Publications by authors named "Haruhiko Sugimura"

274 Publications

CD8-positive peripheral T cell lymphoma in a patient following long-term nivolumab for advanced lung adenocarcinoma: A case report.

Thorac Cancer 2021 May 3. Epub 2021 May 3.

Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

A 54-year-old male smoker presented with hemoptysis. Advanced lung adenocarcinoma, cT1cN3M1b, stage IVB, was diagnosed. Enlargement of multiple intraperitoneal and inguinal lymph nodes and peripheral atypical lymphocytosis appeared after 33 cycles of second-line treatment with nivolumab, and a specimen obtained by left inguinal lymph node biopsy showed peripheral T cell lymphoma (PTCL), not otherwise specified. Lymphoma cells expressed CD3+, CD8+, and CD56+, but not CD4+ or PD-1. Despite systemic chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone, the patient died of PTCL 864 days after the initial visit. The possible relationship between treatment with immune checkpoint inhibitors (ICIs) and PTCL development is discussed here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13966DOI Listing
May 2021

Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.

Cancer Sci 2021 May 1. Epub 2021 May 1.

Division of Genetic Medicine, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Japan.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large-scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA-binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison to those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14919DOI Listing
May 2021

Identification and characterization of primary cilia-positive salivary gland tumours exhibiting basaloid/myoepithelial differentiation.

J Pathol 2021 Apr 30. Epub 2021 Apr 30.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Primary cilia (PC) are non-motile, antenna-like structures on the cell surface. Many types of neoplasms exhibit PC loss, whereas in some neoplasms PC are retained and involved in tumourigenesis. To elucidate the PC status and characteristics of major salivary gland tumours (SGTs), we examined 100 major SGTs encompassing eight histopathological types by immunohistochemical analysis. PC were present in all (100%) of the pleomorphic adenomas (PA), basal cell adenomas (BCA), adenoid cystic carcinomas (AdCC), and basal cell adenocarcinomas (BCAc) examined, but absent in all (0%) of the Warthin tumours, salivary duct carcinomas, mucoepidermoid carcinomas, and acinic cell carcinomas examined. PC were also detected by electron-microscopic analysis using the NanoSuit method. It is worthy of note that the former category and latter category of tumours contained and did not contain a basaloid/myoepithelial differentiation component, respectively. The four types of PC-positive SGTs showed longer PC than normal and exhibited a characteristic distribution pattern of the PC in the ductal and basaloid/neoplastic myoepithelial components. Two PC-positive carcinomas (AdCC and BCAc) still possessed PC in their recurrent/metastatic sites. Interestingly, activation of the Hedgehog signalling pathway, shown by predominantly nuclear GLI1 expression, was significantly more frequently observed in PC-positive SGTs. Finally, we identified tau tubulin kinase 2 (TTBK2) as being possibly involved in the production of PC in SGTs. Taken together, our findings indicate that SGTs that exhibit basaloid/myoepithelial differentiation (PA, BCA, AdCC, and BCAc) are ciliated, and their PC exhibit tumour-specific characteristics, are involved in activation of the hedgehog pathway, and are associated with TTBK2 upregulation, providing a significant and important link between SGT tumourigenesis and PC. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.5688DOI Listing
April 2021

Mass spectrometric profiling of DNA adducts in the human stomach associated with damage from environmental factors.

Genes Environ 2021 Apr 9;43(1):12. Epub 2021 Apr 9.

Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.

Background: A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. Only a few attempts toward this "DNA adductome approach" in human tissues have been reported. Geospatial information on DNA adducts in human organs has been scarce.

Aim: Mass spectrometry of human gastric mucosal DNA was performed to identify DNA adducts associated with environmental factors.

Materials And Methods: From 59 subjects who had received gastrectomy for gastric cancer, 306 samples of nontumor tissues and 15 samples of tumors (14 cases) were taken for DNA adductome analysis. Gastric nontumor tissue from autopsies of 7 subjects without gastric cancer (urothelial cancer, hepatocellular carcinoma, lung cancer each; the other four cases were without any cancers) was also investigated. Briefly, DNA was extracted from each sample with antioxidants, digested into nucleosides, separated by liquid chromatography, and then electrospray-ionized. Specific DNA adducts were identified by mass/charge number and column retention time compared to standards. Information on lifestyle factors such as tobacco smoking and alcohol drinking was taken from the clinical records of each subject.

Results: Seven DNA adducts, including modified bases, C5-methyl-2'-deoxycytidine, 2'-deoxyinosine, C5-hydroxymethyl-2'-deoxycytidine, N6-methyl-2'-deoxyadenosine, 1,N6-etheno-2'-deoxyadenosine, N6-hydroxymethyl-2'-deoxyadenosine, and C8-oxo-2'-deoxyguanosine, were identified in the human stomach and characterized. Intraindividual differences according to the multiple sites of these adducts were noted but were less substantial than interindividual differences. N6-hydroxymethyl-2'-deoxyadenosine was identified in the human stomach for the first time. The amount of C5-hydroxymethyl-2'-deoxycytidine was higher in the stomachs of subjects without gastric cancer than in the nontumor and tumor portions of the stomach in gastric cancer patients. Higher levels of 1,N6-etheno-2'-deoxyadenosine were detected in the subjects who reported both smoking and drinking than in those without these habits. These DNA adducts showed considerable correlations with each other.

