Publications by authors named "Kei Kunimasa"

68 Publications

α-Methylacyl-CoA racemase: a useful immunohistochemical marker of breast carcinoma with apocrine differentiation.

Hum Pathol 2021 Jul 24. Epub 2021 Jul 24.

Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka 5418567, Japan. Electronic address:

Carcinoma with apocrine differentiation is an androgen receptor (AR)-positive subset of triple-negative breast carcinomas. In addition to carcinoma with apocrine differentiation, other AR-positive triple-negative breast carcinomas occur, albeit less frequently. We found that α-methylacyl-CoA racemase (AMACR), also known as P504S, is overexpressed in carcinoma with apocrine differentiation and non-neoplastic apocrine metaplasia. We aimed to evaluate AMACR as a possible marker of carcinoma with apocrine differentiation. We immunohistochemically examined the expression of AMACR in carcinoma with apocrine differentiation and non-apocrine carcinomas and compared it with that of gross cystic disease fluid protein-15 (GCDFP-15). In total, 212 breast carcinomas were evaluated: 39 carcinomas with apocrine differentiation, 28 ductal carcinomas in situ with apocrine morphology (ADCIS), and 145 non-apocrine breast carcinomas. AMACR was expressed in 38 out of 39 (97.4%) carcinomas with apocrine differentiation and in 27 out of 28 (96.4%) ADCIS, consistent with the expression of GCDFP-15. However, in non-apocrine carcinomas, AMACR expression was observed in 32 out of 145 (22.0%) lesions, whereas GCDFP-15 expression was observed in 91 out of 145 (62.7%) lesions. For carcinoma with apocrine differentiation, AMACR was as sensitive as GCDFP-15 (both 97.1%) but more specific (77.9% vs. 37.2%). In selected cases, AMACR mRNA levels were quantitatively determined relative to that of TATA-binding protein mRNA, and they comprised 5.23, 1.33, and 0.60 for carcinomas with apocrine differentiation, non-apocrine carcinomas, and normal breast tissue, respectively. CONCLUSION: Our findings demonstrate that AMACR expression may be utilized for differentiating carcinoma with apocrine differentiation from non-apocrine carcinomas and indicate that AMACR is a more sensitive carcinoma with apocrine differentiation marker than GCDFP-15.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2021.07.005DOI Listing
July 2021

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors.

Cancer Genet 2021 Aug 28;256-257:131-135. Epub 2021 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2021.05.010DOI Listing
August 2021

Atezolizumab with bevacizumab, paclitaxel and carboplatin was effective for patients with SMARCA4-deficient thoracic sarcoma.

Immunotherapy 2021 Jul 25;13(10):799-806. Epub 2021 May 25.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

SMARCA4-deficient thoracic sarcoma (DTS) is a recently noted progressive thoracic malignancy. We recently experienced three cases of SMARCA4-DTS who were treated with atezolizumab in combination with bevacizumab, paclitaxel and carboplatin (ABCP) as the first-line therapy. Immunohistopathological analysis revealed absent expression of SMARCA4 in all cases. The tumor mutational burden was over 11/Mb and mutations in and were detected in all three cases. Partial response to ABCP treatment was observed in all three cases, with a progression-free survival of approximately 6 months or longer and a continuous response of 1 year or longer in one case. The first-line ABCP treatment demonstrated durable efficacy in SMARCA4-DTS regardless of the degree of PD-L1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/imt-2020-0311DOI Listing
July 2021

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

Cancer Genet 2021 Aug 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2021.04.001DOI Listing
August 2021

Is Osimertinib-Induced Cardiotoxicity Really Harmless?

Authors:
Kei Kunimasa

J Clin Oncol 2021 Jun 23;39(18):2050-2051. Epub 2021 Apr 23.

Kei Kunimasa, MD, PhD, Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00266DOI Listing
June 2021

A reply to "Cardiac dysfunction due to Osimertinib".

Authors:
Kei Kunimasa

Lung Cancer 2021 03 14;153:195. Epub 2021 Jan 14.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.01.016DOI Listing
March 2021

STK11 loss drives rapid progression in a breast cancer patient resulting in pulmonary tumor thrombotic microangiopathy.

Breast Cancer 2021 May 2;28(3):765-771. Epub 2021 Jan 2.

Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan.

