Publications by authors named "Shingo Matsumoto"

200 Publications

High proportion of tumor necrosis predicts poor survival in surgically resected high-grade neuroendocrine carcinoma of the lung.

Lung Cancer 2021 Jul 24;157:1-8. Epub 2021 May 24.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. Electronic address:

Objectives: Tumor necrosis is a negative prognostic factor in various cancers. High-grade neuroendocrine carcinomas (HGNEC) of the lung, such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), commonly have histopathological features of tumor necrosis. However, the prognostic value of tumor necrosis remains unknown.

Materials And Methods: A total of 81 patients with HGNEC (SCLC, n = 42; LCNEC, n = 39) who underwent complete resection were enrolled. The proportion of necrosis in the tumor tissues was quantified using digital image analysis. We analyzed the relationship between the proportion of necrosis, clinicopathological factors, and prognosis. Moreover, we examined the correlation between genomic alterations and proportion of necrosis.

Results: The median proportion of necrosis was 10.6 % (range, 0-62.8 %). The proportion of necrosis was not significantly different between SCLC (median, 5.1 %; range, 0-62.8 %) and LCNEC (median: 14.2 %; range, 0-59.3 %) (p =  0.14). The cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were significantly higher in patients with 10 % or higher necrosis (necrosis ≥ 10 %) than in those with less than 10 % (necrosis < 10 %) (hazard ratio [HR], 2.94; 95 % confidence interval [CI], 1.30-6.64, and HR, 2.87; 95 % CI, 1.13-7.29, respectively). In the bivariate analysis, necrosis ≥ 10 % was independently associated with higher CIR and tended to be associated with higher LC-CID. The frequency of genomic alterations in the PI3K/AKT/mTOR pathway, MYC family, MAPK/ERK pathway, and major RTK signaling pathways were not different between the necrosis ≥ 10 % and necrosis < 10 % groups for both SCLC and LCNEC.

Conclusion: High proportion of tumor necrosis (≥ 10 %) had a negative prognostic value in surgically resected HGNEC.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.018DOI Listing
July 2021

Tepotinib in patients with NSCLC harbouring MET exon 14 skipping: Japanese subset analysis from the Phase II VISION study.

Jpn J Clin Oncol 2021 May 25. Epub 2021 May 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: MET exon 14 skipping is an oncogenic driver occurring in 3-4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib.

Methods: In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned.

Results: As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months' follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients' quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively).

Conclusions: Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable.
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http://dx.doi.org/10.1093/jjco/hyab072DOI Listing
May 2021

Examination of gender differences in patients with takotsubo syndrome according to left ventricular biopsy: two case reports.

J Med Case Rep 2021 May 21;15(1):281. Epub 2021 May 21.

Department of Cardiology, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan.

Background: Takotsubo syndrome is a stress-induced disease that makes up 2-3% of acute coronary syndrome cases. However, its onset mechanism remains unclear. Although females are overwhelmingly affected, males end up having more cardiac complications.

Case Presentation: We examined the differences in stress responses in the myocardium between sexes in patients with takotsubo syndrome. We biopsied samples from an over 70-year-old Japanese male and an over 80-year-old Japanese female. Tissues from the left ventricle apex in the acute phase and the apical ballooning-type were examined using histopathology and deoxyribonucleic acid (DNA) microarray analysis. Our data showed that left ventricular ejection fractions were 38% and 56%, and peak creatinine kinase concentrations during hospitalization were 629 U/L and 361 U/L, for the male and female patient, respectively. The pulmonary capillary wedge pressure was 26 mmHg and 11 mmHg for the male and female patient, respectively. Negative T did not return to normal in the male subject after 6 months. Histopathology results indicated that contraction band necrosis and lymphocyte infiltration were more common in the male subject.