Conclusions: We characterized 7 DNA adducts in the nontumor portion of the human stomach in both gastric cancer subjects and nongastric cancer subjects. A reduction in C5-hydroxymethyl-dC even in the nontumor mucosa of patients with gastric cancer was observed. Smoking and drinking habits significantly influenced the quantity of one of the lipid peroxidation-derived adducts, etheno-dA. A more expansive DNA adductome profile would provide a comprehensive understanding of the origin of human cancer in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s41021-021-00186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034090PMC
April 2021

Isolation of New Colibactin Metabolites from Wild-Type and Trapping of a Mature Colibactin Derivative.

J Am Chem Soc 2021 Apr 31;143(14):5526-5533. Epub 2021 Mar 31.

Adenoprevent Co., Ltd., Shizuoka 422-8526, Japan.

Colibactin is a polyketide-nonribosomal peptide hybrid secondary metabolite that can form interstrand cross-links in double-stranded DNA. Colibactin-producing has also been linked to colorectal oncogenesis. Thus, there is a strong interest in understanding the role colibactin may play in oncogenesis. Here, using the high-colibactin-producing wild-type strain we isolated from a clinical sample with the activity-based fluorescent probe we developed earlier, we were able to identify colibactin 770, which was recently identified and proposed as the complete form of colibactin, along with colibactin 788, 406, 416, 420, and 430 derived from colibactin 770 through structural rearrangements and solvolysis. Furthermore, we were able to trap the degrading mature colibactin species by converting the diketone moiety into quinoxaline in the crude culture extract to form colibactin 860 at milligram scale. This allowed us to determine the stereochemically complex structure of the rearranged form of an intact colibactin, colibactin 788, in detail. Furthermore, our study suggested that we were capturing only a few percent of the actual colibactin produced by the microbe, providing a crude quantitative insight into the inherent instability of this compound. Through the structural assignment of colibactins and their degradative products by the combination of LC-HRMS and NMR spectroscopies, we were able to elucidate further the fate of inherently unstable colibactin, which could help acquire a more complete picture of colibactin metabolism and identify key DNA adducts and biomarkers for diagnosing colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.1c01495DOI Listing
April 2021

Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing.

Clin Genet 2021 Feb 28. Epub 2021 Feb 28.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Whole-exome sequencing (WES) enables identification of pathogenic variants, including copy number variants (CNVs). In this study, we performed WES in 101 Japanese patients with unexplained developmental delay (DD) or intellectual disability (ID) (63 males and 38 females), 98 of them with trio-WES. Pathogenic variants were identified in 54 cases (53.5%), including four cases with pathogenic CNVs. In one case, a pathogenic variant was identified by reanalysis of exome data; and in two cases, two molecular diagnoses were identified. Among 58 pathogenic variants, 49 variants occurred de novo in 48 patients, including two somatic variants. The accompanying autism spectrum disorder and external ear anomalies were associated with detection of pathogenic variants with odds ratios of 11.88 (95% confidence interval [CI] 2.52-56.00) and 3.46 (95% CI 1.23-9.73), respectively. These findings revealed the importance of reanalysis of WES data and detection of CNVs and somatic variants in increasing the diagnostic yield for unexplained DD/ID. In addition, genetic testing is recommended when patients suffer from the autism spectrum disorder or external ear anomalies, which potentially suggests the involvement of genetic factors associated with gene expression regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13951DOI Listing
February 2021

Salivary Duct Carcinoma With Rhabdoid Features-No or Aberrant Expression of E-cadherin and Genetic Changes in CDH1: Immunohistochemical and Genetic Analyses of 17 Cases.

Am J Surg Pathol 2021 04;45(4):439-449

Department of Pathology, Shizuoka General Hospital, Shizuoka City.

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic β-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001672DOI Listing
April 2021

Erratum: Retraction notice to "Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability" [BBREP 16C (2018) 130-137].

Biochem Biophys Rep 2020 Dec 25;24:100799. Epub 2020 Sep 25.

Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.

[This corrects the article DOI: 10.1016/j.bbrep.2018.10.014.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrep.2020.100799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767794PMC
December 2020

Tuberous sclerosis patient with neuroendocrine carcinoma of the esophagogastric junction: A case report.

