Publications by authors named "Shiro Fujita"

146 Publications

Novel NR4A1 Arg293Ser Mutation in Patients With Familial Crohn's Disease.

In Vivo 2021 Jul-Aug;35(4):2135-2140

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Aichi, Japan.

Background/aim: The underlying etiology of Crohn's disease remains unknown. The aim of this study was to identify genomic alterations associated with the development of Crohn's disease in one Japanese family with a family history of Crohn's disease.

Materials And Methods: We performed whole-exome sequence and pedigree analysis of a Japanese family in which both sisters developed Crohn's disease. Whole-exome sequencing was performed using the Ion Torrent Proton™ system. Data from the Proton runs were initially processed using the Ion Torrent platform-specific pipeline software Ion Reporter. An autosomal dominant mode of inheritance was assumed, and stringent selection criteria were applied.

Results: A substitution in the NR4A1 gene at codon 293 resulting in an amino acid change from arginine to serine was identified only in the affected sisters.

Conclusion: The impaired DNA-binding capacity of the NR4A1 protein due to an NR4A1 germline mutation may be a possible cause of Crohn's disease.
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http://dx.doi.org/10.21873/invivo.12483DOI Listing
June 2021

Differential diagnosis among benign endobronchial papillary tumors with a glandular component.

Pathol Res Pract 2021 Jun 28;222:153457. Epub 2021 Apr 28.

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

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http://dx.doi.org/10.1016/j.prp.2021.153457DOI Listing
June 2021

Weak-evidence Fusion Candidates Detected by a FusionPlex Assay Using the Ion Torrent System.

In Vivo 2021 Mar-Apr;35(2):993-998

Department of Thoracic Oncology, Aichi Cancer Center, Nagoya, Japan.

Background/aim: The Archer FusionPlex platform is widely used for comprehensive fusion-gene detection in cancer tissues. This platform separately displays results for strong-evidence and weak-evidence fusion candidates (WEFCs). Distinctive fusion patterns are frequently found in the weak-evidence category and information about the patterns is clinically essential.

Patients And Methods: We describe the type and frequency of WEFCs observed using the FusionPlex Sarcoma Panel (S Panel) and the FusionPlex ALK, RET, and ROS1 ver2 Panel (ARR Panel).

Results: A total of 97 specimens were examined and 620 candidates were detected and categorized as WEFCs. A median of five WEFCs were detected per sample. In the S Panel group, there were 13 WEFCs with a frequency of more than 1%. In the ARR Panel group, a total of 16 WEFCs were detected with a frequency of more than 1%.

Conclusion: Specific WEFCs were detected according to the panel selected.
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http://dx.doi.org/10.21873/invivo.12342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045057PMC
June 2021

Alteration of DNA mismatch repair capacity underlying the co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer.

Sci Rep 2021 Feb 11;11(1):3597. Epub 2021 Feb 11.

Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima Minami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.

Both non-small-cell lung cancer cases in never-smokers and nonmedullary thyroid cancer cases have been increasing in developed countries. Some studies have shown an excess of co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer. We aimed to clarify the underlying genetic factors that contribute to the occurrence of these two malignancies. We performed germline exome sequencing in a cohort of 9 patients with the two malignancies. In terms of candidate genes, we performed target resequencing, immunohistochemistry, and microsatellite instability testing on another cohort. Two rare missense heterozygous variants in MSH6 were identified and verified by Sanger sequencing. One available tumour specimen showed heterogeneous MSH6 status in immunohistochemistry. Further exploration with different cohorts (a total of 8 patients with the two malignancies) demonstrated that 2 out of 8 patients had a germline missense or promotor variant of MLH1 and four out of 10 tumour specimens revealed heterogeneous immunohistochemistry staining in any of the four mismatch repair proteins: MLH1, PMS2, MSH2 and MSH6. Although our cohort showed a different disease profile than Lynch syndrome, this study suggests causal roles of impaired DNA mismatch repair capacity in non-small-cell lung cancer and nonmedullary thyroid cancer.
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http://dx.doi.org/10.1038/s41598-021-83177-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878500PMC
February 2021

Novel Resistance Mechanisms Including L1196Q, P1094H, and R1248_D1249 Insertion in Three Patients With NSCLC After ALK Tyrosine Kinase Inhibitor Treatment.

