Publications by authors named "Tomoyuki Yokose"

161 Publications

A case of lung adenocarcinoma with a novel CD74-ROS1 fusion variant identified by comprehensive genomic profiling that responded to crizotinib and entrectinib.

Thorac Cancer 2021 Jul 28. Epub 2021 Jul 28.

Division of Pulmonary Medicine, Department of Medicine, Keiyu Hospital, Yokohama, Japan.

ROS1 rearrangements are found in 1-2% of patients with non-small-cell lung cancer. The detection of the rearrangements is crucial since clinically effective molecular targeted drugs are available for them. We present a case of lung adenocarcinoma with a previously unknown ROS1-CD74 fusion variant, CD74 exon 3 fused to ROS1 exon 34, which was not detected by a conventional RT-PCR-based test for ROS1 fusion gene detection but identified by hybrid capture-based next-generation sequencing. This tumor responded to crizotinib initially and to entrectinib after relapse with brain metastasis, indicating the oncogenic activity of this novel fusion variant.
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http://dx.doi.org/10.1111/1759-7714.14093DOI Listing
July 2021

Clinicopathological and molecular characteristics of endometrial neuroendocrine carcinomas reveal preexisting endometrial carcinoma origin.

Pathol Int 2021 May 20. Epub 2021 May 20.

Department of Pathology, Kanagawa Cancer Center, Kanagawa, Japan.

Endometrial neuroendocrine carcinoma is a rare disease with unknown clinicopathological and molecular characteristics. Therefore, we conducted the present study to elucidate the clinicopathological and molecular characteristics of endometrial neuroendocrine carcinoma, as compared to conventional endometrial carcinoma, and to determine the origin of the former. We analyzed 22 endometrial neuroendocrine carcinomas and 22 conventional endometrial neoplasia cases with respect to clinical, histological and genetic features. Of these, 21/22 neuroendocrine carcinoma cases were admixed carcinomas, with 15 admixed with endometrioid adenocarcinoma. Genetic analysis of hotspot mutations in 50 cancer-related genes revealed that the neuroendocrine carcinoma group carried mutations in PIK3CA (12/22 cases; 54%) and PTEN (8/22 cases; 36%), commonly encountered in endometrioid adenocarcinoma. Comparative statistical analysis of neuroendocrine carcinoma and conventional endometrial neoplasia cases showed a significant trend only in PIK3CA mutation. Moreover, in six mixed-type neuroendocrine carcinoma cases, macrodissection was used to separate the neuroendocrine carcinoma and endometrioid adenocarcinoma components for next-generation sequencing, which revealed several mutations common among the two. These findings suggest that endometrial neuroendocrine carcinoma could originate from conventional endometrial neoplasia, especially endometrioid adenocarcinoma.
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http://dx.doi.org/10.1111/pin.13108DOI Listing
May 2021

Prognostic Role of Tumor-Infiltrating Lymphocytes and Tumor Budding in Early Oral Tongue Carcinoma.

Laryngoscope 2021 May 6. Epub 2021 May 6.

Department of Otolaryngology Head and Neck Surgery, Yokohama City University, Yokohama, Kanagawa, Japan.

Objectives/hypothesis: Occult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate- or high-grade budding scores was investigated as a prognostic marker for occult neck metastases.

Study Design: Retrospective study.

Methods: Specimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin.

Results: Based on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease-free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate- or a high-grade budding score had a poor prognosis for RC according to the log-rank test.

Conclusions: In summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate- or high-grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC.

Level Of Evidence: Step 4 (Level 4) Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29589DOI Listing
May 2021

Signet-ring Cell Carcinoma Component as an Indicator of Anaplastic Lymphoma Kinase Mutations in Colorectal Cancer.

J Anus Rectum Colon 2021 28;5(2):167-172. Epub 2021 Apr 28.

Department of Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Objectives: Molecular profiling of marker mutations has become an essential aspect in the treatment planning for colorectal cancer (CRC). Anaplastic lymphoma kinase () mutations could be used as markers in CRC molecular profiling. However, the extremely low frequency of these mutations makes their confirmation in all patients inefficient. Thus, to determine whether ALK positivity could be indicated by morphological features, we have analyzed ALK positivity in CRC tissues with a signet-ring cell carcinoma (SRCC) component.

Methods: We screened cases of patients who underwent CRC surgical resection at the Department of Gastrointestinal Surgery of the Kanagawa Cancer Center between January 2015 and December 2019. The selected samples were then assessed immunohistochemically using an antibody against p80 ALK.

Results: In total, we were able to retrieve 29 cases of CRC with the SRCC component from the database; however, 5 cases were excluded owing to the absence of formalin-fixed paraffin-embedded tissue sections or the absence of the SRCC component when the tissues were observed. In the immunohistochemical analysis, two cases showed diffused positive immunoreactivity for ALK and were defined as ALK-positive CRC. Thus, the ALK positivity rate in CRC with SRCC was determined to be 8.3%.

