Publications by authors named "Nobuyuki Yamamoto"

471 Publications

RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non-small Cell Lung Cancer.

Clin Cancer Res 2021 Jul 22. Epub 2021 Jul 22.

Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North.

Purpose: In -mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if -activating mutation subtypes impact treatment outcomes in the phase 3 RELAY study. Associations between mutation type and pre-existing co-occurring and treatment-emergent genetic alterations were also explored.

Experimental Design: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg) (RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survial (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses.

Results: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and co-mutational profiles. ne-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline co-mutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. mutation rate at progression was similar between treatment arms and by mutation type.

Conclusions: RAM+ERL provided significant clinical benefit for both ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these mutation types.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0273DOI Listing
July 2021

A Nanocrystal Catalyst Incorporating a Surface Bound Transition Metal to Induce Photocatalytic Sequential Electron Transfer Events.

J Am Chem Soc 2021 Jul 21. Epub 2021 Jul 21.

Department of Chemistry and Biochemistry, San Diego State University, San Diego, California 92182, United States.

Heterogeneous photocatalysis is less common but can provide unique avenues for inducing novel chemical transformations and can also be utilized for energy transductions, i.e., the energy in the photons can be captured in chemical bonds. Here, we developed a novel heterogeneous photocatalytic system that employs a lead-halide perovskite nanocrystal (NC) to capture photons and direct photogenerated holes to a surface bound transition metal Cu-site, resulting in a N-N heterocyclization reaction. The reaction starts from surface coordinated diamine substrates and requires two subsequent photo-oxidation events per reaction cycle. We establish a photocatalytic pathway that incorporates sequential inner sphere electron transfer events, photons absorbed by the NC generate holes that are sequentially funneled to the Cu-surface site to perform the reaction. The photocatalyst is readily prepared via a controlled cation-exchange reaction and provides new opportunities in photodriven heterogeneous catalysis.
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http://dx.doi.org/10.1021/jacs.1c00503DOI Listing
July 2021

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

J Allergy Clin Immunol Pract 2021 Jul 8. Epub 2021 Jul 8.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment.

Objective: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT.

Methods: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed.

Results: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT.

Conclusions: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
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http://dx.doi.org/10.1016/j.jaip.2021.05.045DOI Listing
July 2021

Anterior and posterior glenoid bone augmentation options for shoulder instability: state of the art.

J ISAKOS 2021 Jun 18. Epub 2021 Jun 18.

Division of Orthopaedic Surgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.

Bony lesions are highly prevalent in anterior shoulder instability and can be a significant cause of failure of stabilisation procedures if they are not adequately addressed. The glenoid track concept describes the dynamic interaction between the humeral head and glenoid defects in anterior shoulder instability. It has been beneficial for understanding the role played by bone defects in this entity. As a consequence, the popularity of glenoid augmentation procedures aimed to treat anterior glenoid bone defects; reconstructing the anatomy of the glenohumeral joint has risen sharply in the last decade. Although bone defects are less common in posterior instability, posterior bone block procedures can be indicated to treat not only posterior bony lesions, attritional posterior glenoid erosion or dysplasia but also normal or retroverted glenoids to provide an extended glenoid surface to increase the glenohumeral stability. The purpose of this review was to analyse the rationale, current indications and results of surgical techniques aimed to augment the glenoid surface in patients diagnosed of either anterior or posterior instability by assessing a thorough review of modern literature. Classical techniques such as Latarjet or free bone block procedures have proven to be effective in augmenting the glenoid surface and consequently achieving adequate shoulder stability with good clinical outcomes and early return to athletic activity. Innovations in surgical techniques have permitted to perform these procedures arthroscopically. Arthroscopy provides the theoretical advantages of lower morbidity and faster recovery, as well as the identification and treatment of concomitant pathologies.
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http://dx.doi.org/10.1136/jisakos-2019-000413DOI Listing
June 2021

Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L.

J Thorac Oncol 2021 Jun 9. Epub 2021 Jun 9.

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

Introduction: About 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted.

Methods: Chemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366).

Results: Between August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45-74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%-). The overall response rate was 81.5% (95% CI: 63.3%-91.3%), median PFS was 18.6 months (95% CI: 12.0-24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo-not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each).

Conclusions: This prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.
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http://dx.doi.org/10.1016/j.jtho.2021.05.019DOI Listing
June 2021

Longitudinal Evaluation of PD-L1 Expression on Circulating Tumor Cells in Non-Small Cell Lung Cancer Patients Treated with Nivolumab.

