Publications by authors named "Yohei Miyagi"

224 Publications

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Pathol Int 2021 Jul 9. Epub 2021 Jul 9.

Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.
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http://dx.doi.org/10.1111/pin.13140DOI Listing
July 2021

Clinical Significance of Expression in Gastric Cancer Patients who Receive Gastrectomy and Adjuvant S-1.

Anticancer Res 2021 Jul;41(7):3583-3588

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan;

Background/aim: This study aimed to evaluate the prognostic significance of PLA2G2A expression in patients with locally advanced gastric cancer (GC).

Patients And Methods: PLA2G2A expression levels in cancerous tissue specimens and adjacent normal mucosa obtained from 134 patients with stage II/III GC who received adjuvant chemotherapy with S-1 after curative resection were measured using real-time quantitative polymerase chain reaction. Subsequently, the associations of PLA2G2A expression with clinicopathological features and survival were evaluated.

Results: No association was observed between clinicopathological features and PLA2G2A expression levels. Overall survival was significantly longer in patients with high PLA2G2A expression levels (p=0.022). Multivariate analysis revealed that PLA2G2A expression was a significant, independent prognostic factor (hazard ratio=0.136; 95% confidence interval=0.0185-0.992; p=0.049).

Conclusion: PLA2G2A mRNA expression may serve as a useful prognostic marker in patients with locally advanced GC who receive curative surgery and adjuvant chemotherapy with S-1.
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http://dx.doi.org/10.21873/anticanres.15146DOI Listing
July 2021

Mixed ductal-lobular carcinoma: an analysis of CDH1 DNA copy number variation and mutation.

Breast Cancer 2021 Jun 29. Epub 2021 Jun 29.

Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-Ku, Tokyo, 173-8610, Japan.

Background: Mixed ductal-lobular carcinoma (MDL) of the breast is poorly understood. Dysfunction of E-cadherin, a cell adhesion protein encoded by the CDH1 gene located on 16q22.1, causes loss of cell adhesion and cellular polarity in lobular carcinoma (LC). This study focuses the aberrations of CDH1 in LC, ductal carcinoma (DC), and MDL to investigate the pathogenesis of MDL.

Methods: The CDH1 DNA value (ratio of CDH1 copy number to the reference gene, RNase P) was calculated by digital polymerase chain reaction analysis of a total of 113 breast carcinoma cases (51 LCs, 54 DCs, and 8 MDLs). CDH1 gene mutation assay was performed for 20/51 LCs, 8/54 DCs, and 8 MDLs cases.

Results: The CDH1 DNA values were lower in LCs (average: 0.664) than in DCs (average: 1.296) (p < 0.000). In MDL, The CDH1 DNA values were significantly lower in LC areas (average: 0.58), compared to that of DC areas (average: 1.08) (p = 0.004), and there is no significant difference between the intermingled areas (average: 1.05) and DC areas (p = 0.775). Moreover, CDH1 mutations occurred more frequently in MDLs than in pure LCs and DCs. In one MDL case, the identical CDH1 mutation was found in LC and DC areas.

Conclusion: Our study presented that MDL had more frequent CDH1 mutations. There were two possible processes for cancer cells in LC areas: one process was via DC areas with a common ancestor, and another was an independent process from DC areas.
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http://dx.doi.org/10.1007/s12282-021-01269-2DOI Listing
June 2021

Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late-stage breast cancer.

Oncol Lett 2021 Jul 24;22(1):547. Epub 2021 May 24.

Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III-IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08-5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.
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http://dx.doi.org/10.3892/ol.2021.12808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170180PMC
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

Validation of tissue factor pathway inhibitor 2 as a specific biomarker for preoperative prediction of clear cell carcinoma of the ovary.

Int J Clin Oncol 2021 Jul 19;26(7):1336-1344. Epub 2021 May 19.

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan.

Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC.

Methods: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared.

Results: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125.

Conclusions: High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.
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http://dx.doi.org/10.1007/s10147-021-01914-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213588PMC
July 2021

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

Gut 2021 May 12. Epub 2021 May 12.