Conclusions: We noticed that possible differences may exist between male and female patients using pathological examination and some DNA analyses. In particular, it may help treat acute severity in males. We will elucidate the mechanism of takotsubo syndrome development by increasing the number of samples to support the reliability of the data in the future.
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http://dx.doi.org/10.1186/s13256-021-02856-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139097PMC
May 2021

Hyperpolarized C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in vivo Study.

Chemphyschem 2021 05;22(10):905

Division of Bioengineering & Bioinformatics, Graduate School of Information Science & Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, Hokkaido, 060-0814, Japan.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized C fumarate metabolism to hyperpolarized C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.
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http://dx.doi.org/10.1002/cphc.202100338DOI Listing
May 2021

Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study.

Thorac Cancer 2021 May 14. Epub 2021 May 14.

Department of Pharmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, Tokyo, Japan.

Background: It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune-related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs.

Methods: We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non-small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication-related factors associated with time-to-treatment failure or overall survival (OS).

Results: A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time-to-treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007).

Conclusions: The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.
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http://dx.doi.org/10.1111/1759-7714.14001DOI Listing
May 2021

[Comprehensive Genomic Analysis for Small Cell Lung Cancer].

Gan To Kagaku Ryoho 2021 Apr;48(4):476-485

Dept. of Thoracic Oncology, National Cancer Center Hospital East.

Small cell lung cancer(SCLC)is one of the histological types of lung cancer showing the worst prognosis, and is often diagnosed as an inoperable advanced stage disease. Recently, several comprehensive genomic analyses for SCLC have shown that inactivating mutations of tumor suppressor genes such as TP53 and RB1 and MYC family gene amplifications are involved in the development and progression of SCLC. However, actionable gene alterations for targeted therapies have not yet been identified, and there has been no significant advance in the development of targeted therapies for SCLC. In a nationwide lung cancer genome screening project in Japan, LC‒SCRUM‒Japan, a large‒scale genomic analysis was prospectively performed for Japanese SCLC patients, and based on this genomic analysis, a clinical study to evaluate the efficacy of a targeted therapy for PI3K/AKT/mTOR pathway gene‒altered SCLC(EAGLE‒PAT trial)was conducted. In this article, we describe the results of the genomic analysis in LC‒SCRUM‒Japan and the EAGLE‒PAT trial, and also provide the overview of genetic alterations reported in SCLC and the current and future development of targeted therapies for SCLC.
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April 2021

Clinical and Biomarker Profiles and Prognosis of Elderly Patients With Coronavirus Disease 2019 (COVID-19) With Cardiovascular Diseases and/or Risk Factors.

Circ J 2021 05 29;85(6):921-928. Epub 2021 Apr 29.

Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine.

Background: This study investigated the effects of age on the outcomes of coronavirus disease 2019 (COVID-19) and on cardiac biomarker profiles, especially in patients with cardiovascular diseases and/or risk factors (CVDRF).Methods and Results:A nationwide multicenter retrospective study included 1,518 patients with COVID-19. Of these patients, 693 with underlying CVDRF were analyzed; patients were divided into age groups (<55, 55-64, 65-79, and ≥80 years) and in-hospital mortality and age-specific clinical and cardiac biomarker profiles on admission evaluated. Overall, the mean age of patients was 68 years, 449 (64.8%) were male, and 693 (45.7%) had underlying CVDRF. Elderly (≥80 years) patients had a significantly higher risk of in-hospital mortality regardless of concomitant CVDRF than younger patients (P<0.001). Typical characteristics related to COVID-19, including symptoms and abnormal findings on baseline chest X-ray and computed tomography scans, were significantly less prevalent in the elderly group than in the younger groups. However, a significantly (P<0.001) higher proportion of elderly patients were positive for cardiac troponin (cTn), and B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) levels on admission were significantly higher among elderly than younger patients (P<0.001 and P=0.001, respectively).