J Thorac Oncol 2021 03 6;16(3):477-482. Epub 2020 Nov 6.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.

Objectives: The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation.

Methods: A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens.

Results: Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs.

Conclusions: The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.
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http://dx.doi.org/10.1016/j.jtho.2020.09.023DOI Listing
March 2021

AKT1 Mutations in Peripheral Bronchiolar Papilloma: Glandular Papilloma and Mixed Squamous Cell and Glandular Papilloma Is Distinct From Bronchiolar Adenoma.

Am J Surg Pathol 2021 01;45(1):119-126

Departments of Pathology and Molecular Diagnostics.

Glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) are rare benign pulmonary tumors occurring in the bronchi. Bronchiolar adenoma (BA) was recently characterized as a pulmonary tumor exhibiting alveolar spread. Both GP/MP and BA are composed of a mixture of glandular, ciliated, squamous, and basal cells. We aimed to clarify whether GP/MP and BA represent the same tumor. We evaluated the detailed histologic characteristics of 11 cases involving pulmonary peripheral tumors that exhibited histologic features of GP/MP or BA, and performed genetic analyses using targeted panel sequencing, allele-specific polymerase chain reaction, and digital polymerase chain reaction. Histologically, 4 and 7 tumors were classified as GP/MP and BA, respectively. GP/MP showed endobronchiolar papillary growth with a pseudostratified or stratified epithelium. In contrast, 5 BAs showed a predominant flat structure with a bilayered or pseudostratified epithelium, whereas 2 BAs showed a GP/MP-like papillary architecture. The mean epithelial thickness in each tumor was significantly larger in GP/MPs and BAs with a GP/MP-like morphology (103 to 242 μm) than in flat-predominant BA (23 to 47 μm, P=0.0010). AKT1 E17K mutations were detected in all GP/MPs and BAs with GP/MP-like morphology but were absent in the 5 flat-predominant BAs. AKT1 mutations were always concurrent with BRAF or HRAS mutations, and the variant allele frequency or percentage of mutant copies of AKT1 mutations was equal to those of BRAF or HRAS mutations. GP/MPs are characterized by AKT1 mutations concurrent with BRAF or HRAS mutations. Peribronchiolar papillary tumors with AKT1 mutations may also be classified as GP/MP.
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http://dx.doi.org/10.1097/PAS.0000000000001573DOI Listing
January 2021

Efficacy of local therapy for oligoprogressive disease after programmed cell death 1 blockade in advanced non-small cell lung cancer.

Cancer Sci 2020 Dec 31;111(12):4442-4452. Epub 2020 Oct 31.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non-small-cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty-eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option.
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http://dx.doi.org/10.1111/cas.14605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734009PMC
December 2020

Inverted papilloma of the Oropharynx: A case of extrasinonasal inverted papilloma with an EGFR mutation.

Oral Oncol 2020 12 12;111:104892. Epub 2020 Jul 12.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.

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http://dx.doi.org/10.1016/j.oraloncology.2020.104892DOI Listing
December 2020

Targeted RNA sequencing with touch imprint cytology samples for non-small cell lung cancer patients.

Thorac Cancer 2020 07 5;11(7):1827-1834. Epub 2020 May 5.

Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.

Background: RNA-based sequencing is considered ideal for detecting pathogenic fusion-genes compared to DNA-based assays and provides valuable information about the relative expression of driver genes. However, RNA from formalin-fixed paraffin-embedded tissue has issues with both quantity and quality, making RNA-based sequencing difficult in clinical practice. Analyzing stamp-derived RNA with next-generation sequencing (NGS) can address the above-mentioned obstacles. In this study, we validated the analytical specifications and clinical performance of our custom panel for RNA-based assays on the Ion Torrent platform.