We experienced a case of breast cancer in which liver metastases spread rapidly and the patient died of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is a fatal cancer-associated respiratory complication disease. To reveal genetic alterations of the clinical course, we performed next generation sequencing of the serial specimens using the Ion AmpliSeqTM Comprehensive Cancer Panel and RNA sequencing for transcriptomic data, followed by gene set analysis. The analysis revealed an oncogenic TP53 R213* mutation in all specimens and STK11 loss in tissues sampled after disease progression. Immunohistochemistry with an anti-STK11 antibody confirmed no STK11 expression in the samples after progression. Transcriptome analysis showed a significant downregulation of proteins associated with apoptosis in the specimens with STK11 loss. STK11 loss may have triggered the rapid progression of PTTM from a comprehensive genomic analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12282-020-01200-1DOI Listing
May 2021

Elective Nodal Irradiation for Non-small Cell Lung Cancer Complicated With Chronic Obstructive Pulmonary Disease Affects Immunotherapy Αfter Definitive Chemoradiotherapy.

Anticancer Res 2020 Dec 7;40(12):6957-6970. Epub 2020 Dec 7.

Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients.

Patients And Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC.

Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group.

Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14720DOI Listing
December 2020

Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction.

Lung Cancer 2021 03 16;153:186-192. Epub 2020 Nov 16.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Introduction: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib.

Methods: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration.

Results: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022).

Conclusions: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.10.021DOI Listing
March 2021

Association of Mutation Profiles with Postoperative Survival in Patients with Non-Small Cell Lung Cancer.

Cancers (Basel) 2020 Nov 21;12(11). Epub 2020 Nov 21.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Findings on mutations, associated with lung cancer, have led to advancements in mutation-based precision medicine. This study aimed to comprehensively and synthetically analyze mutations in lung cancer, based on the next generation sequencing data of surgically removed lung tumors, and identify the mutation-related factors that can affect clinical outcomes. Targeted sequencing was performed on formalin-fixed paraffin-embedded surgical specimens obtained from 172 patients with lung cancer who underwent surgery in our hospital. The clinical and genomic databases of the hospital were combined to determine correlations between clinical factors and mutation profiles in lung cancer. Multivariate analyses of mutation-related factors that may affect the prognosis were also performed. Based on histology, was the driver gene in 70.0% of the cases of squamous cell carcinoma. In adenocarcinoma cases, driver mutations were detected in (26.0%), (25.0%), and epidermal growth factor receptor () (23.1%). According to multivariate analysis, the number of pathogenic mutations (≥3), presence of a mutation, and allele fraction >60 were poor prognostic mutational factors. The allele fraction tended to be high in caudally and dorsally located tumors. Moreover, -mutated lung cancers located in segments 9 and 10 were associated with significantly poorer prognosis than those located in segments 1-8. This study has identified mutation-related factors that affect the postoperative prognosis of lung cancer. To our knowledge, this is the first study to demonstrate that the mutation profile varies with the site of lung tumor, and that postoperative prognosis varies accordingly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700403PMC
November 2020

Is the case really a SMARCA4-deficient thoracic sarcoma?

Authors:
Kei Kunimasa

Thorac Cancer 2021 01 19;12(1):140. Epub 2020 Oct 19.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779198PMC
January 2021

Dermatopathic Lymphadenopathy Mimicking Disease Progression During Osimertinib Treatment.

J Thorac Oncol 2020 10;15(10):e178-e180

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.07.015DOI Listing
October 2020

Magnifying endoscopy with crystal violet staining for immune checkpoint inhibitor-associated colitis.

J Gastroenterol Hepatol 2021 May 21;36(5):1180-1186. Epub 2020 Sep 21.

Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background And Aim: There exists no evidence on the relationship between endoscopic and histologic findings. Furthermore, even after multiple biopsy specimens were obtained, histologic examination usually fails to show the characteristic features of immune checkpoint inhibitor-associated colitis. In this study, we explored the endoscopic and histologic findings of immune checkpoint inhibitor-associated colitis.

Methods: Patients diagnosed with immune checkpoint inhibitor-associated colitis at our hospital between March 2018 and December 2018 were retrospectively assessed. The degree of mucosal inflammation was evaluated using endoscopic inflammation grade (inactive, mild, moderate, or severe disease) and further observed using magnifying endoscopy with crystal violet staining. Pit structures were classified into three types: regularly arranged pits with circular or elliptical shape (R type), irregularly arranged pits with inhomogeneous size and morphology (IR type), and pits with reduced density or pits that partially disappeared (AD type).

Results: Eleven patients (median age, 71 years; range, 44-83 years) were diagnosed with immune checkpoint inhibitor-associated colitis. All characteristic histologic findings, including crypt distortion, crypt abscesses, and apoptotic bodies, were observed at sites with moderate-to-severe endoscopic inflammation but not at sites with inactive-to-mild endoscopic inflammation. Characteristic histologic features were observed in 0%, 50%, and 100% of R-type, IR-type, and AD-type mucosa, respectively.