Conclusions: Elderly patients with COVID-19 had a higher risk of mortality during the hospital course, regardless of their history of CVDRF, were more likely to be cTn positive, and had significantly higher BNP/NT-proBNP levels than younger patients.
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http://dx.doi.org/10.1253/circj.CJ-21-0160DOI Listing
May 2021

Association Between Statin Use Prior to Admission and Lower Coronavirus Disease 2019 (COVID-19) Severity in Patients With Cardiovascular Disease or Risk Factors.

Circ J 2021 05 29;85(6):939-943. Epub 2021 Apr 29.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine.

Background: Cardiovascular diseases and/or risk factors (CVDRF) have been reported as risk factors for severe coronavirus disease 2019 (COVID-19).Methods and Results:In total, we selected 693 patients with CVDRF from the CLAVIS-COVID database of 1,518 cases in Japan. The mean age was 68 years (35% females). Statin use was reported by 31% patients at admission. Statin users exhibited lower incidence of extracorporeal membrane oxygenation (ECMO) insertion (1.4% vs. 4.6%, odds ratio [OR]: 0.295, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, P=0.004) despite having more comorbidities such as diabetes mellitus.

Conclusions: This study suggests the potential benefits of statins use against COVID-19.
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http://dx.doi.org/10.1253/circj.CJ-21-0087DOI Listing
May 2021

Late recurrence of lung adenocarcinoma harboring EGFR exon 20 insertion (A763_Y764insFQEA) mutation successfully treated with osimertinib.

Cancer Genet 2021 Apr 10;256-257:57-61. Epub 2021 Apr 10.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae Chuoku, Osaka 541-8567, Osaka, Japan.

The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.001DOI Listing
April 2021

Redox-Sensitive Mapping of a Mouse Tumor Model Using Sparse Projection Sampling of Electron Paramagnetic Resonance.

Antioxid Redox Signal 2021 May 19. Epub 2021 May 19.

Division of Bioengineering and Bioinformatics, Faculty of Information Science and Technology, Hokkaido University, Sapporo, Japan.

This work aimed to establish an accelerated imaging system for redox-sensitive mapping in a mouse tumor model using electron paramagnetic resonance (EPR) and nitroxyl radicals. Sparse sampling of EPR spectral projections was demonstrated for a solution phantom. The reconstructed three-dimensional (3D) images with filtered back-projection (FBP) and compressed sensing image reconstruction were quantitatively assessed for the solution phantom. Mouse xenograft models of a human-derived pancreatic ductal adenocarcinoma cell line, MIA PaCa-2, were also measured for redox-sensitive mapping with the sparse sampling technique. A short-lifetime redox-sensitive nitroxyl radical (N-labeled perdeuterated Tempone) could be measured to map the decay rates of the EPR signals for the mouse xenograft models. Acceleration of 3D EPR image acquisition broadened the choices of nitroxyl radical probes with various redox sensitivities to biological environments. Sparse sampling of EPR spectral projections accelerated image acquisition in the 3D redox-sensitive mapping of mouse tumor-bearing legs fourfold compared with conventional image acquisition with FBP.
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http://dx.doi.org/10.1089/ars.2021.0003DOI Listing
May 2021

A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1 lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations.

Lung Cancer 2021 Jun 7;156:1-4. Epub 2021 Apr 7.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, 700-8558, Japan.

Objectives: Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations.

Results: We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6-RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure.

Conclusions: Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.022DOI Listing
June 2021

Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer.

Lung Cancer 2021 05 10;155:40-45. Epub 2021 Mar 10.

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

Objectives: The LURET phase II study evaluated the efficacy and safety of the multikinase inhibitor vandetanib in patients with previously treatedRET-rearranged advanced non-small cell lung cancer (NSCLC). Among the eligible patients included in the primary analysis, the objective response rate met the primary endpoint (53 %, 90 % confidence interval [CI]: 31-74). Here, we report final survival outcomes of the LURET study.

Materials And Methods: Nineteen patients with previously treated RET-rearranged advanced NSCLC continuously received 300 mg of oral vandetanib daily. This final analysis provides updated data on progression-free survival (PFS), overall survival (OS) and safety. This study was registered with UMIN-CTR (number UMIN 000010095).