Methods: To evaluate our custom RNA lung panel, we first examined the gene sequences of RNA derived from 35 NSCLC tissues with diverse backgrounds by conventional methods and NGS. Next, we moved to the clinical phase, where clinical samples (all stamp-derived RNA) were used to examine variants. In the clinical phase we conducted an NGS analysis while simultaneously applying conventional approaches to assess the feasibility and validity of the panel in clinical practice.

Results: In the prerun phase, all of the variants confirmed with conventional methods were detected by NGS. In the clinical phase, a total of 80 patients were enrolled and 80 tumor specimens were sequenced from February 2018 to December 2018. There were 66 cases in which the RNA concentration was too low to be measured, but sequencing was successful in the vast majority of cases. The concordance between NGS and conventional methods was 95.0%.

Conclusions: RNA extraction using stamp specimens and panel sequencing by NGS were considered applicable in clinical settings.

Key Points: Significant findings of the study Next-generation sequencing using RNA from stamp specimens was able to detect driver gene changes in non-small cell lung cancer including fusion genes with the same accuracy as conventional methods. What this study adds Using RNA from stamp specimens obtained from biopsy increases the number of candidate cases for RNA sequencing in clinical settings.
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http://dx.doi.org/10.1111/1759-7714.13460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327906PMC
July 2020

Salivary Secretory Carcinoma Harboring a Novel ALK Fusion: Expanding the Molecular Characterization of Carcinomas Beyond the ETV6 Gene.

Am J Surg Pathol 2020 07;44(7):962-969

Departments of Pathology and Molecular Diagnostics.

Secretory carcinoma (SC) of the salivary glands is a low-grade carcinoma characterized by a well-defined morphology and immunohistochemical features. ETV6-NTRK3 fusions are detected in the great majority of SCs. Recently, other partners fused to ETV6 have been documented in a small portion of SCs, suggesting the presence of alternative genetic fusion. In this study, we examined the genetic fusion of 9 SCs using fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and next-generation sequencing (ArcherDx). Classic ETV6 exon 5-NTRK3 exon 15 fusion was detected in 8 of 9 SCs. The remaining tumor was negative for the ETV6-NTRK3 fusion but harbored a novel fusion, CTNNA1 exon 11-ALK in exon 20. Immunohistochemically, pan-TRK was positive in 8 tumors with ETV6-NTRK3 fusion but negative in an ALK-rearranged SC, while ALK was positive only in the ALK-rearranged tumor. Histologically, the ALK-rearranged tumor showed dominant macrocystic architecture. In conclusion, we found a case of SC with CTNNA1-ALK fusion. Because ALK fusion after exon 20 on the ALK side (upstream of the tyrosine kinase domain) has been reported to activate a carcinogenic kinase in various ALK-rearranged tumors, ALK inhibitors may be a possible therapeutic option for ALK-rearranged SC. In addition, ALK immunohistochemistry can be a screening tool for ALK-rearranged SC. This study also expands the molecular spectrum of this tumor beyond the ETV6 gene.
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http://dx.doi.org/10.1097/PAS.0000000000001471DOI Listing
July 2020

Minimal residual disease after radical surgery in EGFR-mutant non-small cell lung cancer.

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S391-S394

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Aichi, Japan.

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http://dx.doi.org/10.21037/tlcr.2019.09.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987333PMC
December 2019

Negative reactions of BRAF mutation-specific immunohistochemistry to non-V600E mutations of BRAF.

Pathol Int 2020 May 23;70(5):253-261. Epub 2020 Jan 23.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Aichi, Japan.