Conclusions: This present study sheds light on the morphological features of ALK-positive CRC. Our findings could contribute to the effective screening and improvement of front-line therapy for CRC.
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http://dx.doi.org/10.23922/jarc.2020-068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084530PMC
April 2021

Machine learning-based image analysis for accelerating the diagnosis of complicated preneoplastic and neoplastic ductal lesions in breast biopsy tissues.

Breast Cancer Res Treat 2021 Aug 1;188(3):649-659. Epub 2021 May 1.

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-Ku, Yokohama, Kanagawa, 241-8515, Japan.

Purpose: Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis.

Methods: Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images.

Results: The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS.

Conclusions: These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases.
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http://dx.doi.org/10.1007/s10549-021-06243-2DOI Listing
August 2021

Pulmonary infarction caused by sarcoidosis vascular involvement: A case report.

Pathol Int 2021 Jul 26;71(7):480-484. Epub 2021 Apr 26.

Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Sarcoidosis is a systemic granulomatous disease. In pulmonary sarcoidosis, granulomatous vascular involvement is a common feature that occurs in all types of vessels, including large elastic arteries to venules, but sarcoidosis complicated with pulmonary infarction has not been reported. We report a case of a 60 years old female, who was operated on a clinical diagnosis of lung cancer, and histological examination revealed a pulmonary infarction and sarcoidosis. In the pulmonary elastic arteries, granulomas infiltrated the adventitia and media, and caused elastic fiber collapse and destruction. Arterial occlusion by granulomas was observed in the edge of the infarcted area. It was considered that the arterial sarcoidosis granuloma involvement was the cause of pulmonary infarction. Sarcoidosis is a significant risk factor for cardiovascular events. However, pulmonary infarction is an extremely rare complication of sarcoidosis. Our case suggests that sarcoidosis may cause vascular events in the lungs.
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http://dx.doi.org/10.1111/pin.13104DOI Listing
July 2021

Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component.

Transl Lung Cancer Res 2021 Mar;10(3):1292-1304

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

Background: Fetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs.

Methods: We performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component.

Results: Cancer-related mutations were identified in (7/16 cases), (6/16 cases), (4/16 cases), (3/16 cases), (3/16 cases), (2/16 cases), and (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes and . H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells).

Conclusions: This study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.
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http://dx.doi.org/10.21037/tlcr-20-1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044470PMC
March 2021

Detection of EGFR mutation of pulmonary adenocarcinoma in sputum using droplet digital PCR.

BMC Pulm Med 2021 Mar 23;21(1):100. Epub 2021 Mar 23.

Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.

Background: It is still unclear whether epidermal growth factor receptor (EGFR) mutation of primary lung adenocarcinoma can be detected on sputum samples. This study aimed to examine EGFR mutations of primary lung adenocarcinoma in sputum samples using droplet digital polymerase chain reaction (ddPCR) and compare it with an EGFR mutation in surgically resected lung cancer.

Methods: Sputum was prospectively collected from the patients before complete resection of the primary lung cancer at Kanagawa Cancer Center from September 2014 to May 2016. ddPCR was performed to detect EGFR exon 21 L858R point mutation (Ex21) and EGFR exon 19 deletion mutation (Ex19) in sputum samples from patients with lung adenocarcinoma. The concordance of EGFR mutation status in sputum samples and tumors in surgically resected specimen was evaluated for each positive and negative cytology group.

Results: One hundred and eighteen patients with primary lung adenocarcinoma provided sputum samples. Sputum cytology was positive in 13 patients (11.0%). ddPCR detected two cases of Ex21 and two cases of Ex19 in sputum cytology positive cases. Compared to surgically resected specimens, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 80.0%, 100%, and 100%, respectively, in sputum cytology positive cases. In contrast, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 3.1%, 100%, and 100%, respectively, in sputum cytology negative cases.

Conclusions: EGFR mutations in primary lung adenocarcinoma can be detected with high sensitivity in sputum samples if sputum cytology is positive.
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http://dx.doi.org/10.1186/s12890-021-01468-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988937PMC
March 2021

Suitability of Bronchoscopic Biopsy Tissue Samples for Next-Generation Sequencing.

Diagnostics (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

Kanagawa Cancer Center, Department of Thoracic Oncology, Kanagawa 241-8515, Japan.

A sufficiently large tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥1 mm) and tumor content rate (≥30%) on the success rate of the Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm with large EBUS-GS, and 1.81 ± 0.75 mm with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥1 mm was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS ( = 14), 93.4% (96.9%) for large EBUS-GS ( = 32), 62.5% (100%) for EBB ( = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) ( = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm is adequate for samples to be tested with NGS.
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http://dx.doi.org/10.3390/diagnostics11030391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996548PMC
February 2021

Tissue factor pathway inhibitor‑2 is specifically expressed in ovarian clear cell carcinoma tissues in the nucleus, cytoplasm and extracellular matrix.