World J Gastroenterol 2020 Dec;26(45):7263-7271

First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Background: Tuberous sclerosis complex (TSC) is a rare inherited disease with non-cancerous tumor growths in the skin, brain, kidneys, heart, and lungs. The co-occurrence of neuroendocrine neoplasm (NEN) with TSC is even rarer. There have been few reports on the relationship between TSC and neuroendocrine tumors (NETs), and fewer on the relationship between TSC and neuroendocrine carcinoma (NEC), a subtype of NEN. This is the first reported case of NEC occurring at the esophagogastric junction in a patient with TSC.

Case Summary: A 46-year-old woman visiting our hospital for the treatment of TSC was admitted to the emergency department with tarry stools and dizziness. Computed tomography scans revealed thickness of the gastric cardia, multiple metastatic lesions of the liver, and enlarged lymph nodes near the lesser curvature of the stomach. Esophagogastroduodenoscopy revealed a type 3 tumor located from the esophagogastric junction to the fundus, and the pathological diagnosis by biopsy was NEC. The patient was treated with seven courses of cisplatin + irinotecan, followed by eight courses of ramucirumab + nab-paclitaxel, one course of nivolumab, and two courses of S-1 + oxaliplatin. Twenty-three months after the first treatment, the patient died because of disease progression and deterioration of the general condition.

Conclusion: This case of NEC occurring in a patient with TSC indicates a difference in the occurrence of NETs and NECs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3748/wjg.v26.i45.7263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723665PMC
December 2020

The first evidence for SLFN11 expression as an independent prognostic factor for patients with esophageal cancer after chemoradiotherapy.

BMC Cancer 2020 Nov 20;20(1):1123. Epub 2020 Nov 20.

Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: Schlafen 11 (SLFN11) was recently identified as a dominant determinant of sensitivity to DNA-targeting agents including platinum-based drugs. SLFN11 also reportedly enhances cellular radiosensitivity. In this study, we examined the prognostic value of SLFN11 expression in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT), including the platinum derivative nedaplatin.

Methods: Seventy-three patients with ESCC who received dCRT were examined. SLFN11 expression was analyzed in pre-dCRT biopsies using immunohistochemistry and evaluated using a histo-score (H-score). Correlation between the H-score and overall survival was analyzed. An H-score ≥ 51 was provisionally defined as indicating high SLFN11 expression. Viability assays were performed using previously established isogenic human cell lines differentially expressing SLFN11 to test the usefulness of SLFN11 as marker of response to the dCRT regimen.

Results: High SLFN11 expression was independently associated with better prognosis in ESCC patients (hazard ratio = 0.295, 95% CI = 0.143-0.605, p = 0.001 for multivariate analysis). Kaplan-Meier survival curves showed that the prognostic value of high SLFN11 expression was most evident in patients at clinical stages II and III (p = 0.004). In in vitro study, SLFN11-proficient cells were highly sensitive to platinum derivatives compared to SLFN11-deficient cells.

Conclusion: SLFN11 expression is an independent prognostic factor for ESCC patients treated with dCRT and a potential biomarker for treatment selection of ESCC. Examination of SLFN11 may be particularly useful for clinical Stage II-III patients who wish to choose dCRT (instead of surgery) to preserve esophageal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07574-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678160PMC
November 2020

Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non-small Cell Lung Cancer.

JAMA Netw Open 2020 09 1;3(9):e2011818. Epub 2020 Sep 1.

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Importance: Robust predictors for response to anti-programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non-small cell lung cancer (NSCLC) are not fully characterized.

Objective: To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC.

Design, Setting, And Participants: This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020.

Exposures: Sequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1.

Main Outcomes And Measures: Overall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status.

Results: A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less.

Conclusions And Relevance: In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. External validation with a larger sample size is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.11818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506518PMC
September 2020

Maspin subcellular expression in wild-type and mutant gastric cancers.

World J Gastrointest Oncol 2020 Jul;12(7):741-755

Intensive Care Unit, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania.

Background: Although the role of p53 in the evolution and prognosis of gastric cancer (GC) has been extensively examined, the exact mechanism of action is incompletely understood. In the last years, p53-target genes were supposed to be involved in the p53 pathway. One of them is the tumor-suppressor gene Maspin, which codifies the protein with the same name. Maspin activity depends on its subcellular localization. To our knowledge, the possible role of gene in Maspin subcellular localization, in GC cells, has not yet been studied in a large number of human samples.

Aim: To evaluate the possible role of wild-type and mutated p53 in Maspin subcellular localization.

Methods: The present study included 266 consecutive patients with GC in which gene status, and mutations in exons 2 to 11, respectively, were analyzed and correlated with immunohistochemical expression of p53 and Maspin.