BRAF mutations are rare driver mutations in non-small cell lung cancer (NSCLC), accounting for 1%-2% of the driver mutations, and the mutation spectrum has a wide range in contrast to other tumors. While V600E is a dominant mutation in melanoma, more than half of the mutations in NSCLCs are non-V600E. However, treatment with dabrafenib plus trametinib targets the BRAF V600E mutation exclusively. Therefore, distinguishing between V600E and non-V600E mutations is crucial for biomarker testing in NSCLC in order to determine treatment of choice. Immunohistochemistry (IHC) using the BRAF V600E mutation-specific antibody is clinically used in melanoma patients, but little is known about its application in NSCLC, particularly with regard to the assay performance for non-V600E mutations. In the present study, we examined 117 tumors with BRAF mutations, including 30 with non-V600E mutations, using BRAF mutation-specific IHC. None of the tumors with non-V600E mutations, including two compound mutations, showed a positive reaction. Furthermore, all V600E mutations were positive except for one case with combined BRAF V600E and K601_W604 deletion. Our findings confirmed that the BRAF V600E mutation-specific IHC is specific without any cross-reactions to non-V600E mutations, suggesting that this assay can be a useful screening tool in clinical practice.
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http://dx.doi.org/10.1111/pin.12903DOI Listing
May 2020

Frequent KRAS and HRAS mutations in squamous cell papillomas of the head and neck.

J Pathol Clin Res 2020 04 20;6(2):154-159. Epub 2020 Jan 20.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.

Squamous cell papilloma (SCP) is a benign neoplasm of the head and neck. Human papillomavirus (HPV) has been reported to be a tumourigenic factor for SCP. However, not all SCPs are positive for HPV, suggesting that other possible mechanisms are involved in their development. In this study, we examined the mutational status of 51 SCPs using targeted panel sequencing in addition to HPV status using GP5+/GP6+ PCR. HPV DNA was detected in 6 (12%) SCPs, while KRAS and HRAS mutations were detected in 18 (35%) and 17 (33%) SCPs, respectively. Notably, KRAS mutations, HRAS mutations and HPV infection were mutually exclusive. The larynx and trachea (4/7, 57%) were more preferentially infected by HPV than the other sites (2/44, 5%, p = 0.0019) and HPV was associated with multifocal development (4/5, 80%). In contrast, KRAS and HRAS mutations in SCPs were evenly distributed across the anatomical sites and found only in single SCPs. In conclusion, this study demonstrated that HPV was not frequently involved in SCPs and that RAS mutations were more common alterations. In contrast to inverted sinonasal papillomas and oncocytic sinonasal papillomas, SCP may not be a precursor lesion of carcinoma, because these aetiological events in SCP are distinct from squamous cell carcinoma in the same sites.
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http://dx.doi.org/10.1002/cjp2.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164371PMC
April 2020

Calculating the Tumor Nuclei Content for Comprehensive Cancer Panel Testing.

J Thorac Oncol 2020 01 9;15(1):130-137. Epub 2019 Oct 9.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan. Electronic address:

Comprehensive genetic panel testing generally requires that the analyzed tissues have a percent tumor nuclei (%TN) content of 20% or more to achieve assay performance comparable to the validated specifications. Pathologists play a crucial role in ensuring that the optimal results are achieved by accurately assigning %TN content of the available specimens and selecting the best material to submit for sequencing. This study addresses the issues in evaluating %TN, such as intraobserver variability, and examines whether focused training and feedback can improve pathologist performance. Nine referring institution pathologists (all board-certified and working at the core institute and the alignment hospitals under the National Cancer Genome scheme) evaluated 18 tumors that had been subjected to comprehensive genetic panel testing with the FoundationOne CDx assay. The %TN estimates provided by referring institution pathologists were compared with two standards: %TN assigned by the tumor sequencing institution's pathologist (a board-certified pathologist at Foundation Medicine, Inc.) and the computational %TN estimated from the mutant allele frequencies after sequencing was completed. The pathologists generally overestimated %TN in the first pretraining round of the evaluation, and the differences in the averaged %TN from the tumor sequencing institution and computational standards were statistically significant. However, the posttraining second-round results became significantly concordant with the standards. This study suggests that %TN content is empirically overestimated but the evaluation skill can be improved by providing a training and feedback program.
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http://dx.doi.org/10.1016/j.jtho.2019.09.081DOI Listing
January 2020

Epithelioid hemangioendothelioma of the parotid gland: a case report.