Results: Among the 19 patients in the intention-to-treat population, 42 % had been heavily treated with 3 or more prior chemotherapy regimens. The median PFS was 6.5 months (95 % CI, 3.9-9.3) as determined by an independent radiology review committee. The median OS was 13.5 months (95 % CI, 9.8-28.1) and the overall survival rate at 12 months was 52.6 % (95 % CI 28.7-71.9). The most common adverse events were hypertension (84.2 %), diarrhea (78.9 %), and rash acneiform (63.2 %). Overall, 11 patients (57.9 %) had adverse events leading to a dose reduction, although the safety profile was consistent with that reported in previous studies.

Conclusion: Our results indicated that vandetanib enabled a prolonged and clinically meaningful PFS and OS in patients with previously treatedRET-rearranged advanced NSCLC at the updated final analysis. The safety profile was consistent with that reported in previous studies, although most of the patients experienced off-target adverse events besides RET.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.002DOI Listing
May 2021

Hyperpolarized C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in vivo Study.

Chemphyschem 2021 05 18;22(10):915-923. Epub 2021 Mar 18.

Division of Bioengineering & Bioinformatics, Graduate School of Information Science & Technology, Hokkaido University, North 14, West 9, Kita-ku, Sapporo, Hokkaido, 060-0814, Japan.

Hyperpolarized [1- C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1- C]fumarate metabolism using parahydrogen-induced polarization (PHIP), a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective and high-yield synthetic pathway of hydrogenation precursor [1- C]acetylenedicarboxylate (ADC) was developed. The trans-selectivity of the hydrogenation reaction of ADC using a ruthenium-based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set-up was used to generate hyperpolarized [1- C]fumarate at sufficient C polarization for ex vivo detection of hyperpolarized C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo C MR spectroscopy and imaging in a murine model of acetaminophen-induced hepatitis.
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http://dx.doi.org/10.1002/cphc.202001038DOI Listing
May 2021

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).

Transl Lung Cancer Res 2021 Jan;10(1):314-325

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: Rearranged during transfection () rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for.

Alk: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with.

Ret: rearranged NSCLC.

Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with -rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib.

Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2.

Conclusions: Alectinib exerts limited activity against -rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.
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http://dx.doi.org/10.21037/tlcr-20-549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867784PMC
January 2021

Evaluation of variant frequency in SARS-CoV-2 infection-related genes utilizing lung cancer genomic database.

Lung Cancer 2021 02 24;152:199-201. Epub 2020 Dec 24.

Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

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http://dx.doi.org/10.1016/j.lungcan.2020.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759345PMC
February 2021

Proteasome Inhibition Overcomes ALK-TKI Resistance in -Rearranged/-Mutant NSCLC via Noxa Expression.

Clin Cancer Res 2021 Mar 11;27(5):1410-1420. Epub 2020 Dec 11.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Purpose: In -rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms.

Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). -rearranged NSCLC cell lines expressing wild-type or mutant were used to evaluate cellular apoptosis induced by ALK-TKIs.

Results: In 90 patients with -rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, comutated patients showed significantly worse progression-free survival (PFS) than wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. -rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from -rearranged NSCLC cells with nonfunctional p53.

Conclusions: These clinical and preclinical results indicate concomitant mutations reduce the efficacy of alectinib for -rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for -rearranged/-mutated NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2853DOI Listing
March 2021

Suitability of transbronchial brushing cytology specimens for next-generation sequencing in peripheral lung cancer.

Cancer Sci 2021 Jan 17;112(1):380-387. Epub 2020 Nov 17.

Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Next-generation sequencing (NGS) enables the diagnosis of large numbers of gene aberrations during one examination, and precision medicine has been developed for patients with advanced non-small cell lung cancer (NSCLC). However, peripheral lung lesions account for the majority of advanced lung cancers, especially lung adenocarcinoma. In these cases, it is difficult to obtain tissue samples which contain sufficient tumor cells by transbronchial biopsy (TBB) with forceps. Even when the target lesions are quite small, bronchial brushing can obtain enough tumor cells by endobronchial ultrasonography using guide sheath (EBUS-GS). In this study, we investigate the suitability of bronchial brushing cytology specimens obtained by EBUS-GS-TBB to evaluate the correlation between the success rate of NGS and extracted DNA/RNA yields according to biopsy method. We prospectively collected 222 tumor samples obtained from patients with advanced lung cancer. All patients were enrolled in a prospective nationwide genomic screening project for lung cancer (LC-SCRUM-Japan/Asia). Genomic data were obtained from the clinico-genomic database of LC-SCRUM-Japan/Asia. The extraction yields of DNA/RNA from samples obtained by EBUS-GS-TBB were relatively low compared with tissue samples. The success rate of DNA sequencing for EBUS-GS-TBB was 97.9%, with no significant differences between biopsy methods. The success rate of RNA sequencing for EBUS-GS-TBB was 80.4%, which was relatively low compared with surgical biopsy samples (P = 0.069). However, some rare oncogenic driver aberrations were detected from these specimens. This study demonstrated that cytology samples obtained by transbronchial brushing with EBUS-GS-TBB were suitable for NGS analysis.
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http://dx.doi.org/10.1111/cas.14714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780058PMC
January 2021

Efficacy of exogenous atrial natriuretic peptide in patients with heart failure with preserved ejection fraction: deficiency of atrial natriuretic peptide and replacement therapy.

ESC Heart Fail 2020 Oct 10. Epub 2020 Oct 10.

Department of Cardiology, Tokai University Hospital, Kanagawa, Japan.

Aims: Exogenous atrial natriuretic peptide (ANP) may be a logical treatment for heart failure (HF) patients with ANP deficiency. Lower ANP concentrations may result from HF with preserved ejection fraction (HFpEF), which also results in lower brain natriuretic peptide levels in HFpEF relative to HF with reduced ejection fraction (HFrEF), although clinical features regarding circulating ANP in HFpEF and HFrEF have not been fully investigated during acute HF. Here, we characterized the differential regulation of circulating ANP and the efficacy of exogenous ANP (carperitide) in patients with acute HF, especially HFpEF.

Methods And Results: Serum ANP levels before treatment and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 113 patients with acute HF who were divided into two groups: HFpEF vs. HFrEF. We mainly analysed the impact of baseline ANP levels and the presence of HFpEF on the diuretic effect of exogenous ANP. There was an inverse relationship between ANP levels and the diuretic effect of exogenous ANP (r  = 0.19, P < 0.001). Patients with HFpEF had lower ANP levels (P < 0.001) and a greater diuretic effect of exogenous ANP than patients HFrEF (P < 0.001). HFpEF was an independent predictor of greater diuretic effect of exogenous ANP (P = 0.003), as with a lower baseline ANP level (P = 0.004).

Conclusions: Patients with HFpEF might have an aspect of ANP deficiency and represent a promising therapeutic target for modulating circulating ANP.
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http://dx.doi.org/10.1002/ehf2.13042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754892PMC
October 2020

Morphological, immune and genetic features in biopsy sample associated with the efficacy of pembrolizumab in patients with non-squamous non-small cell lung cancer.

J Cancer Res Clin Oncol 2021 Apr 30;147(4):1227-1237. Epub 2020 Sep 30.

Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Introduction: The usefulness of the histopathology of biopsy samples for predicting the efficacy of immunotherapy in non-squamous, non-small cell lung cancer (NSq NSCLC) patients remains unclear.

Methods: We retrospectively investigated the associations between the histopathological features in biopsy samples and survival outcomes in advanced NSq NSCLC patients receiving pembrolizumab. NSq NSCLC was classified histopathologically as morphological adenocarcinoma or non-small cell carcinoma (NSCC: absence of definitive features of either adenocarcinoma or a squamous morphology). We investigated the association between the tumor morphological features and immune/genetic features by examining the tumor PD-L1 expression and tumor mutation burden (TMB).