Cancers (Basel) 2021 May 11;13(10). Epub 2021 May 11.

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

Although programmed death-ligand 1 (PD-L1) expression on tumor tissue is a validated predictive biomarker for a PD-1 pathway blockade in non-small cell lung cancer (NSCLC), longitudinal changes in its expression during treatment remains elusive. Circulating tumor cells (CTCs) are assumed to reflect the transition of characteristics of the primary tumor undergoing anticancer treatment. Here, we sequentially evaluated the PD-L1 expression on CTCs in NSCLC patients treated with nivolumab. Forty-five patients were enrolled, and CTCs were enriched from 3 mL of peripheral blood using a microcavity array system at baseline and weeks 4, 8, 12, and 24 or until progressive disease. The effective responses to therapy were compared between patients without progressive disease (PD) at week 8 (i.e., non-PD patients) and in those with PD between weeks 4 and 8 (PD patients) in terms of increased vs. decreased or equal CTC status at week 8 (for non-PD patients) or at the point of PD (for PD patients) compared to the baseline. Significantly more non-PD patients were classified as decreased or equal in number and proportion to PD-L1-positive CTCs among the detected CTCs (PD-L1 positivity rates) ( < 0.05). Moreover, progression-free survival was significantly longer in patients with ≥7.7% PD-L1 positivity rates ( = 8) than in those with <7.7% rates ( = 8; < 0.01) at week 8. These results suggest the predictive significance of the early evaluation of PD-L1 expression on CTCs for maintaining the benefits from nivolumab treatment.
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http://dx.doi.org/10.3390/cancers13102290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150706PMC
May 2021

Limited correlation between tumor markers and minimal residual disease detected by seven neuroblastoma-associated mRNAs in high-risk neuroblastoma patients.

Mol Clin Oncol 2021 Jul 19;15(1):137. Epub 2021 May 19.

Department of Public Health, Kobe University Graduate School of Health Science, Kobe, Hyogo 654-0142, Japan.

Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD. In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.
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http://dx.doi.org/10.3892/mco.2021.2299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145602PMC
July 2021

Bloodborne Cytokines for Predicting Clinical Benefits and Immune-Related Adverse Events in Advanced Non-Small Cell Lung Cancer Treated With Anti-Programmed Cell Death 1 Inhibitors.

Clin Lung Cancer 2021 Apr 27. Epub 2021 Apr 27.

Internal Medicine III, Wakayama Medical University, Wakayama-city, Wakayama, Japan.

Background: Programmed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non-small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs).

Patients And Methods: Patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated.

Results: Sixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset.

Conclusions: Serum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment.
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http://dx.doi.org/10.1016/j.cllc.2021.04.007DOI Listing
April 2021

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

Clin Lung Cancer 2021 Apr 27. Epub 2021 Apr 27.

Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address:

Introduction: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069).

Patients And Methods: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%.

Conclusion: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2021.04.006DOI Listing
April 2021

Minimal residual disease in high-risk neuroblastoma shows a dynamic and disease burden-dependent correlation between bone marrow and peripheral blood.

Transl Oncol 2021 Aug 14;14(8):101019. Epub 2021 May 14.

Department of Public Health, Kobe University Graduate School of Health Science, Kobe, Japan. Electronic address:

Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p < 0.001) correlated with each other in overall sample pairs. The correlation became strong (r = 0.725, p < 0.001), weak (r = 0.284, p = 0.008), and insignificant (p = 0.194) in progression, stable, and remission subgroups of sample pairs, respectively. It also became stronger in subgroups of sample pairs with poor treatment responses and poor prognostic factors. Present study suggests that MRD in high-risk NB shows a dynamic and disease burden-dependent correlation between BM and PB.
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http://dx.doi.org/10.1016/j.tranon.2021.101019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138775PMC
August 2021

Comparison of Systemic Inflammatory Response Syndrome and quick Sequential Organ Failure Assessment scores in predicting bacteremia in the emergency department.

Acute Med Surg 2021 Jan-Dec;8(1):e654. Epub 2021 May 1.

Internal Medicine III Wakayama Medical University Wakayama Japan.

Aim: The emergency department requires simple and useful clinical indicators to identify bacteremia. This retrospective study explored the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores for predicting bacteremia.

Methods: Between April and September 2017, we assessed blood cultures of 307 patients in our emergency department. We calculated the SIRS and qSOFA scores for these patients and evaluated their correlation with bacteremia.