Int Cancer Conf J 2019 Jan 29;8(1):39-42. Epub 2018 Nov 29.

1Department of Head and Neck surgery, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681 Japan.

We present the case of a patient with epithelioid hemangioendothelioma of the parotid gland. A 70-year-old female developed swelling and pain in the lower part of the left ear 18 months previously and had visited a local hospital. Fine-needle aspiration cytology revealed no definitive diagnosis, but incisional biopsy under local anesthesia suggested epithelioid hemangioendothelioma. She was then transferred to our hospital, where she underwent total extirpation of the left parotid gland, left cervical lymph node dissection, and postoperative radiation therapy. However, she died from distant metastases 13 months after surgery. No previous study has reported any case of distant metastasis or death due to epithelioid hemangioendothelioma of the parotid gland. To the best of our knowledge, this is the first case report on distant metastasis and death due to the development of parotid gland cancer.
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http://dx.doi.org/10.1007/s13691-018-0351-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498246PMC
January 2019

Biopsy of palliative lesions following radiotherapy.

BJR Open 2019 8;1(1):20180025. Epub 2019 Jan 8.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.

Objective: Definite radiotherapy and/or chemoradiotherapy is often conducted for the treatment of non-small cell lung cancer. However, there is a potential concern regarding the mutagenic effects on tumor cells derived from the therapies, and genomic information regarding cancer cells that survived definitive radiotherapy/chemoradiotherapy is lacking. To evaluate the mutagenic effect of radiotherapy/chemoradiotherapy, we compared genomic signatures of recurrent non-small cell lung cancer tissue with those of pre-treatment.

Methods: We evaluated seven specimens from three patients who developed disease recurrence after definite radiotherapy/chemoradiotherapy, and we ranked the mutations according to the Combined Annotation-Dependent Depletion score.

Results: Some mutations remained in the post-therapy state, and others, including driver mutations, either newly occurred or disappeared during the course of disease. Of the four specimens obtained in the post-radiation period, 21 variants were detected. Compared with single nucleotide substitution (5, 23.8%), substantial number of deletions (16, 76.2%) was observed in specimens obtained after definite radiotherapy/chemoradiotherapy.

Conclusion: Radiotherapy/chemoradiotherapy effects on tumor cells have a wide spectrum, and resequencing of a recurrent lesion is always recommended to discuss the best course of therapy for recurrent non-small cell lung cancer after definitive radiotherapy/chemoradiotherapy.

Advances In Knowledge: With regard to cancer cells that survived definitive radiotherapy/chemoradiotherapy, some mutations remained in the post-therapy state, and others, including driver mutations, either newly occurred or disappeared during the course of disease. Compared with single nucleotide substitution, substantial number of deletions was observed in specimens obtained after definite radiotherapy/chemoradiotherapy.
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http://dx.doi.org/10.1259/bjro.20180025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592476PMC
January 2019

Team Management of Skin Rash Associated with Use of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

Asia Pac J Oncol Nurs 2018 Oct-Dec;5(4):430-434

Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.

Objective: The aim of this study was to evaluate the effectiveness of a rash team management intervention designed by certified nurses, medical physicians, and certified pharmacists. The quality of life (QOL) of patients administered epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) was assessed using the dermatology life quality index (DLQI) and Skindex-29 QOL questionnaires.

Methods: A total of 51 patients with nonsmall cell lung cancer who were treated using EGFR-TKIs were examined between November 1, 2014, and October 31, 2015, at the Institute of Biomedical Research and Innovation in Kobe city, Japan. All the patients were treated daily with erlotinib, gefitinib, or afatinib. The common terminology criteria for adverse events (version 4.0) system were used to grade treatment-induced toxicity events. The multimodality rash management team included nurses, pharmacists, and physicians. The team intervened before the initiation of treatment with EGFR-TKIs and at every visit. Patient QOL characteristics were evaluated using the DLQI and Skindex-29 assessment tools.