Conclusions: We revealed the possible utility of endoscopic images for selecting suitable target sites for biopsy and showed that endoscopic findings could reduce the time lag associated with tissue diagnosis and sampling errors due to biopsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.15246DOI Listing
May 2021

Multiregional sequence revealed SMARCA4 R1192C mutant clones acquired EGFR C797S mutation in the metastatic site of an EGFR-mutated NSCLC patient.

Lung Cancer 2020 10 3;148:28-32. Epub 2020 Aug 3.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Objectives: Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR-mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment.

Materials And Methods: We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site.

Results: MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation.

Conclusion: MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.07.035DOI Listing
October 2020

A Multivariable Regression Model-based Nomogram for Estimating the Overall Survival of Patients Previously Treated With Nivolumab for Advanced Non-small-cell Lung Cancer.

Anticancer Res 2020 Aug;40(8):4229-4236

Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Aim: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms.

Patients And Methods: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS.

Results: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab.

Conclusion: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14424DOI Listing
August 2020

The impact of EGFR mutation status and single brain metastasis on the survival of non-small-cell lung cancer patients with brain metastases.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa064. Epub 2020 May 28.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC.

Methods: This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured.

Results: Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients.

Conclusions: Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/noajnl/vdaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284117PMC
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0332DOI Listing
August 2020

Genome analysis of peeling archival cytology samples detects driver mutations in lung cancer.

Cancer Med 2020 07 29;9(13):4501-4511. Epub 2020 Apr 29.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

Introductions: When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin-fixed paraffin-embedded (FFPE) tumor samples.

Patients And Methods: Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole-exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR-TKI.

Results: A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy-seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR-TKI-resistant mutation (EGFR p.T790M) during the course of treatment.

Conclusion: Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333826PMC
July 2020

Infectious pericarditis caused by induced by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA): A case report.

Respir Med Case Rep 2020 13;30:101057. Epub 2020 Apr 13.

Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.

A 69-year-old man had experienced right chest pain for several months. Chest computed tomography (CT) showed a right upper lobe lung tumor and swelling of multiple mediastinal and right hilar lymph node. Three punctures to 4R lymph nodes and two punctures to 11i lymph nodes were performed, using endobronchial ultrasonography. Thirty days after punctures, he was admitted with appetite loss and general fatigue. Chest CT supposed the evidence of mediastinitis and pericarditis. Despite the antibiotics, cardiac tamponade developed on the third hospital day. Pericardial fenestration and pericardial drainage were performed. Gram-positive cocci were identified and was eventually identified as the microbial identification system. Like the former reports, the necessity of surgical procedure for late onset of mediastinitis and pericarditis. caused by EBUS-TBNA was suggested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2020.101057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183228PMC
April 2020

Switching from first or second generation EGFR-TKI to osimertinib in mutation-positive NSCLC.

Lung Cancer Manag 2020 Mar 19;9(2):LMT29. Epub 2020 Mar 19.

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

Aim: We evaluated the efficacy of a novel switch protocol for EGFR-TKIs for mutation-positive NSCLC.

Materials & Methods: Clinical records were collected from the patients who had received one of two sequential combination strategies of EGFR-TKIs: Salvage use of osimertinib for -mediated acquired resistance to an prior EGFR-TKI or switch use of osimertinib where an EGFR-TKI was switched to osimertinib before disease progression.

Results: Progression-free survival of osimertinib and time from the start of treatment until progression to osimertinib was comparable between the salvage use and switch use of osimertinib.

Conclusion: Switch use of osimertinib seemed to produce improved efficacy for patients with activating mutations, because of the lack of patient selection via .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/lmt-2020-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186852PMC
March 2020

Favorable response to pembrolizumab after durvalumab failure in a stage III sarcomatoid carcinoma of the lung: a case report.

BMC Pharmacol Toxicol 2020 04 3;21(1):26. Epub 2020 Apr 3.

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

Background: Pulmonary sarcomatoid carcinoma is a rare non-small-cell lung cancer (NSCLC) subtype with a poor prognosis. In the phase III PACIFIC study, durvalumab significantly improved progression-free survival and overall survival versus placebo, in patients with stage III NSCLC who do not have disease progression after concurrent chemoradiotherapy. However, treatments for patients who discontinue durvalumab due to disease progression, are unknown.

Case Presentation: We report a case of favorable response to pembrolizumab in a patient with disease progression during durvalumab consolidation therapy after chemoradiotherapy for stage III pulmonary sarcomatoid carcinoma with high programmed cell death ligand 1 (PD-L1) and PD-L2 expression.

Conclusion: Here, we present what, to the best of our knowledge, is the first reported case in which durvarumab resistance after definitive chemoradiotherapy in a patient with stage III pulmonary sarcomatoid carcinoma was overcome by pembrolizumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40360-020-00404-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118808PMC
April 2020

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges.