Oncol Rep 2021 03 20;45(3):1023-1032. Epub 2021 Jan 20.

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241‑8515, Japan.

Tissue factor pathway inhibitor‑2 (TFPI‑2) is a promising candidate as a serum biomarker of ovarian clear cell carcinoma (OCCC), a lethal histological subtype of epithelial ovarian cancer (EOC). TFPI‑2 is a secreted serine protease inhibitor that suppresses cancer progression through the inhibition of matrix protease activities. Previous studies have also identified TFPI‑2 in the nucleus, and a possible function of nuclear TFPI‑2 as a transcriptional repressor of matrix metalloproteinase‑2 (MMP‑2) was recently demonstrated. We are currently establishing TFPI‑2 as a serum biomarker for OCCC patients; however, TFPI‑2 expression in OCCC tissues has not been previously investigated. In the present study, we examined TFPI‑2 expression and its localization in 11 OCCC cell lines by western blotting and enzyme‑linked immune assay. Four cell lines expressed TFPI‑2 in the nucleus, cytoplasm and culture plate-attached extracellular fraction, while four other cell lines expressed TFPI‑2 only in the extracellular fraction. In the remaining three cell lines, TFPI‑2 was not identified in any fraction. The amount of secreted soluble TFPI‑2 showed similar trends to that of the plate‑attached fraction. We next investigated the expression levels and distribution of TFPI‑2 in surgically resected EOC tissues by immunohistochemistry. In 52 of the 77 (67.5%) OCCC tumors, TFPI‑2 expression was detected in at least one of the nuclear, cytoplasmic and extracellular matrix fractions. In contrast, we did not identify TFPI‑2 in the other EOC subtypes (n=65). TFPI‑2‑positive expression distinguished CCC from the other EOC tissues with a sensitivity of 67.5% and specificity of 100%. Although the inherent tumor suppressor function, statistical analyses failed to demonstrate correlations between TFPI‑2 expression and clinical parameters, including 5‑year overall survival, except for the patient age. In conclusion, we identified TFPI‑2 expression in the nucleus, cytoplasm and extracellular matrix in OCCC tissues. The high specificity of TFPI‑2 may support its use for diagnosis of OCCC in combination with existing markers.
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http://dx.doi.org/10.3892/or.2021.7944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859994PMC
March 2021

Tissue surface area and tumor cell count affect the success rate of the Oncomine Dx Target Test in the analysis of biopsy tissue samples.

Thorac Cancer 2021 01 13;12(2):194-200. Epub 2020 Nov 13.

Department of Surgery, Yokohama City University, Yokohama, Japan.

Background: The Oncomine Dx Target Test (ODxTT) is a next-generation sequencing-based companion diagnostic test which has been recently developed; however, its analysis success rate could be improved, especially for small samples. The aim of this study was to identify the pathological factors associated with biopsy specimens that affect the analysis success rate of ODxTT.

Methods: We retrospectively investigated 119 cases subjected to ODxTT at Kanagawa Cancer Center. Data pertaining to the results of BRAF V600E mutation analysis in ODxTT and pathological factors based on microscope slides were collected. Pathological factors including tissue surface area, tumor cell count, and tumor content rate were assessed. We constructed receiver operating characteristic curves and determined the optimal cutoff values of each pathological factor. Multivariate logistic analysis was used to identify significant factors.

Results: A total of 98 of 119 samples were successfully analyzed (75.6%). The tissue surface area and tumor cell count were significantly higher in the group associated with analysis success (P < 0.001 and P = 0.011, respectively), and their optimal cutoff values were 1.04 mm and 375 cells, respectively. A tissue surface area > 1.04 mm and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT (odds ratio [OR] 0.10; 95% confidence interval [CI]: 0.03-0.35; P < 0.001 and OR 0.25; 95% CI: 0.07-0.90; P = 0.033, respectively).

Conclusions: Selecting samples with a tissue surface area > 1.04 mm and a tumor cell count >375 cells might improve the analysis success rate of ODxTT.

Key Points: Significant findings of the study: We found that a tissue surface area > 1.04 mm and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT in the analysis of biopsy tissue samples.

What This Study Adds: It is sometimes necessary to assess genetic alterations with a small biopsy sample in daily practice. The criteria mentioned above will help to determine which tests should be performed, ODxTT or multiple single-gene testing.
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http://dx.doi.org/10.1111/1759-7714.13743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812068PMC
January 2021

Clinical Significance of Tumour CD44v and MIST1 Expression in Patients With Non-small-cell Lung Cancer.