Results: The number of patients with high-grade toxicity decreased when the multimodal approach was used. No grade 3 skin toxicities were recorded in the postintervention cohort. QOL scores for symptoms and feelings (emotions) were impaired in patients who were treated with EGFR-TKIs.

Conclusions: The rash team management approach may be useful for patients treated with EGFR-TKIs. Specific QOL evaluation tools for the assessment of the effects of a team approach for rash management should be developed.
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http://dx.doi.org/10.4103/apjon.apjon_33_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103195PMC
October 2018

Targeting minimal residual disease after surgery with molecular targeted therapy: the real path to a cure?

J Thorac Dis 2018 Jun;10(Suppl 17):S1982-S1985

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Aichi, Japan.

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http://dx.doi.org/10.21037/jtd.2018.04.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036056PMC
June 2018

Relationship between Paronychia and Drug Concentrations of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Oncology 2018 14;95(4):251-256. Epub 2018 Jun 14.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Purpose: The purpose of the study was to evaluate the site of paronychia in patients with non-small cell lung cancer harboring an epidermal growth factor receptor (EGFR) gene activating mutation who were treated with EGFR tyrosine kinase inhibitors (EGFR TKIs).

Patients And Methods: The study included 55 patients with non-small-cell lung cancer who were treated with an EGFR TKIs. Resulting all toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0 system. Drug concentrations were determined with use of a quantum triple-quadrupole mass spectrometer and dried blood spots testing.

Results: Paronychia most commonly occurred in the thumb and the big toe. There was no correlation between the severity of paronychia and the drug concentration of each EGFR TKI at the site of paronychia. The mean penetration rates of the drug from plasma to the tip of the finger and toe were 74.1% (erlotinib), 82.2% (gefitinib), and 99.9% (afatinib).

Conclusions: High concentrations of an EGFR TKI at the affected site did not play a role in the onset mechanism of paronychia. Therefore, educating patients about ways to avoid compression may be a better approach to managing this adverse event than reducing the dose of the EGFR-TKI or stopping treatment.
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http://dx.doi.org/10.1159/000490177DOI Listing
October 2018

Development and validation of a method for gefitinib quantification in dried blood spots using liquid chromatography-tandem mass spectrometry: Application to finger-prick clinical blood samples of patients with non-small cell lung cancer.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Jun 13;1087-1088:1-5. Epub 2018 Apr 13.

Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of gefitinib in dried blood spots (DBSs). Gefitinib was extracted with methanol from DBS of 3 mm in diameter and detected using a triple quadrupole mass spectrometer. The method was validated by evaluating its precision, accuracy, selectivity, carryover, matrix effect, recovery, and stability. For clinical validation, paired finger-prick DBS and plasma concentrations were compared for 10 patients with non-small cell lung cancer (NSCLC) taking gefitinib. The calibration linear range was 37.5-2400 ng/mL (coefficient of determination [R] = 0.99), encompassing the therapeutic concentrations of gefitinib. The accuracy and precision were within 15% of the quality control (QC) concentrations of 80, 200, and 2000 ng/mL. The lower limit of quantification was determined to be 40 ng/mL. Gefitinib was stable in DBSs for up to 5 months at room temperature and -20 °C, and at 40 °C for 24 h. A good correlation was observed between the gefitinib levels measured by the DBS method and plasma concentrations (R = 0.99). This method provides a simple, fast, and accurate approach to the quantitative analysis of gefitinib in finger-prick DBSs. The method would be useful for minimally invasive evaluation of the clinical gefitinib blood concentration.
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http://dx.doi.org/10.1016/j.jchromb.2018.04.027DOI Listing
June 2018

Programmed death-ligand 1 expression according to epidermal growth factor receptor mutation status in pretreated non-small cell lung cancer.

Oncotarget 2017 Dec 1;8(69):113807-113816. Epub 2017 Dec 1.

Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan.

Background: Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor () mutations, implying lower PD-L1 expression in -mutant NSCLC than in -wild type.

Methods: We retrospectively analyzed correlation between PD-L1 expression and status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+.