Results: None of the 266 cases showed mutations in exon 9. The rate of mutations was 33.83%. The mutation rate was slightly higher in distally-located GCs, with a lower degree (≤ 5 buds/ high power fields) of dyscohesivity ( < 0.01). The wild-type cases had a longer survival, compared with mutant GCs, especially in patients without lymph node metastases, despite the high depth of tumor infiltration ( = 0.01). The Dukes-MAC-like staging system was proved to have the most significant independent prognostic value ( < 0.01). The statistical correlations proved that gene mutations in exon 7 might induce knockdown of Maspin, but wild-type p53 can partially restore nuclear Maspin expression and decrease the metastatic potential of gastric adenocarcinoma cells.

Conclusion: Downregulated Maspin might be induced by mutations in exon 7 of the gene but wild-type p53 can partially restore nuclear Maspin expression. These findings should be proved in experimental studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4251/wjgo.v12.i7.741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428795PMC
July 2020

Sphingomyelin(d35:1) as a novel predictor for lung adenocarcinoma recurrence after a radical surgery: a case-control study.

BMC Cancer 2020 Aug 24;20(1):800. Epub 2020 Aug 24.

First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.

Background: To improve the postoperative prognosis of patients with lung cancer, predicting the recurrence high-risk patients is needed for the efficient application of adjuvant chemotherapy. However, predicting lung cancer recurrence after a radical surgery is difficult even with conventional histopathological prognostic factors, thereby a novel predictor should be identified. As lipid metabolism alterations are known to contribute to cancer progression, we hypothesized that lung adenocarcinomas with high recurrence risk contain candidate lipid predictors. This study aimed to identify candidate lipid predictors for the recurrence of lung adenocarcinoma after a radical surgery.

Methods: Frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent a radical surgery were retrospectively reviewed. Recurrent and non-recurrent cases were assigned to recurrent (n = 10) and non-recurrent (n = 10) groups, respectively. Extracted lipids from frozen tissue samples were subjected to liquid chromatography-tandem mass spectrometry analysis. The average total lipid levels of the non-recurrent and recurrent groups were compared. Candidate predictors were screened by comparing the folding change and P-value of t-test in each lipid species between the recurrent and non-recurrent groups.

Results: The average total lipid level of the recurrent group was 1.65 times higher than that of the non-recurrent group (P < 0.05). A total of 203 lipid species were increased (folding change, ≥2; P < 0.05) and 4 lipid species were decreased (folding change, ≤0.5; P < 0.05) in the recurrent group. Among these candidates, increased sphingomyelin (SM)(d35:1) in the recurrent group was the most prominent candidate predictor, showing high performance of recurrence prediction (AUC, 9.1; sensitivity, 1.0; specificity, 0.8; accuracy, 0.9).

Conclusion: We propose SM(d35:1) as a novel candidate predictor for lung adenocarcinoma recurrence. Our finding can contribute to precise recurrence prediction and qualified postoperative therapeutic strategy for lung adenocarcinomas.

Trial Registration: This retrospective study was registered at the UMIN Clinical Trial Registry ( UMIN000039202 ) on 21st January 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07306-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446133PMC
August 2020

Microsatellite frameshift variants in of gastric cancer are not always associated with MSI status.

J Clin Pathol 2020 Aug 19. Epub 2020 Aug 19.

First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

Aims: Although frameshift variants in the microsatellite area of shugoshin 1 () have been reported in the context of microsatellite instability-high (MSI-H)/deficient mismatch repair gastrointestinal cancer, most have been evaluated only in early stage I-III patients, and only two of its five microsatellite regions have been evaluated. Therefore, we investigated the frequency and MSI status of microsatellite frameshift variants in gastric cancer cases, including stage IV.

Methods: In a total of 55 cases, 30 gastric cancer resection and 25 non-resection cases, DNA was extracted from both tumour and normal parts and PCR was performed. The variant was confirmed by TA cloning, and MSI was evaluated using GeneMapper software.

Results: A frameshift variant of c.973delA was observed in 16 of the 45 evaluable cases. Its frequency was 35.6%. Of the 25 cases that could be assessed for MSI status, two cases of MSI-H were associated with the c.973delA variant. However, c.973delA variant was also observed in four cases of microsatellite stable.

Conclusion: Our study shows that frameshift variants are not always associated with MSI status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-206934DOI Listing
August 2020

Genetic associations of single nucleotide polymorphisms in the l-DOPA receptor (GPR143) gene with severity of nicotine dependence in Japanese individuals, and attenuation of nicotine reinforcement in Gpr143 gene-deficient mice.

J Pharmacol Sci 2020 Oct 16;144(2):89-93. Epub 2020 Jul 16.

Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. Electronic address:

l-3,4-dihydroxyphenylalanine (l-DOPA) is a candidate neurotransmitter. l-DOPA is released by nicotine through nicotinic receptors. Recently, G-protein coupled receptor GPR143, was identified as a receptor for l-DOPA. In this study, genetic association studies between GPR143 genetic polymorphisms and smoking behaviors revealed that the single-nucleotide polymorphism rs6640499, in the GPR143 gene, was associated with traits of smoking behaviors in Japanese individuals. In Gpr143 gene-deficient mice, nicotine-induced hypolocomotion and rewarding effect were attenuated compared to those in wild-type mice. Our findings suggest the involvement of GPR143 in the smoking behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphs.2020.07.003DOI Listing
October 2020

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Lancet Oncol 2020 08;21(8):e386-e397

Department of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30219-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116190PMC
August 2020

Sporadic Multifocal Gastrinoma Mimicking a Duodenal GIST, in a Patient with MEN1 Gene Polymorphism D418D: an Unusual Case Report.