Anticancer Res 2020 Nov;40(11):6407-6416

Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan.

Background: Cancer stem cells (CSCs) are involved in cancer metastasis and relapse. Therefore, identification of CSC biomarkers might help determine the success of a treatment. In this study, we examined the expression of four CSC markers: Cluster of differentiation 44 variant (CD44v), leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), frizzled 7 (FZD7), and muscle, intestine and stomach expression 1 (MIST1), in cancer tissues of patients with non-small-cell lung cancer at >5 years after resection, and its clinical significance.

Patients And Methods: We examined the expression of each CSC marker in 360 patients with NSCLC (n=360) who underwent curative resection by immunohistochemical analysis of tissue microarrays, and determined its relationship with survival.

Results: High expression of MIST1 was related to better overall survival (p<0.05); high CD44v expression was associated with poor overall and recurrence-free survival (p<0.001 for both) and thus, CD44v was defined as an independent prognostic factor (p<0.05), according to a multivariate analysis.

Conclusion: Tumoral CD44v expression might be a useful prognostic marker for patients after curative resection of NSCLC.
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http://dx.doi.org/10.21873/anticanres.14662DOI Listing
November 2020

Lung adenocarcinoma in a patient with a cis EGFR L858R-K860I doublet mutation identified using NGS-based profiling test: Negative diagnosis on initial companion test and successful treatment with osimertinib.

Thorac Cancer 2020 12 9;11(12):3599-3604. Epub 2020 Oct 9.

Center for Cancer Genome Medicine, Kanagawa Cancer Center, Yokohama, Japan.

Tyrosine kinase inhibitors are used as first-line treatment for non-small cell lung cancer (NSCLC) patients harboring driver mutations in EGFR, ALK, ROS1, and BRAF. Currently, standard molecular testing approaches help identify single genes for such targetable driver mutations in NSCLC; however, next-generation sequencing (NGS)-based genetic profiling provides a more comprehensive approach and is hence strongly recommended. This case study aimed to highlight the benefits of NGS-based tests for the diagnosis of complex EGFR L858R mutations. A patient was diagnosed with stage IVB NSCLC using a government-approved in vitro diagnostic test and was noted to have a high programmed death-ligand 1 tumor proportion score. This patient was treated with pembrolizumab monotherapy followed by cisplatin and pemetrexed owing to the lack of actionable driver gene mutations, including EGFR mutations. After treatment failure, a sample harvested from the same transbronchial lung biopsy specimen (formalin-fixed and paraffin-embedded) used for the initial EGFR test was subjected to NGS-based broad genetic profiling. The NGS-based test identified an EGFR L858R-K860I cis doublet mutation; however, neither of these mutations was identified upon initial molecular testing. The patient was then successfully treated with a third-generation EGFR-tyrosine kinase inhibitor, osimertinib. In this study, we delved deeper into the realm of L858R and K860I mutations in NSCLC and discuss the potential causes underlying our initial negative diagnosis. Furthermore, this study highlighted the additional benefits of replacing typical molecular tests with NGS-based broad profiling approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The EGFR L858R-K860I cis doublet mutation was not detected by a PCR-based EGFR test. A next generation sequencing (NGS)-based test was able to identify the L858R-K860I cis doublet mutation. WHAT THIS STUDY ADDS: Osimertinib was effective in an NSCLC patient with EGFR L858R and K860I mutations.
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http://dx.doi.org/10.1111/1759-7714.13694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705914PMC
December 2020

Multiplex gene-panel testing for lung cancer patients.

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

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

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

Membrane type 1 matrix metalloproteinase regulates anaplastic thyroid carcinoma cell growth and invasion into the collagen matrix.

Biochem Biophys Res Commun 2020 09 4;529(4):1195-1200. Epub 2020 Aug 4.

Organoid Biology Unit, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Electronic address:

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancer types; however, the molecular mechanism contributing to the aggressive characteristics remain unclear. Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an important role in cancer invasion and has been associated with a poor prognosis in various malignant neoplasms. In this study, we investigated the relationship between MT1-MMP expression and the proliferation and invasion of ATC cells, along with the association with clinicopathologic factors in patients with ATC. Suppression of MT1-MMP reduced the proliferation and invasion of ATC cells, and suppressed ERK activity, indicating a role in cancer cell proliferation in collagen matrix culture conditions. The expression of MT1-MMP was detected in 29 of 34 (85.3%) surgical specimens from ATC patients. In addition, the expression of MT1-MMP in the tumor lesion was higher than that of normal and stromal tissues. Collectively, these results suggest that elevated MT1-MMP expression plays a role in the pathogenesis of ATC, which may promote its aggressive characteristics such as proliferation and invasion, highlighting a potential new therapeutic target.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.043DOI Listing
September 2020

Biomarker analysis to predict the pathological response to neoadjuvant chemotherapy in locally advanced gastric cancer: An exploratory biomarker study of COMPASS, a randomized phase II trial.