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

Objective: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.

Design: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.

Results: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022).

Conclusion: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.

Trial Registration Number: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).
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http://dx.doi.org/10.1136/gutjnl-2021-324060DOI Listing
May 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

Quality Control of Breast Cancer Surgery Samples: Introducing Time Stamp Checking.

Biopreserv Biobank 2021 Apr 29. Epub 2021 Apr 29.

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

Analytical information obtained from clinical tissue samples has recently become more important due to recent advancements in the clinical practice of medicine, for example, gene panel testing. However, acquiring and managing the sample quality, which greatly influences the analyses, are not sufficient and hence requires immediate attention. We introduced time stamp (TS) recording and documentation using the Standard PREanalytical Code (SPREC) for breast cancer surgery samples to monitor and control their quality. The TS recording used SPREC for quality control of each sample by recording seven factors: type of sample, type of collection, warm ischemia time (WIT), cold ischemia time (CIT), fixation type, fixation time (FT), and long-term storage. The responsibilities to record each factor were assigned among group members (breast surgeons, anesthesiologists, pathologists, operating room nurses, and medical technologists in pathology). Records based on SPREC were recorded for 393 surgical cases of first-time breast cancer patients performed at the Kanagawa Cancer Center from May 2018 to April 2019. The vascular clamp time was defined as when skin flap formation was completed, regardless of the surgical procedure. An anesthesiologist recorded the vascular clamp time and sample collection time, and the pathologist recorded the fixation start time and fixation end time. WIT was 23 (3-116) minutes (breast-conserving surgery, 11 [3-38] minutes; mastectomy, 26 [5-116] minutes; and nipple-sparing mastectomy, 39 [31-43] minutes), CIT was 37 (3-1052) minutes, and FT was 43 (17-115) hours. The median CIT and FT were significantly shortened after introducing the TS system, and the variabilities were reduced. A TS system for quality control of breast cancer surgical sample functions well due to the establishment of highly versatile WIT and a working group consisting of multiple members of different occupations who shared roles.
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http://dx.doi.org/10.1089/bio.2020.0133DOI Listing
April 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

Clinical Significance of Stanniocalcin2 mRNA Expression in Patients With Colorectal Cancer.

Anticancer Res 2021 Apr;41(4):2117-2122

Department of Gastrointestinal Surgery, Kanagawa Cancer Centre, Yokohama, Japan;

Background/aim: Stanniocalcin2 (STC2) is associated with proliferation, invasion, and metastasis in various cancers. We examined the clinical significance of STC2 mRNA expression in patients with colorectal cancer (CRC).

Patients And Methods: Relative expression levels of STC2 mRNA in CRC tissues and corresponding normal mucosa obtained from 202 patients were measured using quantitative real-time reverse transcriptase-polymerase chain reaction.

Results: Expression of STC2 mRNA was higher in the cancer tissue than in the adjacent normal mucosa. STC2 mRNA expression in cancer tissues was associated with tumour size, liver metastasis, venous invasion, and lymph node metastasis. High expression of STC2 mRNA was significantly associated with poorer postoperative survival (p=0.0003). Multivariate analysis showed that high expression of STC2 mRNA was an independent predictor of postoperative survival.

Conclusion: High expression of STC2 mRNA in CRC tissue may be a useful prognostic marker in patients with CRC.
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http://dx.doi.org/10.21873/anticanres.14983DOI Listing
April 2021

Treatment of primary and metastatic breast and pancreatic tumors upon intravenous delivery of a PRDM14-specific chimeric siRNA/nanocarrier complex.

Int J Cancer 2021 Aug 13;149(3):646-656. Epub 2021 Apr 13.

Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

PRDM14 is highly expressed in several cancers but is not detected in normal tissues. It confers cancer stem cell-like properties, including chemoresistance and distant metastasis, to cancer cells. Herein, we aimed to develop a highly effective therapy against advanced stage cancer based on intravenously delivered PRDM14-targeted siRNA. First, we examined PRDM14 expression and gene amplification in breast and pancreatic tumors and cell lines. PRDM14 was expressed in breast cancer, including the triple-negative subtype, and pancreatic cancer. PRDM14 was amplified in 23.8% of patients with PRDM14 breast cancer. Next, we investigated the inoculated tumor growth and distant metastasis following PRDM14 depletion by administering mice with PRDM14-specific chimeric siRNA combined with a novel branched PEGylated poly-L-ornithine (PLO)-based intravenous drug delivery system, designated PRDM14 unit polyion complex (uPIC) (n = 6/group). Inhibition of PRDM14 expression with PRDM14 uPIC by systemic intravenous injection effectively reduced tumor size and metastasis in vivo, thereby improving survival. Finally, pharmacokinetic/toxicokinetic analyses were performed on PRDM14 uPIC, which was intravenously administered to rats (n = 10-15/group) and cynomolgus monkeys (n = 3-5/group), twice weekly for 4 weeks. This revealed that PRDM14 uPIC was relatively nontoxic and the siRNA exposure in serum was greater than that predicted by the administered dose ratio when delivered as a uPIC. Taken together, our study indicated that PRDM14 uPIC is highly effective in suppressing malignant features of solid cancers and does not cause severe toxicity, making it a promising therapeutic agent for cancer treatment.
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http://dx.doi.org/10.1002/ijc.33579DOI Listing
August 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

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

Aldehyde Dehydrogenase 1-related Genes in Triple-negative Breast Cancer Investigated Using Network Analysis.

Anticancer Res 2020 Dec;40(12):6733-6742

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.

Background/aim: Aldehyde dehydrogenase 1 (ALDH1) is known as a breast cancer stem cell (CSC) marker. This study aimed to identify genes associated with ALDH1.

Materials And Methods: ALDH1-positive and -negative breast cancer cells were isolated using laser capture microdissection from five tissue samples of ALDH1-positive breast cancer patients. Messenger RNA expression levels were compared between ALDH1-positive and -negative cells.

Results: We found 104 differentially expressed genes between ALDH1-positive and -negative cells. Gene ontology and pathway analysis revealed that these genes were correlated with CSC functions and pathways. Network analyses identified 10 genes that were closely associated with ALDH1. We validated these 10 genes utilizing The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium cohort, and found that they were associated with ALDH1 expression and correlated with Wnt pathway signaling.

Conclusion: The 10 genes we identified could be potential targets for CSC therapy of breast cancer.
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http://dx.doi.org/10.21873/anticanres.14696DOI Listing
December 2020

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

Clinical Significance of Glioma-associated Oncogene 1 Expression in Patients With Locally Advanced Gastric Cancer Administered Adjuvant Chemotherapy With S-1 After Curative Surgery.

Anticancer Res 2020 Oct;40(10):5815-5821

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

Background/aim: Glioma-associated oncogene 1 (GLI1) is an important transcription factor in the hedgehog signalling pathway and tumour formation. We evaluated the clinical significance of GLI1 expression as a prognostic factor in patients with locally advanced gastric cancer (GC).

Patients And Methods: GLI1 expression levels were measured by quantitative real-time polymerase chain reaction analysis of cancerous and adjacent normal mucosa specimens obtained from 142 patients with Stage II/III GC administered adjuvant chemotherapy with S-1 after curative resection. The associations of GLI1 expression with clinicopathological features and survival were evaluated.

Results: Clinicopathological features and GLI1 expression showed no association. Overall survival was significantly poorer in the high compared to the low GLI1 expression group (p=0.04). Multivariate analysis revealed that GLI1 expression was a significant independent prognostic factor [p=0.019, hazard ratio (HR)=1.94, 95% confidence interval (CI)=1.70-3.38].

Conclusion: GLI1 expression may be a useful prognostic marker in patients with locally advanced GC.
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http://dx.doi.org/10.21873/anticanres.14599DOI Listing
October 2020

Collective cancer cell invasion in contact with fibroblasts through integrin-α5β1/fibronectin interaction in collagen matrix.