Results: Of 307 patients, 66 (21.5%) had bacteremia, 237 (77.2%) were SIRS-positive, and 123 (40.0%) were qSOFA-positive. The sensitivity and specificity of the SIRS score for predicting bacteremia were 87.9% and 25.7%, respectively. The sensitivity and specificity of the qSOFA score were 47.0% and 61.8%, respectively. Multivariate analysis revealed that body temperature (odds ratio, 2.16; 95% confidence interval, 1.22-3.84;  = 0.009) and blood pressure (odds ratio, 2.72; 95% confidence interval, 1.39-5.35;  = 0.004) significantly associated with bacteremia.

Conclusions: The SIRS score was a more sensitive indicator than the qSOFA score for predicting bacteremia.
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http://dx.doi.org/10.1002/ams2.654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088398PMC
May 2021

Tumor microenvironment disparity in multiple primary lung cancers: Impact of non-intrinsic factors, histological subtypes, and genetic aberrations.

Transl Oncol 2021 Jul 27;14(7):101102. Epub 2021 Apr 27.

Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Introduction: Multiple primary lung cancers (MPLCs) occur in common carcinogenetic risks such as lifestyle, biological aging, immune responses, hormones, and metabolism. Although MPLCs harbor various genetic profiles within the same individuals, differences in the tumor microenvironment (TME) are unclear. We investigated the impact of genetic aberrations, non-intrinsic factors, and pathological subtypes on tumor immunity.

Materials And Methods: In total, 73 surgically resected specimens from 32 patients with MPLC were analyzed. PD-L1 expression in tumor cells (TCs) and immune cells (ICs), CD3-positive tumor-infiltrating lymphocytes (TILs), CD8/CD3 ratios, and FOXP3-positive TILs that compose TMEs were evaluated by immunohistochemistry and classified on a score of 0-2. 38 tumors were sequenced for somatic mutations in 409 cancer-associated genes.

Results: Females and never or light smokers had a higher incidence of PD-L1-negative tumors and a higher concordance rate. PD-L1 positivity in TCs and ICs was significantly less frequent in EGFR-mutated than in wild-type tumors. Differences in the score of TMEs were observed between the KRAS-mutated-only tumor and the KRAS and TP53-co-mutated tumors, and between the KRAS-mutated-only tumor and the KRAS and STK11-co-mutated tumors. Significantly more FOXP3-high TILs were observed in invasive pathological subtypes than in non-invasive ones.

Conclusion: Comparing TMEs among MPLCs revealed that non-smokers or light smokers and females were unlikely to express PD-L1 regardless of tumor site and confirmed that the EGFR mutations and co-occurring KRAS and STK11 or TP53 mutations were associated with TME. Pathological subtypes may impact the efficacy of immune therapy due to their potential correlations with regulatory T cells.
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http://dx.doi.org/10.1016/j.tranon.2021.101102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102176PMC
July 2021

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

J Thorac Oncol 2021 Apr 27. 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
April 2021

Changes in shoulder muscle activities and glenohumeral motion after rotator cuff repair: an assessment using ultrasound real-time tissue elastography.

J Shoulder Elbow Surg 2021 Apr 22. Epub 2021 Apr 22.

Department of Physical Medicine and Rehabilitation, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Although rotator cuff repair is performed to restore the function of the rotator cuff muscles and glenohumeral (GH) joint motion, little has been known regarding the recovery process. The purpose of this study was (1) to investigate changes over time in activities of the supraspinatus and deltoid muscles assessed by ultrasound real-time tissue elastography (RTE) after rotator cuff repair and (2) to determine contributions of the activities of these muscles to the GH joint motion.

Methods: Twenty patients after rotator cuff repair and 13 control participants were enrolled in this study. Elasticity of the supraspinatus and middle deltoid muscles were measured at rest and 30° of humerothoracic elevation in the scapular plane (scaption) by using RTE. The elasticity at 30° of scaption was normalized to that at rest in each muscle to quantify their muscle activities. In addition, the supraspinatus-to-middle deltoid (SSP/MD) ratio for the normalized elasticity was calculated. The GH elevation angle was measured with a digital inclinometer, which was calculated by subtracting the scapular upward rotation angle from 30° of scaption. For patients after rotator cuff repair, all measurements were performed at 6 weeks, 8 weeks, 3 months, and 6 months after surgery. Rotator cuff integrity was examined with magnetic resonance imaging at 6 months after surgery.