J Gastrointest Cancer 2021 Mar;52(1):351-354

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12029-020-00461-5DOI Listing
March 2021

Two independent families with strongly suspected hereditary diffuse gastric cancer based on the probands' endoscopic findings.

Clin J Gastroenterol 2020 Oct 27;13(5):754-758. Epub 2020 Jun 27.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Hereditary diffuse gastric cancer (HDGC) is the most famous of hereditary gastric cancer syndromes with an autosomal dominant inheritance pattern, and its diagnosis can be made by identifying a pathogenic germline variant in CDH1. We report two independent families that were strongly suspected of having HDGC based on endoscopic findings (multiple tiny, pale areas) obtained in the probands; the probands were pathologically diagnosed as having signet ring cell carcinoma (SRCC) and were genetically confirmed to have a pathogenic CDH1 germline variant. Although the updated International Gastric Cancer Linkage Consortium (IGCLC)'s clinical guidelines for HDGC (2015) state that screening/surveillance endoscopy should be performed (Cambridge protocol), the endoscopic findings obtained in the two presently reported families suggest that pale areas should be suspected as indicating the presence of SRCCs, and biopsies should be performed in addition to obtaining a precise family history in cases suspected of having HDGC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-020-01163-yDOI Listing
October 2020

Characterization of Colibactin-Producing Escherichia coli Isolated from Japanese Patients with Colorectal Cancer.

Jpn J Infect Dis 2020 Nov 29;73(6):437-442. Epub 2020 May 29.

Department of Pharmaceutical Sciences, University of Shizuoka, Japan.

We investigated the relationship between colibactin-producing (clb) Escherichia coli and colorectal adenocarcinoma. In total, 729 E. coli colonies were isolated from tumor and surrounding non-tumor regions in resected specimens from 34 Japanese patients; 450 colonies were from the tumor regions and 279 from the non-tumor regions. clb bacteria were found in tumor regions of 11 patients (11/34, 32.4%) and they were also detected in the non-tumor regions of 7 out of these 11 patients (7/34, 20.6%). The prevalence of clb isolates was 72.7% (327/450) and 44.1% (123/279) in tumor and non-tumor regions, respectively. All the recovered clb isolates belonged to the phylogenetic group B2 and were the most predominant type in tumor regions. Hemolytic (α-hemolysin-positive, hlyA) and non-hemolytic (α-hemolysin-negative, hlyA) clb isolates were obtained from patient #19; however, the prevalence of hlyA clb isolates was significantly higher in tumor regions (35/43, 81.4%) than in non-tumor regions (3/19, 15.8%). Moreover, a significantly higher production of N-myristoyl-D-asparagine, a by-product of colibactin biosynthesis, was observed in hlyA clb isolates than in hlyA clb isolates. Our results suggest that hlyA clb E. coli may have a selective advantage in colorectal colonization and, consequently, might play a role in carcinogenesis. The presence of hlyA clb bacteria in healthy individuals is a potential risk marker of colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7883/yoken.JJID.2020.066DOI Listing
November 2020

CD200 and CD200R1 are differentially expressed and have differential prognostic roles in non-small cell lung cancer.

Oncoimmunology 2020 7;9(1):1746554. Epub 2020 Apr 7.

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

CD200, a member of the immunoglobulin superfamily, interacts with its receptor CD200R1 to modulate cancer immune microenvironments. Here, we explored the clinicopathological and prognostic implications of the CD200/CD200R1 axis in non-small-cell lung cancer (NSCLC) patients. We evaluated CD200/CD200R1 expression in the tumors and stroma of 632 NSCLC patients using immunohistochemistry. Associations between CD200/CD200R1 expression levels and clinicopathological data were analyzed. We also examined their expression in lung cancer cell lines. Changes in endogenous immune-related factors and cell proliferation were evaluated by CD200 and CD200R1 knockdown and CD200Fc fusion protein administration. CD200 expression was observed mainly in the tumor, and also in the stroma among a few cases, whereas CD200R1 expression was observed in both the tumor and stroma. High tumoral CD200 expression was significantly associated with female sex, never-smoking status, adenocarcinoma histology, mutation, and a low density of tumor-infiltrating lymphocytes. Meanwhile, high CD200R1 expression in the tumor and stroma was associated with ever smoking, non-adenocarcinoma histology, and increased tumor-infiltrating lymphocytes. High CD200R1 expression was associated with worse survival (log-rank, <.001 for both tumor and stroma), whereas high CD200 expression was associated with better survival outcomes (log-rank, <.001). The transient knockdown of CD200R1 in lung cancer cell lines impaired cell proliferation, and the modulation of CD200 and CD200R1 altered endogenous oncogenic and inflammation-related gene expression. CD200R1 expression was associated with poor prognosis, whereas CD200 expression was an independent favorable prognostic factor. Our results suggest the importance of CD200 and CD200R1 in lung cancer biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1746554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204521PMC
April 2020

Leucine-Rich α-Glycoprotein as a Potential Biomarker for Immune-related Colitis After Anti-PD-L1 Therapy: A Report of a Case Series.