Results: Among 33 advanced NSq NSCLC patients with tumor PD-L1 scores ≥ 50% receiving pembrolizumab as first-line therapy, a biopsy diagnosis of NSCC was associated with a significantly longer progression-free survival [median 16.8 vs. 2.3 months; hazard ratio (HR) 0.26; 95% CI 0.10-0.62, P = 0.01] and overall survival (median NR vs. 10.1 months; HR 0.35; 0.12-0.97, P = 0.04) as compared to that of morphological adenocarcinoma. In an analysis of 367 biopsy samples, the NSCC group showed a higher percentage of samples with PD-L1 scores ≥ 50% than the morphological adenocarcinoma group (35% vs. 10%). The NSCC group (n = 8) also showed a significantly higher TMB than the morphological adenocarcinoma group (n = 7) (median 236 vs. 25 mutations/whole exome, P = 0.01).

Conclusion: Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.
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http://dx.doi.org/10.1007/s00432-020-03413-5DOI Listing
April 2021

Multiplex gene-panel testing for lung cancer patients.

Pathol Int 2020 Dec 21;70(12):921-931. Epub 2020 Sep 21.

Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.
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http://dx.doi.org/10.1111/pin.13023DOI Listing
December 2020

The relationship between coronary artery calcium density and optical coherence tomography-derived plaque characteristics.

Atherosclerosis 2020 10 29;311:30-36. Epub 2020 Aug 29.

Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.

Background And Aims: Although coronary artery calcium (CAC) density has been associated with plaque stability, pathological evidence is lacking. We investigated the relationship between coronary computed tomography (CCT)-derived CAC density and multiple calcified and high-risk plaque (HRP) characteristics using optical coherence tomography (OCT).

Methods: We analyzed 83 plaques from 33 stable angina patients who underwent both CCT and OCT. CAC density was measured at calcium plaques with ≥90 Hounsfield units (HU) and ≥130 HU using custom CT software. The correlation between median CAC density and OCT-derived calcium size (thickness and area) was assessed. To investigate whether median CAC densities measured at the 90 HU threshold were associated with plaque vulnerability, OCT-derived plaque characteristics and HRP characteristics were compared between the low (90-129 HU), intermediate (130-199 HU) and high (≥200 HU) CAC HU groups.

Results: Median CAC densities at 130 HU were moderately associated with calcium thickness (R = 0.573, p < 0.001) and area (R = 0.560, p < 0.001). Similar results were observed at 90 HU (thickness, R = 0.615, p < 0.001; area, R = 0.612, p < 0.001). Among groups with low, intermediate and high HU levels, calcium thickness (0.42 ± 0.14 mm, 0.60 ± 0.17 mm and 0.77 ± 0.19 mm, respectively; p < 0.001) and area (0.55 ± 0.29 mm, 1.20 ± 0.58 mm and 1.78 ± 0.87 mm, respectively; p < 0.001) were significantly greater in the high HU group. HRP characteristics, however, did not differ among the three groups.

Conclusions: OCT-derived calcium size, but not HRP characteristics, were associated with CAC density, suggesting that CAC density is driven mainly by calcified plaque size but not local plaque vulnerability.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.08.010DOI Listing
October 2020

Coronary spastic angina after the administration of intravenous immunoglobulin in myasthenia gravis: a case report.

BMC Neurol 2020 Aug 28;20(1):319. Epub 2020 Aug 28.

Division of Neurology, Toho University Omori Faculty of Medicine, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.

Background: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies that block or destroy nicotinic acetylcholine receptors at the neuromuscular junction. Most of MG patients need immunosuppression agents in addition to treatments that alleviate the symptoms. Intravenous immunoglobulin (IVIg) and plasma exchange are specific treatments given to patients with severe MG and myasthenia gravis crisis. IVIg therapy can cause an increase in serum viscosity; therefore, the risk for thromboembolic events, such as stroke, myocardial infarction, and pulmonary embolism, are reported after IVIg therapy.

