.doi.org/10.1002/cam4.2974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196069PMC
May 2020

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases.

J Thorac Oncol 2020 05 10;15(5):803-815. Epub 2020 Jan 10.

Department of Solid Tumor Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.

Introduction: Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, noninterventional trials, and case series or studies.

Methods: Patients had uncommon EGFR mutations, which were categorized as follows: (1) T790M; (2) exon 20 insertions; (3) "major" uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations. Key end points were overall response rate (ORR), duration of response, and time to treatment failure (TTF).

Results: In EGFR TKI-naive patients (n = 315), afatinib demonstrated activity against major uncommon mutations (median TTF = 10.8 mo; 95% confidence interval [CI]: 8.1-16.6; ORR = 60.0%), compound mutations (median TTF = 14.7 mo; 95% CI: 6.8-18.5; ORR = 77.1%), other uncommon mutations (median TTF = 4.5 mo; 95% CI: 2.9-9.7; ORR = 65.2%), and some exon 20 insertions (median TTF = 4.2 mo; 95% CI: 2.8-5.3; ORR = 24.3%). The median duration of response for major uncommon mutations, compound mutations, other uncommon mutations, and some exon 20 insertions was 17.1, 16.6, 9.0, and 11.9 months, respectively. Activity of afatinib was also observed in EGFR TKI-pretreated patients (n = 378). A searchable database of these outcomes by individual genotype was generated.

Conclusions: Afatinib has clinical activity in NSCLC against major uncommon and compound EGFR mutations. It also has broad activity against other uncommon EGFR mutations and some exon 20 insertions. The data support the use of afatinib in these settings.
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http://dx.doi.org/10.1016/j.jtho.2019.12.126DOI Listing
May 2020

Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study.

BMC Cancer 2019 Dec 2;19(1):1170. Epub 2019 Dec 2.

Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.

Background: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer.

Methods: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α-microglobulin, β-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment.

Results: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline.

Conclusions: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.
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http://dx.doi.org/10.1186/s12885-019-6398-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889728PMC
December 2019

Efficient sampling of shiitake-inoculated oak logs to determine the log-to-mushroom transfer factor of stable cesium.

PeerJ 2019 24;7:e7825. Epub 2019 Oct 24.

Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Background: Stable cesium (Cs) naturally exists in the environment whereas recently deposited radionuclides (e.g., Cs) are not at equilibrium. Stable cesium has been used to understand the long-term behavior of radionuclides in plants, trees and mushrooms. We are interested in using Cs to predict the future transfer factor (TF) of radiocesium from contaminated logs to shiitake mushrooms in Eastern Japan. However, the current methodology to obtain a representative wood sample for Cs analysis involves mechanically breaking and milling the entire log (excluding bark) to a powder prior to analysis. In the current study, we investigated if sawdust obtained from cutting a log along its length at eight points is as robust but a faster alternative to provide a representative wood sample to determine the TF of Cs between logs and shiitake.

Methods: Oak logs with ready-to-harvest shiitake fruiting bodies were cut into nine 10-cm discs and each disc was separated into bark, sapwood and heartwood and the concentration of Cs was measured in the bark, sapwood, heartwood, sawdust (generated from cutting each disc) and fruiting bodies (collected separately from each disc), and the wood-to-shiitake TF was calculated.

Results: We found that the sawdust-to-shiitake TF of Cs did not differ ( = 0.223) compared to either the sapwood-to-shiitake TF or heartwood-to-shiitake TF, but bark did have a higher concentration of Cs ( < 0.05) compared to sapwood and heartwood. Stable cesium concentration in sawdust and fruiting bodies collected along the length of the logs did not differ ( > 0.05).

Discussion: Sawdust can be used as an alternative to determine the log-to-shiitake TF of Cs. To satisfy the goals of different studies and professionals, we have described two sampling methodologies (Methods I and II) in this paper. In Method I, a composite of eight sawdust samples collected from a log can be used to provide a representative whole-log sample (i.e., wood and bark), whereas Method II allows for the simultaneous sampling of two sets of sawdust samples-one set representing the whole log and the other representing wood only. Both methodologies can greatly reduce the time required for sample collection and preparation.
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http://dx.doi.org/10.7717/peerj.7825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815652PMC
October 2019

Efficacy of EGFR-TKIs with or without upfront brain radiotherapy for EGFR-mutant NSCLC patients with central nervous system metastases.

Thorac Cancer 2019 11 10;10(11):2106-2116. Epub 2019 Sep 10.

Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases.

Methods: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy.

Results: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival.

Conclusion: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.
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http://dx.doi.org/10.1111/1759-7714.13189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825912PMC
November 2019

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BMC Cancer 2019 May 31;19(1):528. Epub 2019 May 31.

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

Background: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study.

Methods: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development.

Discussion: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer.

Trial Registration: Registered at August 23, 2017. Registry number: UMIN000028801 .
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http://dx.doi.org/10.1186/s12885-019-5762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544995PMC
May 2019
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