Clin Lung Cancer 2020 11 13;21(6):e516-e522. Epub 2020 Apr 13.

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2020.04.005DOI Listing
November 2020

Genotyping of a gene cluster for production of colibactin and in vitro genotoxicity analysis of strains obtained from the Japan Collection of Microorganisms.

Genes Environ 2020 11;42:12. Epub 2020 Mar 11.

2Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Introduction: Colibactin is a small genotoxic molecule produced by enteric bacteria, including certain () strains harbored in the human large intestine. This polyketide-peptide genotoxin is considered to contribute to the development of colorectal cancer. The colibactin-producing () microorganisms possess a 54-kilobase genomic island ( gene cluster). In the present study, to assess the distribution of the gene cluster, genotyping analysis was carried out among strains randomly chosen from the Japan Collection of Microorganisms, RIKEN BRC, Japan.

Findings: The analysis revealed that two of six strains possessed a gene cluster. These strains JCM5263 and JCM5491 induced genotoxicity in in vitro micronucleus (MN) tests using rodent CHO AA8 cells. Since the induction level of MN by JCM5263 was high, a bacterial test was carried out with a cell extract of the strain, revealing that the extract had SOS-inducing potency in the tester bacterium.

Conclusion: These results support the observations that the gene cluster is widely distributed in nature and having genotoxic potencies is not rare among microorganisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s41021-020-00149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065307PMC
March 2020

Elucidation of the relationships of MET protein expression and gene copy number status with PD-L1 expression and the immune microenvironment in non-small cell lung cancer.

Lung Cancer 2020 03 7;141:21-31. Epub 2020 Jan 7.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Objectives: Alterations in the MET gene, such as mutations and high-level amplification, are important drivers of non-small cell lung cancer (NSCLC). The efficacy of immune checkpoint inhibitors (ICIs) in lung cancer with MET abnormalities is unclear. We evaluate the potential relationship between MET alterations and the tumor immune microenvironment and PD-1/PD-L1 axis.

Material And Methods: MET and phospho-MET protein expression were assessed in 622 resected NSCLC specimens. MET amplification was assessed by fluorescence in-situ hybridization in 272 tumors. PD-L1 expression was evaluated by immunohistochemistry. CD8+, Foxp3+, CD45RO, and PD-1+ tumor-infiltrating lymphocytes (TILs) in the tumor nest and surrounding stroma were profiled. Associations with MET alterations were explored.

Results: The cohort comprised 425 male patients (68.3 %), 184 never-smokers (29.6 %), and 408 adenocarcinoma (ADC) patients (65.6 %). Median age was 68 years. MET alteration was observed mainly in ADCs (18.9 % MET-positive, 3.9 % phospho-MET-positive, and 15.1 % with MET amplification). PD-L1 expression was significantly increased in MET-altered ADCs (P < 0.001 for MET; P = 0.002 for phospho-MET; P = 0.019 for MET amplification). Most TIL subset numbers in the tumor nest were significantly increased in MET-altered tumors. Only MET amplification was independently associated with tumoral CD8 + TILs. Three of the six patients responded to ICI treatment; two of them showed MET overexpression and an increase in MET copy number.

Conclusion: MET-altered tumors showed significantly stronger PD-L1 expression and more abundant tumoral TILs than non-MET-altered tumors. Among the MET alterations assessed, MET amplification was particularly implicated in the inflamed microenvironment, suggesting that MET-amplified tumors might respond to ICIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.01.005DOI Listing
March 2020

Utility of Scanning Electron Microscopy Elemental Analysis Using the 'NanoSuit' Correlative Light and Electron Microscopy Method in the Diagnosis of Lanthanum Phosphate Deposition in the Esophagogastroduodenal Mucosa.

Diagnostics (Basel) 2019 Dec 18;10(1). Epub 2019 Dec 18.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

Background: We have recently developed the correlative light and electron microscopy of hematoxylin and eosin (H&E)-stained glass slides using the 'NanoSuit' method. The aim of this study is to explore the utility of the new NanoSuit-correlative light and electron microscopy method combined with scanning electron microscopy-energy dispersive X-ray spectroscopy elemental analysis for the diagnosis of lanthanum phosphate deposition in the H&E-stained glass slides.