Int J Mol Sci 2020 Jan 17;21(2). Epub 2020 Jan 17.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21020597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014343PMC
January 2020

Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.

Cancer Genet 2020 02 25;241:51-56. Epub 2019 Dec 25.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials And Methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2019.12.006DOI Listing
February 2020

Extrinsic Upregulation of PD-L1 Induced by Pembrolizumab Combination Therapy in Patients with NSCLC with Low Tumor PD-L1 Expression.

J Thorac Oncol 2019 10;14(10):e231-e233

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka City, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.05.026DOI Listing
October 2019

Quantitative detection of ALK fusion breakpoints in plasma cell-free DNA from patients with non-small cell lung cancer using PCR-based target sequencing with a tiling primer set and two-step mapping/alignment.

PLoS One 2019 12;14(9):e0222233. Epub 2019 Sep 12.

Laboratory of Medical Genomics, Nara Institute of Science and Technology, Ikoma, Nara, Japan.

Background: Tyrosine kinase inhibitors targeted to anaplastic lymphoma kinase (ALK) have been demonstrated to be effective for lung cancer patients with an ALK fusion gene. Application of liquid biopsy, i.e., detection and quantitation of the fusion product in plasma cell-free DNA (cfDNA), could improve clinical practice. To detect ALK fusions, because fusion breakpoints occur somewhere in intron 19 of the ALK gene, sequencing of the entire intron is required to locate breakpoints.

Results: We constructed a target sequencing system using an adapter and a set of primers that cover the entire ALK intron 19. This system can amplify fragments, including breakpoints, regardless of fusion partners. The data analysis pipeline firstly detected fusions by alignment to selected target sequences, and then quantitated the fusion alleles aligning to the identified breakpoint sequences. Performance was validated using 20 cfDNA samples from ALK-positive non-small cell lung cancer patients and samples from 10 healthy volunteers. Sensitivity and specificity were 50 and 100%, respectively.

Conclusions: We demonstrated that PCR-based target sequencing using a tiling primer set and two-step mapping/alignment quantitatively detected ALK fusions in cfDNA from lung cancer patients. The system offers an alternative to existing approaches based on hybridization capture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222233PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742348PMC
March 2020

Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?

Anticancer Res 2019 Jul;39(7):3923-3929

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background/aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group).

Materials And Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions.

Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195).

Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.13544DOI Listing
July 2019

Patients with SMARCA4-deficient thoracic sarcoma and severe skeletal-related events.

Lung Cancer 2019 06 8;132:59-64. Epub 2019 Apr 8.

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

Objectives: SMARCA4-deficient thoracic sarcoma(DTS) is a recently identified new entity of thoracic malignancies characterized by inactivation of SMARCA4. Patients with SMARCA4-DTS have a particulary aggresive clinical course and no effective treatments. However, the detailed clinical features of SMARCA4-DTS remain unclear. Here, we report the clinical courses and molecular profiles of two cases of SMARCA4-DTS.

Materials And Methods: We experienced strikingly similar two patients of SMARCA4-DTS. The clinicopathologic features were reviewed, and detailed immunohistochemical and comprehensive cancer panel analysis with next generation sequencing confirmed the diagnosis.

Results: Our cases had many clinical and radiological observations characteristic of SMARCA4-DTS in common. Immunohistochemical staing showed complete loss of SMARCA4 in tumor cells. Loss of function mutations were detected in SMARCA4. We found that severe SREs comprise a new significant clinical feature of SMARCA4-DTS.

Conclusion: Integrated clinico-radiologic-pathologic-genetic diagnosis is essential for SMARCA4-DTS and physicians should pay attention to severe SREs during the clinical course of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.03.029DOI Listing
June 2019

Phase II Study of Weekly Amrubicin for Refractory or Relapsed Non-small Cell Lung Cancer.

In Vivo 2019 Jan-Feb;33(1):163-166

Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Background: Amrubicin is usually administered on days 1-3 every 3 weeks by intravenous infusion. However, it causes severe hematological toxicity, especially febrile neutropenia. It was reported that weekly administration confers higher dose intensity, less severe adverse events, and anti-tumor activity that is as effective as that of treatment with a conventional schedule.

Patients And Methods: Weekly amrubicin was administered at a dose of 60 mg/m on days 1 and 8 every 3 weeks. The primary endpoint was overall response rate.

Results: A total of 33 patients were enrolled. The overall response rate was 6.1% (95% confidence interval(CI)=0.7-20.2%) and the disease control rate after 2 months was 51.5%. The median progression-free survival was 2.93 months. Febrile neutropenia was observed in only two patients.

Conclusion: The primary endpoint was not met in this study. However, weekly amrubicin achieved a high disease control rate and good tolerability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.11453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364089PMC
April 2019
-->