Results: Fifteen of 20 patients who remained intact at 6 months after surgery completed this study. The supraspinatus activity at 6 weeks was significantly smaller than that at 3 months (P = .006) and 6 months (P = .010). There was no significant difference in the supraspinatus activity between the patients at 3 months and the control participants (P = .586). The middle deltoid activity at 6 weeks was significantly greater than that at 6 months (P = .003). There was positive correlation between GH elevation angle and the activity of the supraspinatus relative to the deltoid at 6 weeks (r = 0.75, P = .001) and 8 weeks (r = 0.53, P = .041).

Conclusion: The supraspinatus activity increased from 6 weeks to 3 months after surgery. The supraspinatus activity at 3 months after surgery was the same level as that in healthy individuals. On the other hand, the deltoid activity decreased from 6 weeks to 6 months after surgery. The increase in activity of the supraspinatus relative to the deltoid was likely to be related to the increase in GH elevation during postoperative at 8 weeks.
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http://dx.doi.org/10.1016/j.jse.2021.04.013DOI Listing
April 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 Jun 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

EGFR tyrosine kinase inhibitors for mutation-positive non-small-cell lung cancer: outcomes in Asian populations.

Future Oncol 2021 Jun 15;17(18):2395-2408. Epub 2021 Apr 15.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, 100, Taiwan.

Few data are available that have compared outcomes with different EGFR tyrosine kinase inhibitors (TKIs) specifically in Asian patients with mutation-positive non-small-cell lung cancer. In this narrative review, we have collated available data from prospective studies that have assessed first-, second- and third-generation EGFR TKIs in Asian populations, including subanalyses in individual countries (China and Japan). These data indicate that outcomes with first- and second-generation TKIs are broadly similar in Asian and non-Asian populations. However, while the third-generation EGFR TKI, osimertinib, confers significant overall survival benefit over erlotinib/gefitinib in non-Asians, this is not apparent in Asians, particularly in countries like Japan with well-resourced healthcare. Head-to-head comparisons of second- and third-generation EGFR TKIs, with OS as a primary end point, should be considered in Asia.
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http://dx.doi.org/10.2217/fon-2021-0195DOI Listing
June 2021

Chemotherapy plus atezolizumab for a patient with small cell lung cancer undergoing haemodialysis: a case report and review of literature.

Respirol Case Rep 2021 May 25;9(5):e00741. Epub 2021 Mar 25.

Internal Medicine III Wakayama Medical University Wakayama Japan.

Little is known about the safety of chemotherapy plus atezolizumab for patients with extensive-stage small cell lung cancer (ES-SCLC) undergoing haemodialysis (HD). An 80-year-old male received carboplatin [area under the concentration-time curve (AUC) = 5 on day 1], etoposide (40 mg/m on days 1, 2, and 3), and atezolizumab (1200 mg/body on day 1) as the first-line therapy for ES-SCLC. He was undergoing HD thrice a week for seven years. HD was provided 16 h after carboplatin administration. During the first cycle, grade 4 neutropenia (neutrophil count: 74/μL) and leukopenia (white blood cell count: 680/μL) occurred. Therefore, chemotherapy was administered with a reduced dose of carboplatin (AUC = 4) and etoposide (30 mg/m) from the second to fourth cycles. After four cycles, no severe non-haematological adverse events occurred, showing a remarkable response. We conclude that the carboplatin, etoposide, and atezolizumab combination can be safely administered to cancer patients undergoing HD.
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http://dx.doi.org/10.1002/rcr2.741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991827PMC
May 2021

Treatment of irreparable rotator cuff tears with superior capsular reconstruction.

J Exp Orthop 2021 Mar 27;8(1):23. Epub 2021 Mar 27.

Department of Orthopaedic Surgery, Tohoku University School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

The treatment of irreparable rotator cuff tears with severe muscle atrophy and fatty infiltration remains a challenge, especially in young patients. Many surgical procedures for these tears have been reported. No one surgical treatment has proven to be an optimal solution. Recently, reconstruction of the superior capsule with an allograft or autograft has gained popularity. In this manuscript, we reviewed the biomechanical and clinical reports that have assessed superior capsular reconstruction and clarified the issues about the surgical techniques and indication which have been discussed recently. Reconstruction of the superior capsule has shown promising early results with good clinical outcomes. Biomechanical studies have suggested various mechanisms of this procedure. Although good clinical results and biomechanical data are available, more research is necessary to further define the surgical indications and improve the surgical outcomes of this procedure. LEVEL OF EVIDENCE: Level V.
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http://dx.doi.org/10.1186/s40634-021-00342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997932PMC
March 2021

Mutational landscape of multiple primary lung cancers and its correlation with non-intrinsic risk factors.