Oncotarget 2020 Jul 28;11(30):2906-2918. Epub 2020 Jul 28.

Tokai Central Hospital, Kakamigahara, Gifu 504-8601, Japan.

Background: The findings of COMPASS, a randomized phase II study, suggested that the regimens and courses of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) did not affect the pathological response. However, pathological complete response was achieved in 10% patients who received four courses of either S-1/cisplatin or paclitaxel/cisplatin. We hypothesized that if relevant biomarkers could be used to predict the suitable NAC regimen before treatment initiation, further improvements could be ensured in the outcomes of locally advanced GC.

Materials And Methods: mRNA extraction, real-time polymerase chain reaction, and immunohistochemical analyses were performed using endoscopic biopsy specimens of primary tumors, collected prior to NAC, to determine the clinically relevant biomarkers.

Results: , , , , , , and were identified as biomarker candidates, since their expression was significantly associated with the pathological responses to each NAC regimen. Furthermore, and were identified as predictive biomarkers of the pathological response to each NAC regimen.

Conclusions: The effective prediction of the pathological response to NAC regimens in locally advanced GC using biomarkers identified from endoscopic biopsy specimens indicates the possibility of personalizing NAC based on biomarker analysis.
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http://dx.doi.org/10.18632/oncotarget.27658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392622PMC
July 2020

Analysis of targeted somatic mutations in pleomorphic carcinoma of the lung using next-generation sequencing technique.

Thorac Cancer 2020 08 23;11(8):2262-2269. Epub 2020 Jun 23.

Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.

Background: Pleomorphic carcinoma (PC) of the lung is a rare type of lung cancer with aggressive characteristics and a poor prognosis. Because it is rare, the molecular characteristics of PC remain unclear.

Methods: A gene mutation analysis was performed using next-generation sequencing (NGS) in patients with PC of the lung who had undergone surgical resection.

Results: A total of nine patients were enrolled in the study. All the patients were male and eight had a history of smoking. Eight tumors contained spindle cells and three contained giant cells. Mutations considered significant were found in eight of the nine patients: in TP53 in five patients, in MET in two patients, and in ALK, ERBB2, PIK3CA, APC, NF1, and CDKN2A in one patient each. No EGFR mutation was detected in our analysis. Co-mutations were detected in three patients: TP53 with MET and NF1, TP53 with ERBB2, and PIK3CA with CDKN2A.

Conclusions: TP53 mutations were detected most frequently in PC of the lung with NGS analysis. Different co-mutations were seen in several specimens.

Key Points: Significant findings of the study This study demonstrates that mutations in the TP53 gene are frequently found and co-mutations are sometimes found in pleomorphic carcinoma of the lung using genomic profiling analysis. What this study adds Our results will help to analogize the genetic characteristics and potential target of molecular-targeted agents of pleomorphic carcinoma of the lung.
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http://dx.doi.org/10.1111/1759-7714.13536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396383PMC
August 2020

Characterization of KIF20A as a prognostic biomarker and therapeutic target for different subtypes of breast cancer.

Int J Oncol 2020 Jul 7;57(1):277-288. Epub 2020 May 7.

Department of Medical Oncology and Cancer Center, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan.

The aim of the present study was to identify novel prognostic biomarkers and therapeutic targets for breast cancer; thus, genes that are frequently overexpressed in several types of breast cancer were screened. Kinesin family member 20A (KIF20A) was identified as a candidate molecule during this process. Immunohistochemical staining performed using tissue microarrays from 257 samples of different breast cancer subtypes revealed that KIF20A was expressed in 195 (75.9%) of these samples, whereas it was seldom expressed in normal breast tissue. KIF20A protein was expressed in all types of breast cancer observed. However, it was more frequently expressed in human epidermal growth factor receptor 2 (HER2)‑positive and triple‑negative breast cancer than in the luminal type. Moreover, KIF20A expression was significantly associated with the poor prognosis of patients with breast cancer. A multivariate analysis indicated that KIF20A expression was an independent prognostic factor for patients with breast cancer. The suppression of endogenous KIF20A expression using small interfering ribonucleic acids or via treatment with paprotrain, a selective inhibitor of KIF20A, significantly inhibited breast cancer cell growth through cell cycle arrest at the G2/M phase and subsequent mitotic cell death. These results suggest that KIF20A is a candidate prognostic biomarker and therapeutic target for different types of breast cancer.
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http://dx.doi.org/10.3892/ijo.2020.5060DOI Listing
July 2020

A Case of Unresectable Papillary Thyroid Carcinoma Treated with Lenvatinib as Neoadjuvant Chemotherapy.

Case Rep Endocrinol 2020 11;2020:6438352. Epub 2020 May 11.

Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.