Methods: Nine H&E-stained glass slides of the upper gastrointestinal tract mucosa containing the brown pigmented areas by light microscopic observation, which were suspected as lanthanum phosphate deposition, were observed and analyzed by scanning electron microscopy-energy dispersive X-ray spectroscopy using the NanoSuit-correlative light and electron microscopy method.

Results: In all nine slides, the new NanoSuit-correlative light and electron microscopy method combined with scanning electron microscopy-energy dispersive X-ray spectroscopy revealed the accumulation of both lanthanum and phosphorus in the tissue area corresponding to the brown pigment deposition. In addition to the existence of lanthanum phosphate in the stomach and duodenum, known target organs, we observed deposition in the esophagus for the first time. Furthermore, we observed lanthanum phosphate deposition in the background mucosa of stomach containing primary adenocarcinoma.

Conclusions: Scanning electron microscopy-energy dispersive X-ray spectroscopy analysis using the NanoSuit-correlative light and electron microscopy method is useful for the diagnosis of lanthanum phosphate deposition in the H&E-stained glass slides. Lanthanum phosphate deposition occurs not only in the stomach and duodenum but also in the esophagus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics10010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167806PMC
December 2019

In vitro genotoxicity analyses of colibactin-producing E. coli isolated from a Japanese colorectal cancer patient.

J Toxicol Sci 2019 ;44(12):871-876

Department of Pharmaceutical Sciences, University of Shizuoka.

Colibactin is a polyketide-peptide genotoxin produced by enteric bacteria such as E. coli, and is considered to contribute to the development of colorectal cancer. We previously isolated E. coli strains from Japanese colorectal cancer patients, and in the present study we investigated the genotoxic potency of the colibactin-producing (clb) E. coli strains that carry the polyketide synthases "pks" gene cluster (pks) and an isogenic clb mutant in which the colibactin-producing ability is impaired. Measurement of phosphorylated histone H2AX indicated that DNA double strand breaks were induced in mammalian CHO AA8 cells infected with the clb E. coli strains. Induction of DNA damage response (SOS response) by crude extract of the clb strains was 1.7 times higher than that of the clb E. coli in an umu assay with a Salmonella typhimurium TA1535/pSK1002 tester strain. Micronucleus test with CHO AA8 cells revealed that infection with the clb strains induced genotoxicity, i.e., the frequencies of micronucleated cells infected with clb strain were 4-6 times higher than with the clb strain. Since the intestinal flora are affected by dietary habits that are strongly associated with ethnicity, these data may contribute to both risk evaluation and prevention of colorectal cancer in the Japanese population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2131/jts.44.871DOI Listing
April 2020

The clinicopathological and prognostic significance of PD-L1 expression assessed by immunohistochemistry in lung cancer: a meta-analysis of 50 studies with 11,383 patients.

Transl Lung Cancer Res 2019 Aug;8(4):429-449

Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.

Background: We conducted a meta-analysis to systematically evaluate the relationship between programmed death-ligand 1 (PD-L1) expression and survival in patients with lung cancer.

Methods: The electronic databases PubMed, Embase, Cochrane, and Web of Science were searched up to January 2, 2018, for articles relating to PD-L1 expression detected by immunohistochemistry (IHC) and lung cancer patient prognosis.

Results: Fifty studies including 11,383 patients published between 2011 and 2017 were enrolled in this meta-analysis. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that PD-L1 IHC expression was related to poor overall survival (OS) (HR =1.45, 95% CI: 1.24-1.68). In subgroup analysis categorized according to sample type, cut-off value, ethnicity and TNM stage, the pooled results demonstrated inferior survival in the PD-L1 positive group when the PD-L1 expression was detected by resection specimens (P=0.000), 5% was taken as the cutoff value (P=0.000), the patients were in early stage (I-III) (P=0.000), and the geographic setting of the study was in Asia (P=0.000). Besides, patients with high PD-L1 expression had shorter OS in NSCLC (P=0.000), ADC (P=0.000), SCC (P=0.353) and LELC (P=0.810), while no significant difference was observed in SCLC (P=0.000). The pooled odds ratios (ORs) suggested that PD-L1 expression was associated with male (P<0.001), smoker (P<0.001), poor tumor differentiation (P=0.014), large tumor size (P=0.132), positive lymph nodal metastasis (P=0.002), wild-type status (P<0.001) and mutations (P=0.393). However, age (P=0.15) and rearrangements (P=0.567) had no bearing on PD-L1 expression.

Conclusions: PD-L1 expression that is associated with several clinicopathological feactures may serve as a poor prognostic biomarker for patients with lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr.2019.08.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749117PMC
August 2019

Simultaneous Occurrence of Sarcoidosis and Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis in a Patient with Lung Cancer.

Intern Med 2019 Nov 22;58(22):3299-3304. Epub 2019 Jul 22.