Case Presentation: An MG patient was treated with pyridostigmine bromide and prednisolone. The patient's symptoms worsened 26 days after the commencement of treatment and was presented with head drop and dyspnea. The patient was diagnosed with MG crisis and IVIg was initiated. However, the patient reported chest pain and dyspnea 3 days after IVIg had started. An electrocardiogram (ECG) revealed ST elevations in leads II, III, and aVF. A cardiac catheterization was performed and stenosis, obstruction, and sclerosis were ruled out. Glyceryl trinitrate relieved the patient's symptoms, suggesting coronary spastic angina (CSA).

Conclusions: We report the first case of CSA after IVIg. Practitioners should be aware of the potential risks of CSA when administering IVIg for MG patients, in particular in old patients with vascular risk factors.
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http://dx.doi.org/10.1186/s12883-020-01901-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453555PMC
August 2020

MET amplification results in heterogeneous responses to osimertinib in EGFR-mutant lung cancer treated with erlotinib.

Cancer Sci 2020 Oct 1;111(10):3813-3823. Epub 2020 Sep 1.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is approved for untreated, or previously EGFR-TKI-treated T790M-positive EGFR-mutated non-small cell lung carcinoma (NSCLC). We investigated the heterogeneity of responses to osimertinib and its underlying mechanisms. A patient with EGFR-L858R-mutated NSCLC was treated with erlotinib. Following treatment, he developed brain and multiple bone metastases and was eventually diagnosed with NSCLC with EGFR-T790M mutation. The responses of various tumor specimens to osimertinib were heterogeneous. We investigated EGFR-T790M and MET amplification using PCR and FISH in autopsy specimens of the cervical spine, lumbar spine, and brain. We established the KNZ osimertinib-resistant (KNZ_OR) tumor cell line with MET amplification using a cervical spine lesion that was intrinsically resistant to osimertinib. We evaluated the effects of MET knockdown and MET inhibitor on KNZ_OR cell sensitivity to osimertinib in vitro and in vivo. Osimertinib-resistant lesions (cervical spine and brain) showed EGFR-L858R and MET amplification, but not EGFR-T790M, whereas osimertinib-sensitive lesions (lumbar spine) showed EGFR-L858R and -T790, but not MET amplification. Osimertinib decreased the association of amplified MET with L858R-mutated EGFR but increased that with human epidermal growth factor receptor 3 in KNZ_OR cells. MET knockdown or MET inhibitor sensitized KNZ_OR cells to osimertinib in vitro, indicating that MET amplification induced osimertinib resistance. Combination with osimertinib plus crizotinib induced tumor shrinkage in the KNZ_OR xenograft model. Hence, MET amplification might induce heterogeneous responses to osimertinib in EGFR-mutated NSCLC. Further investigations on mutated EGFR and amplified MET might lead to the development of effective therapies.
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http://dx.doi.org/10.1111/cas.14593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540985PMC
October 2020

Successful treatment of an osimertinib-resistant lung adenocarcinoma with an exon 18 EGFR mutation (G719S) with afatinib plus bevacizumab.

Invest New Drugs 2021 Feb 18;39(1):232-236. Epub 2020 Jun 18.

Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Otemae 3-1-69, Chuo-ku, Osaka City, Osaka, 541-8567, Japan.

Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.
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http://dx.doi.org/10.1007/s10637-020-00966-7DOI Listing
February 2021

Improvement strategies for successful next-generation sequencing analysis of lung cancer.

Future Oncol 2020 Aug 3;16(22):1597-1606. Epub 2020 Jun 3.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, 541-8567, Japan.

We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.
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http://dx.doi.org/10.2217/fon-2020-0332DOI Listing
August 2020

Feasibility and utility of transbronchial cryobiopsy in precision medicine for lung cancer: Prospective single-arm study.