A 75-year-old woman visited a nearby clinic with complaints of right clavicle discomfort, and she underwent diagnostic thoracoscopic lung biopsy, being diagnosed with lung metastasis and a right-upper mediastinal mass. The superior mediastinum mass was extrapulmonary and covered by the pleura, and it was not biopsied. Papillary thyroid carcinoma was diagnosed following biopsy of the lung metastasis. Only a small tumor, with a maximum diameter of 70 mm from the right neck to the superior mediastinum, in the thyroid gland invades the internal jugular vein and subclavian vein, forming a tumor embolus in the right brachiocephalic vein and reaching the vicinity of the superior vena cava. For life-saving purposes, we obtained approval from the Cancer Board of Kanagawa Cancer Center and used lenvatinib according to unresectable undifferentiated cancer IRB approval number 28-41. The tumor had shrunk after 4 months, and surgery was performed. The postoperative course has been good, and the patient is being followed up. The patient is alive three months after surgery, and lung metastases have disappeared on CT images. This case is reported as a successful case of neoadjuvant chemotherapy and interval debulking surgery.
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http://dx.doi.org/10.1155/2020/6438352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238324PMC
May 2020

A case of spindle cell dominant histiocytic sarcoma showing a complete remission after first-line chemotherapy with doxorubicin and ifosfamide.

J Chemother 2020 Dec 20;32(8):445-450. Epub 2020 May 20.

Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.

Histiocytic sarcoma (HS), an extremely rare malignancy, usually follows a progressive time course, and patients die within two years of diagnosis. At present, there is no consensus for effective chemotherapy. We report the case of a 54-year-old man who presented with low back pain and left hip joint pain. Imaging for the pain revealed multiple lesions in the mediastinum, vertebral bodies, and left ilium. Biopsies of the mediastinal and vertebral lesions yielded a diagnosis of soft tissue sarcoma. He received standard chemotherapy for sarcoma with doxorubicin and ifosfamide, as the initial pathological diagnosis was soft tissue sarcoma. This is called AI therapy and commonly used for soft tissue sarcoma. Palliative radiation therapy to the left iliac lesion was added for pain control. Complete remission (CR) was achieved after two courses of AI therapy. Subsequent immunopathological examination revealed that the tumor was spindle cell dominant HS. CR was maintained for more than three years. To the best of our knowledge, this is the first report that a CR was achieved by AI therapy as first-line treatment for spindle cell dominant HS, combined with focal bone palliative irradiation. AI therapy could be an effective option as chemotherapy for HS.
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http://dx.doi.org/10.1080/1120009X.2020.1767477DOI Listing
December 2020

Effect of epidermal growth factor receptor mutation on early-stage non-small cell lung cancer according to the 8th TNM classification.

Lung Cancer 2020 07 11;145:111-118. Epub 2020 May 11.

Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.

Objective: This study evaluated the effect of EGFR mutation on early-stage non-small cell lung cancer (NSCLC) based on the 8th TNM classification.

Materials And Methods: The study retrospectively examined 1231 patients who underwent curative resection for pathological stage 0-I (8th TNM classification) NSCLC and EGFR mutation analysis from January 2006 to December 2018 at Kanagawa Cancer Center. The disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS) of EGFR-mutant lung cancer (Mt) and EGFR wild-type lung cancer (Wt) patients at each stage were compared between two patient groups using the log-rank test. Cox regression analyses were performed to identify prognostic factors.

Results: The number of stage 0, IA1, IA2, IA3, and IB Mt/Wt patients was 79/92, 202/189, 145/144, 45/75, and 74/186, respectively. There was no statistically significant difference in DFS between Mt and Wt patients at any pathological stage. The 5-year OS of Mt/Wt patients was 96.9 %/98.5 % for stage 0 (p = 0.671), 92.2 %/92.2 % for stage IA1 (p = 0.997), 93.9 %/82.6 % for stage IA2 (p = 0.039), 87.3 %/91.4 % for stage IA3 (p = 0.768), and 85.3 %/69.3 % for stage IB (p = 0.017). The 5-year DSS of Mt/Wt patients was 95.7 %/95.4 % for stage IA2 (p = 0.684) and 93.2 %/77.5 % for stage IB (p = 0.016). In Cox regression analyses, Mt was not identified as a prognostic factor for OS among stage IA2 NSCLC patients (HR, 0.62; 95 % CI, 0.20-1.93; p = 0.413). However, Mt was a favorable prognostic factor for OS (HR, 0.44; 95 % CI, 0.19-1.00; p = 0.049) and DSS (HR, 0.38; 95 % CI, 0.17-0.87; p = 0.022) among stage IB NSCLC patients.