Results: We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in -mutant samples (n=65) was 3 (range, 0-150), whereas -wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in -mutant vs. -wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and mutation status (p=0.0490) as significant factors. Multivariate analysis identified mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients.

Conclusions: PD-L1 expression was significantly lower in -mutant NSCLC samples than in wild-type samples. Its expression could be dynamic and affected by age of sample.
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http://dx.doi.org/10.18632/oncotarget.22837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768364PMC
December 2017

Validation of the digital PCR system in tyrosine kinase inhibitor-resistant EGFR mutant non-small-cell lung cancer.

Pathol Int 2018 Mar 17;68(3):167-173. Epub 2018 Jan 17.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Aichi, Japan.

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.
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http://dx.doi.org/10.1111/pin.12630DOI Listing
March 2018

Not like breast cancer, but like breast cancer: micrometastasis and micropapillary structure in lung cancer.

J Thorac Dis 2017 Nov;9(11):4171-4173

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Aichi, Japan.

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http://dx.doi.org/10.21037/jtd.2017.09.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721054PMC
November 2017

Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer.

ESMO Open 2016 7;1(4):e000108. Epub 2017 Mar 7.

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

Objective: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC.

Methods: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety.

Results: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab.

Conclusions: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression.

Trial Registration Number: JapicCTI-132073.
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http://dx.doi.org/10.1136/esmoopen-2016-000108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566979PMC
March 2017

Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer.

Lung Cancer 2017 09 20;111:182-189. Epub 2017 Jul 20.

Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan.

Background: Differential biology and prognosis between T790M+ and T790M- populations imply immunological differences also.

Methods: We retrospectively analyzed programmed death-ligand 1 (PD-L1) expression and T790M status in rebiopsied samples of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry was performed using the SP142 antibody for tumour cell (TC) and tumour-infiltrating immune cell (IC) and the 28-8 antibody for TC. PD-L1+ was defined as TC or IC ≥1%.

Results: We investigated 67 available rebiopsied histologic samples in 47 patients. Using the SP142, prevalence of PD-L1 any+, moderate+, and strong+ in T790M+ vs. T790M- samples were 31% vs. 61%, 8% vs. 15%, and 0% vs. 2%, respectively, representing PD-L1+ prevalence of T790M+ samples was significantly lower than that of T790M- (p=0.0149). Prevalence of any TC+/IC+ in T790M+ vs. T790M- samples were TC: 31% vs. 51% (p=0.0997) and IC: 8% vs. 27% (p=0.0536), respectively. Using the 28-8, median percentage of PD-L1+ in T790M+ samples was 1.9 (range, 0-27.2), whereas T790M- was 4.1 (range, 0-89.8) (p=0.0801). Prevalence of PD-L1+ ≥1%, ≥5%, and ≥10% in T790M+ vs. T790M- samples were 77% vs. 83% (p=0.5476), 31% vs. 49% (p=0.1419), and 12% vs. 27% (p=0.1213), respectively. In 9 of 11 patients receiving multiple rebiopsies, T790M and/or PD-L1 expression revealed temporal dynamism. Survival curves according to PD-L1 expression/T790M status suggested better prognosis in PD-L1-/T790M+ population.

Conclusions: T790M+ status was correlated to lower PD-L1 expression. PD-L1 expression might have a prognostic value and interaction with T790M mutation in EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2017.07.022DOI Listing
September 2017

Single nucleotide variant sequencing errors in whole exome sequencing using the Ion Proton System.

Biomed Rep 2017 Jul 17;7(1):17-20. Epub 2017 May 17.

Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe 650-0047, Japan.