Cancer Sci 2020 Jul 7;111(7):2488-2498. Epub 2020 Jul 7.

Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed death-ligand 1 (PD-L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single-center, prospective single-arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% [90% confidence interval: 2%-9%]) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm vs forceps 2 mm ) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD-L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer.
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http://dx.doi.org/10.1111/cas.14489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385344PMC
July 2020

Circumventing huge volume strain in alloy anodes of lithium batteries.

Nat Commun 2020 Apr 13;11(1):1584. Epub 2020 Apr 13.

Institute for Materials Research, Tohoku University, Sendai, 980-8577, Japan.

Since the launch of lithium-ion batteries, elements (such as silicon, tin, or aluminum) that can be alloyed with lithium have been expected as anode materials, owing to larger capacity. However, their successful application has not been accomplished because of drastic structural degradation caused by cyclic large volume change during battery reactions. To prolong lifetime of alloy anodes, we must circumvent the huge volume strain accompanied by insertion/extraction of lithium. Here we report that by using aluminum-foil anodes, the volume expansion during lithiation can be confined to the normal direction to the foil and, consequently, the electrode cyclability can be markedly enhanced. Such a unidirectional volume-strain circumvention requires an appropriate hardness of the matrix and a certain tolerance to off-stoichiometry of the resulting intermetallic compound, which drive interdiffusion of matrix component and lithium along the normal-plane direction. This metallurgical concept would invoke a paradigm shift to future alloy-anode battery technologies.
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http://dx.doi.org/10.1038/s41467-020-15452-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154030PMC
April 2020

[Imaging of Tumor-Specific Hypoxia Dynamics and Its Significance in Radiation Biology].

Igaku Butsuri 2020 ;40(1):13-18

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute.

Hypoxia has been known to be a feature associated with tumor radioresistance. So far, clinical strategies to overcome chronic hypoxia due to the limitation of the oxygen diffusion have been designed. However, intermittent or acute/cycling hypoxia, whose frequency can range between a few cycles per minutes to hours, is receiving increased attention, because this type of hypoxia has been reported to have an influence on tumor malignancy as well as treatment resistance via increased expression of pro-survival pathways. Therefore, a priori information on fluctuating hypoxia can be important in clinical treatment planning, but complicated dynamics makes it difficult to elucidate biological significance of intermittent hypoxia.Here, we illustrate the use of pulsed electron spin resonance imaging (ESRI) as a novel imaging method to directly monitor fluctuating oxygenation i.e. cycling hypoxia in transplanted tumors. A common resonator platform for both ESRI and magnetic resonance imaging (MRI) provided pO maps with anatomical guidance without positional movement. Oxygen images every 3 min in pO could visualize the rapid oxygen fluctuation and distinguish the cycling hypoxia and chronic hypoxia. Furthermore, we have examined the vascular renormalization process by longitudinally pO mapping during treatments with a multi-tyrosine kinase inhibitor sunitinib. Transient improvement in tumor oxygenation and the decrease of cycling tumor hypoxia were visualized by ESRI 2 to 4 days following antiangiogenic treatments. Radiation treatment during this time period of improved oxygenation by antiangiogenic therapy resulted in a synergistic delay in tumor growth.In conclusion, this ESRI technique combined with MRI, may offer a powerful clinical tool to noninvasively detect variable hypoxic status in tumors and to identify a window of vascular renormalization to maximize the effects of combination therapy with antiangiogenic drugs.
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http://dx.doi.org/10.11323/jjmp.40.1_13DOI Listing
September 2020

Phase II, open-label, multicenter trial of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study.

Trials 2020 Mar 30;21(1):298. Epub 2020 Mar 30.

Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.

Background: MET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations.

Methods: Co-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients.

Discussion: The results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer.

Trial Registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.
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http://dx.doi.org/10.1186/s13063-020-4221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104510PMC
March 2020