Conclusion: EGFR mutation had no effect on the prognosis of stage 0-IA NSCLC but significantly affected the OS and DSS of stage IB NSCLC. Effect of EGFR mutations on postoperative prognosis of patients with stage 0-I NSCLC differed with each stage.
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http://dx.doi.org/10.1016/j.lungcan.2020.04.012DOI Listing
July 2020

Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma.

Cancer Immunol Immunother 2020 Oct 18;69(10):2041-2051. Epub 2020 May 18.

Research Institute, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.

Recently, the effectiveness of anti-programmed death 1 (PD-1) antibody therapy in the treatment of renal cell carcinoma (RCC) has been established. Nevertheless, efficacy has been reported to be limited to only 10-30% of patients. To develop more effective immunotherapy for RCC, we analyzed the immunological characteristics in RCC tissues by immunohistochemistry (IHC). We prepared a tissue microarray that consisted of tumor tissue sections (1 mm in diameter) from 83 RCC patients in Kanagawa Cancer Center between 2006 and 2015. IHC analysis was performed with antibodies specific to immune-related (CD8 and Foxp3) and immune checkpoint (programmed death ligand 1 (PD-L1) and 2 (PD-L2), B7-H4 and galectin-9) molecules. The numbers and proportions of positively stained tumor cells or immune cells were determined in each section. From multivariate analysis of all 83 patients, higher galectin-9 expression was detected as a factor associated with worse overall survival (OS) (P = 0.029) and that higher stage and higher B7-H4 expression were associated with worse progression-free survival (PFS) (P < 0.001 and P = 0.021, respectively). Similarly, in multivariate analysis of 69 patients with clear cell RCC, though not statistically significant, there was a trend for association between higher galectin-9 expression and worse OS (P = 0.067), while higher stage was associated with worse PFS (P < 0.001). This study suggests that higher galectin-9 expression is an independent adverse prognostic factor of OS in RCC patients. Therefore, to develop more effective personalized immunotherapy to treat RCC, it may be important to target not only PD-1/PD-L1, but also other immune checkpoint molecules such as galectin-9.
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http://dx.doi.org/10.1007/s00262-020-02608-6DOI Listing
October 2020

Impact of the micropapillary component on the timing of recurrence in patients with resected lung adenocarcinoma.

Eur J Cardiothorac Surg 2020 11;58(5):1010-1018

Department of Surgery, Yokohama City University, Yokohama, Japan.

Objectives: A micropapillary (MIP) component is reported to be associated with a poor prognosis in patients with completely resected lung adenocarcinoma. The purpose of this study was to investigate the impact of an MIP component on the timing of postoperative recurrence using hazard curves.

Methods: A total of 1289 patients with lung adenocarcinoma who underwent complete pulmonary resection from 2008 to 2015 were studied. Hazard curves representing the changes in hazard over time were evaluated.

Results: The hazard curve displayed an initial wide, high peak within 1 year after surgery in patients with an MIP component, whereas some gentle peaks around the second year were noted in patients without an MIP component. The presence of an MIP component was associated with a worse recurrence-free survival and an early recurrence in stage I patients but not in advanced-stage patients. In multivariable Cox regression, the presence of an MIP component and lymph node metastasis, pleural invasion and gender were associated with a poor prognosis.

Conclusions: Patients with an MIP component retained a high risk of early recurrence after surgery, and the risk for recurrence persisted over the long term. Even after complete resection in stage I lung adenocarcinoma patients, an MIP component remains correlated with a poor prognosis.
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http://dx.doi.org/10.1093/ejcts/ezaa138DOI Listing
November 2020

Risk factors for progressive sarcopenia 6 months after complete resection of lung cancer: what can thoracic surgeons do against sarcopenia?

J Thorac Dis 2020 Mar;12(3):307-318

Department of Thoracic Surgery, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan.

Background: Our previous report described how postoperative progression of sarcopenia predicted long-term prognosis after complete resection of non-small cell lung cancer (NSCLC) in heavy smokers. However, there are currently no effective means to treat progressive sarcopenia. In this study, we aimed to confirm our previous findings in a larger population and to identify factors associated with postoperative progression of sarcopenia to propose possible preventative measures.

Methods: This retrospective study analyzed the data of 1,095 patients who underwent curative lobar resection for NSCLC at Kanagawa Cancer Center. We divided patients into four groups according to sex and Brinkman index (BI) above or below 600. Six-month postoperative changes in the skeletal muscle index (SMI) were calculated and associations between clinicopathological factors including changes in SMI and mortality from postoperative 6 months were examined. Only in groups in which postoperative depletion of SMI was shown to be associated with the prognosis, we identified clinicopathological factors associated with depletive SMI.