Sci Rep 2021 Mar 11;11(1):5680. Epub 2021 Mar 11.

Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-cho, Abeno-ku, Osaka, 545-8585, Japan.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.
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http://dx.doi.org/10.1038/s41598-021-83609-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952588PMC
March 2021

Differences in scapular motion and parascapular muscle activities among patients with symptomatic and asymptomatic rotator cuff tears, and healthy individuals.

JSES Int 2021 Mar 15;5(2):238-246. Epub 2020 Dec 15.

Department of Physical Medicine and Rehabilitation, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Altered scapular motion is thought to be one of the factors associated with the development of symptomatic rotator cuff tears. However, the differences in kinematics and muscle activities of scapular upward/downward rotation between patients with symptomatic and asymptomatic tears are unclear. The purpose of this study was to compare the differences in kinematics and muscle activities of scapular rotation among patients with symptomatic and asymptomatic tears, and healthy individuals.

Methods: Twenty-three patients with rotator cuff tears and 9 healthy individuals (healthy group) participated in this study. Based on a visual analog scale (VAS, 0-100 mm), the patients were divided into symptomatic (13 patients; VAS ≥20 mm) and asymptomatic (10 patients; VAS <20 mm) groups. Scapular upward rotation was measured with a digital inclinometer. Elasticities of the upper trapezius, levator scapulae, and rhomboid major were assessed by using ultrasound real-time tissue elastography to quantify their muscle activities. All measurements were performed at 0°, 60°, 90°, and 120° of active arm elevation in the scapular plane.

Results: Scapular upward rotation was significantly less in the symptomatic group (9.4° ± 5.6°) compared with the asymptomatic group (15.7° ± 6.0°;  = .022) at 90° of arm elevation. The activity of the levator scapulae was significantly higher in the symptomatic group compared with the asymptomatic and healthy groups ( = .013 and  = .005, respectively) at 90° of arm elevation. The activity of the upper trapezius was significantly higher in the symptomatic group compared with the healthy group ( = .015) at 120° of arm elevation.

Conclusion: Patients with symptomatic rotator cuff tears showed less scapular upward rotation and higher activity of the levator scapulae at 90° of arm elevation compared to patients with asymptomatic rotator cuff tears.
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http://dx.doi.org/10.1016/j.jseint.2020.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910733PMC
March 2021

Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in .

Pediatr Hematol Oncol 2021 Feb 24:1-16. Epub 2021 Feb 24.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is [NM_001022.4]. Nearly 180 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.
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http://dx.doi.org/10.1080/08880018.2021.1887984DOI Listing
February 2021

A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with mutation (West Japan Oncology Group 11719L/ADJUST study).

Ther Adv Med Oncol 2021 21;13:1758835920987647. Epub 2021 Jan 21.

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

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with mutated NSCLC.

Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with mutation. Accrued patients will be pathological stage II-IIIA with completely resected NSCLC and whose tumors have mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study.

Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
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http://dx.doi.org/10.1177/1758835920987647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841658PMC
January 2021

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

Clin Lung Cancer 2021 Jan 25. Epub 2021 Jan 25.

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

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

Catheter-related blood stream infection caused by in a child with myeloid leukemia associated with Down syndrome.

Clin Case Rep 2021 Feb 18;9(2):835-840. Epub 2020 Dec 18.

Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan.

Rapidly growing nontuberculous mycobacteria should be considered if GPRs gram-positive rods are detected in blood cultures 2-3 days after the blood sample collection.
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http://dx.doi.org/10.1002/ccr3.3646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869324PMC
February 2021

Treatment of acromioclavicular joint separations in Japan: a survey.

JSES Int 2021 Jan 31;5(1):51-55. Epub 2020 Oct 31.

Scientific Research Project Committee, Japan Shoulder Society, Tokyo, Japan.

Background: Treatment options for acromioclavicular joint (ACJ) separations are highly dependent on severity, as well as the patient's background. Furthermore, some patients can be switched from conservative to surgical treatment. In this study, we conducted a mail-based questionnaire survey of members of the Japan Shoulder Society on the administration of treatments for ACJ separations.

Methods: A questionnaire survey with 5 categories was mailed to all 1655 members of the Japan Shoulder Society (including 59 councilors): initial treatment, whether surgery was performed, indications for surgery based on severity, switching from conservative to surgical treatment, and surgical methods.