Cancer Sci 2020 Dec 12;111(12):4381-4392. Epub 2020 Oct 12.

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

Interaction of cancer cells with cancer-associated fibroblasts (CAFs) plays critical roles in tumor progression. Recently we proposed a new tumor invasion mechanism in which invasive cancer cells individually migrate on elongate protrusions of CAFs (CAF fibers) in 3-D collagen matrix. In this mechanism, cancer cells interact with fibronectin fibrils assembled on CAFs mainly through integrin-α5β1. Here we tested whether this mechanism is applicable to the collective invasion of cancer cells, using two E-cadherin-expressing adenocarcinoma cell lines, DLD-1 (colon) and MCF-7 (breast). When hybrid spheroids of DLD-1 cells with CAFs were embedded into collagen gel, DLD-1 cells collectively but very slowly migrated through the collagen matrix in contact with CAFs. Epidermal growth factor and tumor necrosis factor-α promoted the collective invasion, possibly by reducing the E-cadherin junction, as did the transforming growth factor-β inhibitor SB431542 by stimulating the outgrowth of CAFs. Transforming growth factor-β itself inhibited the cancer cell invasion. Efficient collective invasion of DLD-1 cells required large CAF fibers or their assembly as stable adhesion substrates. Experiments with function-blocking Abs and siRNAs confirmed that DLD-1 cells adhered to fibronectin fibrils on CAFs mainly through integrin-α5β1. Anti-E-cadherin Ab promoted the single cell invasion of DLD-1 cells by dissociating the E-cadherin junction. Although the binding affinity of MCF-7 cells to CAFs was lower than DLD-1, they also collectively invaded the collagen matrix in a similar fashion to DLD-1 cells. Our results suggest that the direct interaction with CAFs, as well as environmental cytokines, contributes to the collective invasion of cancers.
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http://dx.doi.org/10.1111/cas.14664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734169PMC
December 2020

Differences in drug sensitivity between two-dimensional and three-dimensional culture systems in triple-negative breast cancer cell lines.

Biochem Biophys Res Commun 2020 12 18;533(3):268-274. Epub 2020 Sep 18.

Department of Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan. Electronic address:

Three-dimensional (3D) culture reflects tumor biology complexities compared with two-dimensional (2D) culture. Thus, 3D culture has attracted attention in cell biology studies including drug sensitivity tests. Herein, we investigated differences in anticancer drug sensitivities between 2D and 3D culture systems in triple-negative breast cancer (TNBC) cell lines. Thirteen TNBC cell lines were maintained in 2D and 3D cultures for 3 days before drug exposure. Cell morphology in the 3D culture was examined by phase-contrast microscopy. Sensitivities to epirubicin (EPI), cisplatin (CDDP), and docetaxel (DTX) were investigated by cell viability assay in both cultures and compared. The IC50s of all 3 drugs were significantly higher in the 3D culture than in the 2D culture in most cell lines. Those were correlated between the 2D and 3D cultures in EPI (R = 0.555) and CDDP (R = 0.955), but not in DTX (R = 0.221). Round spheroid-forming cells were more resistant to agents than grape-like types. In conclusion, 3D culture was more resistant to all 3 drugs than 2D culture in most TNBC cell lines. Sensitivity to CDDP was highly correlated between the 2D and 3D cultures, but not to DTX. 2D culture may be acceptable for sensitivity test for DNA-damaging agents.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.075DOI 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

Hypothesis-free deep survival learning applied to the tumour microenvironment in gastric cancer.

J Pathol Clin Res 2020 10 27;6(4):273-282. Epub 2020 Jun 27.

Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.