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Japan.

A 71-year-old woman with abnormal pulmonary shadows and multiple enlarged thoracic lymph nodes was diagnosed with stage IIB lung adenocarcinoma, pulmonary sarcoidosis, and sarcoidosis-associated lymphadenopathy after biopsies from multiple organ sites. She also had rapidly progressive renal dysfunction, microhematuria, and high myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) concentrations. A renal biopsy revealed granulomatous tubulointerstitial nephritis and necrotizing glomerulonephritis with crescent formation. She was diagnosed with nephritis caused by both sarcoidosis and ANCA-associated vasculitis. Oral prednisolone was administered to treat her nephritis, resulting in improvement in both her renal dysfunction and her sarcoidosis-associated lymphadenopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.3004-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911755PMC
November 2019

Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites.

Lung Cancer 2019 08 5;134:202-209. Epub 2019 Jun 5.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Objectives: Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages where small biopsy specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are sometimes the only available samples for diagnosis. We aimed to determine whether EBUS-TBNA specimens are suitable for the evaluation of PD-L1 protein expression and copy number alterations (CNAs).

Materials And Methods: PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Sixty-eight corresponding transbronchial biopsy (TBB) specimens from primary sites, thirteen resected primary tumors, and six resected metastases were comparatively analyzed. PD-L1 expression in tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cutoff. PD-L1 CNAs were assessed with fluorescent in situ hybridization and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens was calculated.

Results: The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS-TBNA and other specimens was moderate; κ = 0.63 for EBUS-TBNA vs. TBB, κ = 0.68 for EBUS-TBNA vs. resected primary tumors, and κ = 1.0 for EBUS-TBNA vs. resected metastases. The concordance of PD-L1 CNA status was comparable with that of PD-L1 expression: κ = 0.60 for EBUS-TBNA vs. TBB and κ = 0.74 for EBUS-TBNA vs. resected primary tumors. When PD-L1 copy number was assessed as a continuous variable, the correlation of PD-L1 CNAs was superior to that of PD-L1 expression. Intratumorally, PD-L1 copy number was less heterogeneous than protein expression in whole sections of resected tumors.

Conclusion: EBUS-TBNA specimens can be used to assess PD-L1 CNAs and protein expression. Although spatial heterogeneity should be considered for accurate interpretation, the evaluation of PD-L1 CNAs provides more reproducible results than that of protein expression levels especially with regard to intratumoral heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.06.002DOI Listing
August 2019

Activity-Based Probe for Screening of High-Colibactin Producers from Clinical Samples.

Org Lett 2019 06 13;21(12):4490-4494. Epub 2019 Jun 13.

Department of Pharmaceutical Sciences , University of Shizuoka , Shizuoka 422-8526 , Japan.

While high-colibactin-producing Escherichia coli is thought to be associated with colorectal oncogenesis, this study is complicated part due to an inability to isolate colibactin adequately. Here, we created fluorescent probes activated by ClbP, the colibactin-maturing peptidase, to identify high-colibactin-producing strains. Our probe served as a valuable clinical diagnostic tool that allowed simple high-throughput diagnostic screening of clinical samples. Furthermore, the probe also allowed identification of high-colibactin producers that would help advance our understanding of colibactin biosynthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.9b01345DOI Listing
June 2019

POLQ Overexpression Is Associated with an Increased Somatic Mutation Load and PLK4 Overexpression in Lung Adenocarcinoma.

Cancers (Basel) 2019 May 24;11(5). Epub 2019 May 24.

Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs). In the present study, we examined whether abnormal POLQ expression may be involved in the pathogenesis of lung adenocarcinoma (LAC). First, we found overexpression of POLQ at both the mRNA and protein levels in LAC, using data from the Cancer Genome Atlas (TCGA) database and by immunohistochemical analysis of our LAC series. POLQ overexpression was associated with an advanced pathologic stage and an increased total number of somatic mutations in LAC. When H1299 human lung cancer cell clones overexpressing POLQ were established and examined, the clones showed resistance to a DSB-inducing chemical in the clonogenic assay and an increased frequency of mutations in the forward mutation assay. Further analysis revealed that POLQ overexpression was also positively correlated with Polo Like Kinase 4 (PLK4) overexpression in LAC, and that PLK4 overexpression in the POLQ-overexpressing H1299 cells induced centrosome amplification. Finally, analysis of the TCGA data revealed that POLQ overexpression was associated with an increased somatic mutation load and PLK4 overexpression in diverse human cancers; on the other hand, overexpressions of nine TLS polymerases other than POLQ were associated with an increased somatic mutation load at a much lower frequency. Thus, POLQ overexpression is associated with advanced pathologic stage, increased somatic mutation load, and PLK4 overexpression, the last inducing centrosome amplification, in LAC, suggesting that POLQ overexpression is involved in the pathogenesis of LAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11050722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562496PMC
May 2019