Results: Altogether, 183 members, including 56 councilors, responded. Regarding the initial treatment, 17 respondents opted for treatment without immobilization or fixation and 166 opted for immobilization or fixation. Of the members, 11 opted for only conservative treatment whereas 172 chose surgery depending on the case; of the latter, 9 considered it for patients with a Rockwood classification of type 2 or higher; 120, for patients with type 3 or higher; and 172, for patients with types 4-6. Furthermore, 75 of 172 members had experience switching to surgical treatment during conservative treatment. For 64 of 172 members, the modified Cadenat method was the most common surgical method.

Conclusions: Only 11 members opted for conservative treatment of ACJ separations, and approximately 95% of physicians chose surgery. Furthermore, >70% of physicians considered surgery for an injury classified as type 3 or higher, and 37% of members performed the modified Cadenat method. However, the popularization of arthroscopic surgery may affect the selection of surgical methods in the future.
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http://dx.doi.org/10.1016/j.jseint.2020.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846705PMC
January 2021

Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 03 26;22(2):134-141. Epub 2020 Dec 26.

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

Background: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer.

Patients And Methods: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m; days 1 and 8, vinorelbine 20 mg/m). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period.

Results: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%.

Conclusion: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.cllc.2020.12.012DOI Listing
March 2021

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation.

Anticancer Res 2021 Feb;41(2):911-917

Internal Medicine III, Wakayama Medical University, Wakayama, Japan.

Background/aim: To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma.

Patients And Methods: Six advanced lung adenocarcinoma patients with EGFR mutation were treated with osimertinib 80 mg/day plus ramucirumab 10 mg/kg, every two weeks. Defined dose-limiting toxicity (DLT) was assessed within the first two treatment cycles.

Results: Of those enrolled, five patients had both EGFR exon 20 T790M mutation and sensitizing mutation. DLT was observed in one patient (grade 3 appetite loss). During the entire period, no other severe adverse event was observed. Five patients showed partial response and one disease progression. Median progression-free survival for patients with EGFR T790M was 9.2 months. In an exploratory analysis, changes of cell-free DNA at 2 weeks predicted radiological tumor responses.

Conclusion: The safety results of osimertinib plus ramucirumab in Japanese lung adenocarcinoma patients with EGFR mutation will lead to further efficacy investigation.
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http://dx.doi.org/10.21873/anticanres.14844DOI Listing
February 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 Mar 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

Prognostic impact of geriatric assessment in elderly patients with non-small cell lung cancer: an integrated analysis of two randomized phase III trials (JCOG1115-A).

Jpn J Clin Oncol 2021 Apr;51(5):685-692

Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.

Objective: Patients' actual age and performance status do not always accurately identify the 'fit elderly' for chemotherapy. This study aimed to determine whether four geriatric assessment tools could predict prognosis.

Methods: This study were analyzed using the data of two randomized phase III trials (JCOG0207 and JCOG0803/WJOG4307L) for elderly patients with advanced non-small cell lung cancer and included all eligible patients who were assessed before treatment with four geriatric assessment tools: the Barthel activities of daily living index, Lawton instrumental activities of daily living scale, Mini-Mental State Examination, and Geriatric Depression Scale-15. Univariable and multivariable analyses for overall survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as strata.

Results: This analysis included 330 patients aged 70-74, 75-79 or 80 or more (n = 95/181/54), with a performance status of 0 or 1 (n = 119/211). Patients were divided into three groups based on Mini-Mental State Examination and two groups based on Geriatric Depression Scale, but over 80% of patients had perfect scores for both activities of daily living and instrumental activities of daily living. In overall survival subgroup analyses by GA tool, only Mini-Mental State Examination scores were associated with substantial outcome differences (median survival times: 21.2, 13.5 and 12.2 months for scores 30, 29-24 and ≤23). After adjusting for baseline factors, the Mini-Mental State Examination, sex and performance status were tended to be worse overall survival.

Conclusion: MMSE scores, performance status and sex, but not chronological age, effectively predicted the prognosis of elderly patients. Further studies should confirm that the Mini-Mental State Examination is useful for determining the indication of chemotherapy in elderly patients with advanced non-small cell lung cancer.
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http://dx.doi.org/10.1093/jjco/hyaa257DOI Listing
April 2021

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Intest Res 2021 Jan 22. Epub 2021 Jan 22.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.
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http://dx.doi.org/10.5217/ir.2020.00041DOI Listing
January 2021
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