The biological complexity reflected in histology images requires advanced approaches for unbiased prognostication. Machine learning and particularly deep learning methods are increasingly applied in the field of digital pathology. In this study, we propose new ways to predict risk for cancer-specific death from digital images of immunohistochemically (IHC) stained tissue microarrays (TMAs). Specifically, we evaluated a cohort of 248 gastric cancer patients using convolutional neural networks (CNNs) in an end-to-end weakly supervised scheme independent of subjective pathologist input. To account for the time-to-event characteristic of the outcome data, we developed new survival models to guide the network training. In addition to the standard H&E staining, we investigated the prognostic value of a panel of immune cell markers (CD8, CD20, CD68) and a proliferation marker (Ki67). Our CNN-derived risk scores provided additional prognostic value when compared to the gold standard prognostic tool TNM stage. The CNN-derived risk scores were also shown to be superior when systematically compared to cell density measurements or a CNN score derived from binary 5-year survival classification, which ignores time-to-event. To better understand the underlying biological mechanisms, we qualitatively investigated risk heat maps for each marker which visualised the network output. We identified patterns of biological interest that were related to low risk of cancer-specific death such as the presence of B-cell predominated clusters and Ki67 positive sub-regions and showed that the corresponding risk scores had prognostic value in multivariate Cox regression analyses (Ki67&CD20 risks: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.15-1.89, p = 0.002; CD20&CD68 risks: HR = 1.33, 95% CI = 1.07-1.67, p = 0.009). Our study demonstrates the potential additional value that deep learning in combination with a panel of IHC markers can bring to the field of precision oncology.
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http://dx.doi.org/10.1002/cjp2.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578283PMC
October 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

Qualitative analysis of cancer telephone consultations: Differences in the counseling needs of Japanese men and women.

Patient Educ Couns 2020 May 16. Epub 2020 May 16.

Department of Psycho-Oncology, National Cancer Center Hospital East, Japan.

Objective: To analyze large-scale data obtained from telephone cancer consultations and clarify sex differences in the information sought by callers to guide future cancer survivor support.

Methods: We qualitatively analyzed 10,534 cases of telephone consultations with cancer patients. The relationships between callers' words and sex were visualized through a correspondence analysis, and the keywords extracted were visualized with a dependency relationship to the words "worry" and "anxiety," which had a high prevalence in the text data.

Results: Most of the male callers sought consultation about stomach cancer (11.8%), the consultations were predominantly about "suspicion of having cancer" (25.2%), and males indicated that the goal was to gather accurate information. Female callers mostly sought consultation about breast cancer (18.4%) were mainly interested in learning about "treatment" (31.0%), and mostly used the keywords "worry" and "anxiety." The total number of callers without a definitive diagnosis accounted for 20% of all consultations.

Conclusions: Healthcare providers need to understand unique sex-based coping styles and perform regular follow-ups. There is also a need for online platforms that provide information from the patient's perspective.

Practical Implications: Providing a cancer consultation support system and easy-to-understand medical information will improve communication between survivors, their families, and medical staff.
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http://dx.doi.org/10.1016/j.pec.2020.05.012DOI Listing
May 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

HEG1, BAP1, and MTAP are useful in cytologic diagnosis of malignant mesothelioma with effusion.

Diagn Cytopathol 2021 May 22;49(5):622-632. Epub 2020 May 22.

Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Background: The specificity and sensitivity of HEG1 for malignant mesothelioma (MM) is high. The use of BAP1/MTAP immunohistochemistry (IHC) is recommended to separate benign and malignant mesothelial proliferations. We determined how ancillary techniques can be used for the cytological diagnosis of MM with effusion.

Methods: Cell blocks from effusions from cases with MM, reactive mesothelial cells (RMCs), and carcinomas were analyzed by IHC with HEG1, BAP1, and MTAP and with homozygous deletion (HD) of CDKN2A by fluorescence in situ hybridization. Staining scores were calculated for IHC by adding the number of categories for the staining intensity and the staining extension.