Results: The overall survival rates of 1,095 patients were 89.8% and 82.5% at 3 and 5 years, respectively. The median 6-month change in SMI was -3.4% (range, -22.3% to +17.9%). Multivariate analysis revealed that poor prognosis was independently predicted by a large reduction in the SMI (cut-off value: -10%) in males with a BI ≥600. In 391 heavy-smoking males, factors associated with a postoperative change in SMI ≤-10% were history of other cancers (including gastric cancer) low forced expiratory volume in one second (FEV 1.0, cut-off value: 1,870 mL), and prolonged operation time (cut-off value: 200 minutes).

Conclusions: Perioperative measures to prevent postoperative sarcopenia are appropriate for heavy smokers. We obtained some clues regarding countermeasures, one of which may be avoiding long-time operation. Further studies including clinical trials to assess perioperative anti-sarcopenia treatments, are needed.
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http://dx.doi.org/10.21037/jtd.2020.01.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138994PMC
March 2020

[A Case of Long-Term Survival after Multidisciplinary Treatment for Gastrointestinal Neuroendocrine Carcinoma].

Gan To Kagaku Ryoho 2019 Dec;46(13):2270-2272

Dept. of Gastrointestinal Surgery, Kanagawa Cancer Center.

A 55-year-old man was admitted to our hospital for examination and treatment of a transverse colon tumor detected at a nearby hospital. After CT, FDG-PET, and laparotomy biopsy, he was diagnosed with neuroendocrine cancer(Ki-67 index 40%)without distant metastasis. He underwent transverse colectomy. The pathological diagnosis was transverse colon neuroendocrine cancer(Ki-67 index 24.7%). Six courses of carboplatin and etoposide therapy as adjuvant chemotherapy were administered. Seven months after surgery, he developed lung metastasis that was surgically removed by partial lung resection. Eighteen months after the initial surgery, liver metastasis developed in S5 and S8. A right hepatic lobectomy was performed and there has been no recurrence after hepatectomy. The patient remains alive at 3 years and 4 months after initial treatment.
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December 2019

Desmoid-type fibromatosis arising from thoracotomy incision.

Clin Case Rep 2020 Feb 29;8(2):389-390. Epub 2019 Dec 29.

Departments of Thoracic Surgery Kanagawa Cancer Center Yokohama Japan.

Desmoid-type fibromatosis following thoracotomy is rare and has been previously reported only in <20 cases; however, it might mimic chest wall recurrence of previous cancer and needs differential diagnosis. When the tumor location corresponded to the thoracotomy incision, we should consider desmoid-type fibromatosis as a differential diagnosis.
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http://dx.doi.org/10.1002/ccr3.2634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044401PMC
February 2020

Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study.

Eur J Clin Pharmacol 2020 May 7;76(5):703-709. Epub 2020 Feb 7.

Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama City, Kanagawa, Japan.

Purpose: Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC).

Methods: We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated.

Results: The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1-not estimable [NE]), and 4.6 (95% CI 1.1-NE) months, respectively (p = 0.003).

Conclusions: Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.
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http://dx.doi.org/10.1007/s00228-020-02842-yDOI Listing
May 2020

A prophylaxis study of acute exacerbation of interstitial pneumonia after lung cancer surgery.

Jpn J Clin Oncol 2020 Feb;50(2):198-205

Department of Surgery, Yokohama City University, Yokohama, Japan.

Introduction: Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures.

Method: Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days.

Results: Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I.

Conclusions: Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP.
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http://dx.doi.org/10.1093/jjco/hyz164DOI Listing
February 2020

Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.

Int Immunol 2020 03;32(3):175-186

Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.
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http://dx.doi.org/10.1093/intimm/dxz074DOI Listing
March 2020

Prognostic value of IL-34 in colorectal cancer patients.

Immunol Med 2019 Dec 23;42(4):169-175. Epub 2019 Nov 23.

Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

The mortality of colorectal cancer is expected to increase in some countries including the United States, which necessitates the identification of new molecules that help in prognosis assessment and survival improvement. In this brief report, we evaluated the potential of interleukin-34 (IL-34) as a prognostic factor in colorectal cancer. IL-34 was reported for the first time in 2008 as a novel cytokine that controls the biology of the myeloid cell lineage. Accumulating evidence suggests important roles for IL-34 in modifying the tumor microenvironment and enhancing therapeutic resistance of cancer. In this study, we found that IL-34 expression was detectable in various colorectal cancer cell lines in addition to primary cancer tissues from a cohort of Japanese colorectal cancer patients, ranging from high to absent. A Kaplan-Meier analysis showed that high expression of IL-34 correlated with poor survival of colorectal cancer patients. Importantly, in both univariate and multivariate analysis, high IL-34 expression correlated with unfavorable prognosis. A similar relationship between IL-34 expression and the poorer prognosis was also observed in a cohort of colorectal cancer patients registered at The Cancer Genome Atlas. Together, these findings indicate a potential role for IL-34 as a prognostic factor in colorectal cancer.
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http://dx.doi.org/10.1080/25785826.2019.1691429DOI Listing
December 2019
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