Errors in sequencing are a major obstacle in the interpretation of next-generation sequencing (NGS) results. In the present study, sequencing errors identified from analysis of single nucleotide variants (SNVs) identified during exome sequencing of human germline DNA were studied using the Thermo Fisher Ion Proton System. Two consanguineous cases were selected for sequencing using the AmpliSeq Exome capture kit, and SNVs found in both cases were validated using Sanger sequencing. A total of 98 SNVs detected by NGS were randomly selected for further analysis. Nine of the analyzed SNVs were shown to be false positives when confirmed by Sanger sequencing. All but one SNV were considered to be homopolymer regions, mainly through the insertion or deletion of nucleotides. The remaining error was considered to be related to the primer. The present results revealed that the majority of the SNV sequencing errors originated from homopolymer insertion/deletion errors, which are commonly observed when using the Ion Torrent system.
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http://dx.doi.org/10.3892/br.2017.911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492560PMC
July 2017

PD-L1 Expression in Patients with Non-small Cell Lung Cancer.

Anticancer Res 2017 05;37(5):2269-2274

Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.

Aim: The aim of this study was to evaluate whether irradiation induces the expression of tumor programed cell death ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC).

Patients And Methods: Seventeen patients with NSCLC who received chemoradiotherapy and underwent tumor resection and six patients whose pre-treatment biopsy specimens were available, were analyzed by immunohistochemistry for PD-L1 expression between September 2011 and June 2016 at the Institute of Biomedical Research and Innovation Hospital.

Results: Among six patients for which pre-irradiation biopsy samples were available, the H-score for PD-L1 was reduced after irradiation following staining with two different antibody clones (SP28-8 and SP142). A PD-L1 H-score >5 with SP28-8 antibody (hazard ratio=6.46; 95% confidence interval=1.209-34.53; p=0.029) was a significant negative factor for duration of progression-free survival after curative operation or chemoradiation.

Conclusion: We showed that tumor PD-L1 expression decreased in patients with NSCLC who received chemoradiotherapy and radiation resistance might be due to pre-treatment PD-L1 expression.
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http://dx.doi.org/10.21873/anticanres.11564DOI Listing
May 2017

Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

Cancer Chemother Pharmacol 2017 04 9;79(4):689-695. Epub 2017 Mar 9.

Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.

Purpose: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC).

Methods: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group).

Results: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients.

Conclusions: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.
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http://dx.doi.org/10.1007/s00280-017-3259-zDOI Listing
April 2017

Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer.

Cancer Sci 2017 May 26;108(5):1000-1006. Epub 2017 Apr 26.

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

Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.

Clinical Trial Registration Number: JapicCTI-132072.
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http://dx.doi.org/10.1111/cas.13225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448646PMC
May 2017

Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer.

Lung Cancer 2017 02 21;104:111-118. Epub 2016 Dec 21.

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

Objectives: Drug-induced interstitial lung disease (ILD) is often associated with high mortality; however it is difficult to predict and manage. we examined the clinical findings and imaging characteristics of nivolumab induced ILD reported in the two phase II studies patients with recurrent or advanced non-small-cell lung cancer.

Materials And Methods: We examined the clinical findings and imaging characteristics of all cases of ILD reported in two phase II trials of nivolumab, an anti-programmed death-1 antibody, in Japanese patients with recurrent or advanced non-small-cell lung cancer. These studies are registered with the Japan Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073.

Results: Eight (7.2%; two with squamous cell carcinoma, six with non-squamous cell carcinoma) of the 111 patients included in these two studies experienced ILD, and a causal relationship with nivolumab could not be ruled out in any of them. ILD of ≥grade 3 severity was found in four patients (3.6%), and ILD was considered a serious treatment-related adverse event in seven patients (6.3%). All of the patients who experienced ILD were male and had a history of smoking, with a median age of 65 years (range 52-78 years). In seven of the eight patients who experienced ILD, their events were rapidly resolving or resolved spontaneously or with steroid therapy; one patient died of respiratory failure without resolution of ILD, after docetaxel treatment was initiated following nivolumab discontinuation. Chest computed tomography images for the seven patients with resolving or resolution of ILD showed a pattern of organizing pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis, while the patient who died had traction bronchiectasis.

Conclusion: Although the risk factors for nivolumab-induced ILD were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab.
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http://dx.doi.org/10.1016/j.lungcan.2016.12.016DOI Listing
February 2017
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