Results: HEG1 was positive in all (41/41) MMs, but negative in carcinomas, except for ovarian carcinomas. Overall 76.9% (20/26) of RMCs and 28.6% (6/21) of ovarian carcinomas expressed HEG1. BAP1 loss was found in 71.1% of MMs, but none was found in RMCs. MTAP loss was found in 76.2% of MMs, but none was found in RMCs. 73.9% of MMs harbored HD of CDKN2A. There was concordance between loss of MTAP and HD of CDKN2A in 95% of MMs.

Conclusion: HEG1 is a good marker for mesothelial differentiation in effusion cytology. HD of CDKN2A is frequently observed in cell blocks from effusions of MMs, and MTAP IHC may act as a surrogate for HD of CDKN2A. Cell block analysis is recommended for effusions of unknown origins with the following methods: IHC with HEG1 and claudin 4 to validate the mesothelial origin, followed by BAP1 and MTAP IHC to confirm malignancy.
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http://dx.doi.org/10.1002/dc.24475DOI Listing
May 2021

A phase II study of atezolizumab for pretreated advanced/recurrent non-small cell lung cancer with idiopathic interstitial pneumonias: rationale and design for the TORG1936/AMBITIOUS study.

Ther Adv Med Oncol 2020 8;12:1758835920922022. Epub 2020 May 8.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama-city, Kanagawa Prefecture, Japan.

Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) are complicated with comorbid interstitial pneumonia (IP) with a poor prognosis. The pharmacotherapy for advanced lung cancer occasionally induces fatal acute exacerbation of pre-existing IP. Due to the lack of prospective studies, there is an urgent need to establish a safe and effective pharmacotherapy, especially for second-line or later settings. Atezolizumab, an anti-programmed cell death-ligand 1 antibody, is thought to be the safest candidate for second-line therapy among various immune checkpoint inhibitors. Moreover, compared with patients without IP, the patients with comorbid IP may have higher tumor mutation burden (TMB) or microsatellite instability (MSI), which are partly associated with a more favorable response to immune checkpoint inhibitors.

Methods: The Thoracic Oncology Research Group 1936/AMBITIOUS study is an ongoing, multicenter, single-arm, phase II trial to assess the safety and efficacy of atezolizumab for pretreated advanced/recurrent patients with NSCLC complicated with idiopathic, chronic fibrotic IP with a forced vital capacity of >70%. The patients will receive atezolizumab (1200 mg, day 1) every 3 weeks until the discontinuation criteria are met. The primary end point of this study is the 1-year survival rate, and a sample size of 38 patients is set. As a translational research, we will perform the analysis of TMB, somatic mutations, and MSI for nucleic acids extracted from archival tumor samples.

Discussion: Since there is no standard second-line or later therapy of advanced NSCLC with IP, the results of this study are expected to have a major impact on clinical practice.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190084, registered 26 August 2019 - retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084.
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http://dx.doi.org/10.1177/1758835920922022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222231PMC
May 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

EZH2 and MMSET Were Identified as Potentially Useful Therapeutic Targets in Metaplastic Breast Carcinoma.

Anticancer Res 2020 Apr;40(4):2133-2139

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

Background/aim: Metaplastic breast carcinoma (MBC) is a rare malignancy, which is often triple-negative for the hormone receptors and human epidermal growth factor receptor 2, and thus, does not benefit from targeted therapy. In this study, we examined the expression of methylation and demethylation enzymes by immunostaining MBC and the adjacent normal tissues or triple-negative ductal carcinoma (TNDC), and identified alterations that may be used as therapeutic targets.

Materials And Methods: We retrospectively studied surgical specimens from 15 patients who underwent surgery for MBC at Kanagawa Cancer Center between 2005 and 2016, and similarly from 14 patients with TNDC. The frequencies of high methylation/demethylation enzyme expression were compared among them.

Results: The frequencies of high enhancer of zeste homolog 2 (EZH2) and multiple myeloma SET domain (MMSET) expression were significantly higher in both MBC and TNDC than in normal tissue.

Conclusion: EZH2 and MMSET may be useful therapeutic targets in MBC.
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http://dx.doi.org/10.21873/anticanres.14172DOI Listing
April 2020
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