Publications by authors named "Yoshinao Oda"

806 Publications

Tumor microenvironment in giant cell tumor of bone: evaluation of PD-L1 expression and SIRPα infiltration after denosumab treatment.

Sci Rep 2021 Jul 20;11(1):14821. Epub 2021 Jul 20.

Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα, FOXP3, and CD8 cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.
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http://dx.doi.org/10.1038/s41598-021-94022-wDOI Listing
July 2021

Effect of the 2013 ASCO-CAP HER2 Testing Guideline on the Management of IHC/HER2 2+ Invasive Breast Cancer.

Anticancer Res 2021 Aug;41(8):4143-4149

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background/aim: With advances in anti-HER2 treatment and improved prognoses of HER2-positive breast cancer, the American Society of Clinical Oncology and the American Society of Pathologists (ASCO/CAP) have revised the HER2 diagnostic guidelines several times. We examined how to respond clinically to the revisions of the interpretation of the immunohistochemistry (IHC) method.

Patients And Methods: We re-evaluated 254 patients diagnosed as HER2 IHC equivocal, who underwent fluorescence in situ hybridization (FISH) before and after the IHC diagnostic criteria update in 2013.

Results: Twenty of 131 (15.3%) IHC equivocal cases by the ASCO/CAP 2007 guideline were IHC score 3+ and one of 20 (0.76%) was negative for FISH. Five of 123 (4.1%) IHC equivocal cases by the ASCO/CAP 2013 guideline were negative for IHC as per the 2007 guideline and four were positive for FISH.

Conclusion: After revision of the ASCO/CAP 2013 guideline, 3.3% of HER2-negative cases before the revision should have received anti-HER2 treatment.
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http://dx.doi.org/10.21873/anticanres.15217DOI Listing
August 2021

Impact of Metabolic Activity in Hepatocellular Carcinoma: Association With Immune Status and Vascular Formation.

Hepatol Commun 2021 Jul 26;5(7):1278-1289. Epub 2021 Mar 26.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

We evaluated the prognostic value of fluorine-18 fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in hepatocellular carcinoma (HCC). Their association with programmed death ligand 1 (PD-L1) expression and vascular formation was further investigated. In this retrospective study, using a database of 418 patients who had undergone F-FDG PET/CT before hepatic resection for HCC, immunohistochemical staining of PD-L1, clusters of differentiation (CD) 8, CD68, and CD34 was performed. Patients with a high maximum standardized uptake value (SUVmax) on F-FDG PET/CT showed a significantly worse recurrence-free survival (RFS) (hazard ratio [HR]: 1.500; 95% confidence interval [CI]: 1.088-2.069;  = 0.0133) and overall survival (OS) (HR: 2.259; 95% CI: 1.276-4.000;  = 0.0052) than patients with a low SUVmax. Logistic regression analysis showed that a high SUVmax in HCC was significantly associated with PD-L1-positive expression (odds ratio: 4.407; 95% CI: 2.265-8.575;  < 0.0001). SUVmax values of HCC were associated with intratumoral CD8-positive T-cell counts ( = 0.0044) and CD68-positive macrophage counts ( = 0.0061). Stratification based on SUVmax, PD-L1 expression, and the vessels that encapsulate tumor clusters (VETC) status was also significantly associated with RFS and OS. SUVmax, VETC, and PDL1 expression were independently predictive of survival on multivariable analysis. Our large cohort study showed that a high SUVmax on F-FDG PET/CT is associated with a poor clinical outcome and PD-L1 expression in patients with HCC. Additionally, stratification of patients based on the combination of SUVmax, PD-L1 expression, and the VETC status predicts poor clinical outcome.
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http://dx.doi.org/10.1002/hep4.1715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279470PMC
July 2021

A case of primary orbital solitary fibrous tumor with lung metastases 41 years after initial treatment.

Orbit 2021 Jul 14:1-5. Epub 2021 Jul 14.

Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Here, we report a case of an orbital solitary fibrous tumor (SFT) with multiple local recurrences, even after orbital exenteration, and lung metastases after 41 years. The report discusses the clinical and histopathological findings of this case. A 34-year-old female patient with an orbital SFT was treated with orbital exenteration after local resection failed to prevent a recurrence. Ten years later, the patient underwent radiation therapy, followed by two rounds of gamma knife treatment, leading to remission. Forty-one years after the first treatment, the patient, at the age of 75 years, was found to have lung metastases along with orbital recurrence for the eighth time. The patient underwent radiation therapy but died from radiation pneumonitis. Our case emphasizes the need for long-term follow-up of patients with orbital tumors, even after orbital exenteration, to monitor for metastasis.
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http://dx.doi.org/10.1080/01676830.2021.1954665DOI Listing
July 2021

Lymphocyte-to-C-reactive protein ratio as a prognostic factor for hepatocellular carcinoma.

Int J Clin Oncol 2021 Jul 12. Epub 2021 Jul 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent resections for hepatocellular carcinoma (HCC).

Methods: We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation.

Results: LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8 T-cell counts than low LCR patients.

Conclusions: Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.
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http://dx.doi.org/10.1007/s10147-021-01985-xDOI Listing
July 2021

ASO Visual Abstract: Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Jul 6. Epub 2021 Jul 6.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.

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http://dx.doi.org/10.1245/s10434-021-10248-yDOI Listing
July 2021

Correction to: Expression of CD44 variant 9 induces chemoresistance of gastric cancer by controlling intracellular reactive oxygen spices accumulation.

Gastric Cancer 2021 Jul 5. Epub 2021 Jul 5.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

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http://dx.doi.org/10.1007/s10120-021-01205-5DOI Listing
July 2021

PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma.

Mod Pathol 2021 Jul 3. Epub 2021 Jul 3.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.
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http://dx.doi.org/10.1038/s41379-021-00868-wDOI Listing
July 2021

Neoantigens elicit T cell responses in breast cancer.

Sci Rep 2021 Jun 30;11(1):13590. Epub 2021 Jun 30.

Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Neoantigens are tumour-specific antigens that arise from non-synonymous mutations in tumour cells. However, their effect on immune responses in the tumour microenvironment remains unclear in breast cancer. We performed whole exome and RNA sequencing of 31 fresh breast cancer tissues and neoantigen prediction from non-synonymous single nucleotide variants (nsSNVs) among exonic mutations. Neoantigen profiles were determined by predictive HLA binding affinity (IC < 500 nM) and mRNA expression with a read count of ≥ 1. We evaluated the association between neoantigen load and expression levels of immune-related genes. Moreover, using primary tumour cells established from pleural fluid of a breast cancer patient with carcinomatous pleurisy, we induced cytotoxic T lymphocytes (CTLs) by coculturing neoantigen peptide-pulsed dendritic cells (DCs) with autologous peripheral lymphocytes. The functions of CTLs were examined by cytotoxicity and IFN-γ ELISpot assays. Neoantigen load ranged from 6 to 440 (mean, 95) and was positively correlated to the total number of nsSNVs. Although no associations between neoantigen load and mRNA expression of T cell markers were observed, the coculture of neoantigen-pulsed DCs and lymphocytes successfully induced CTLs ex vivo. These results suggest that neoantigen analysis may have utility in developing strategies to elicit T cell responses.
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http://dx.doi.org/10.1038/s41598-021-91358-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245657PMC
June 2021

Identification of SLC38A7 as a Prognostic Marker and Potential Therapeutic Target of Lung Squamous Cell Carcinoma.

Ann Surg 2021 Jun 18. Epub 2021 Jun 18.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan Department of Thoracic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, 810-8563, Japan. Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: No effective molecular targeted therapy has been established for squamous cell lung cancer (SCC). We conducted a comprehensive study of SCC patients using RNA-sequencing and The Cancer Genome Atlas (TCGA) dataset in order to clarify the driver oncogene of SCC.

Method: Forty-six samples of 23 patients were totally analyzed with RNA-sequencing. We then searched for candidate-oncogenes of SCC using the TCGA database. To identify candidate oncogenes, we used the following two criteria: 1) the genes of interest were overexpressed in tumor tissues of SCC patients in comparison to normal tissues; and 2) using an integrated mRNA expression and DNA copy number profiling analysis using the TCGA dataset, the DNA copy number of the genes was positively correlated with the mRNA expression.

Result: We identified 188 candidate-oncogenes. Among those, the high expression of SLC38A7 was a strong prognostic marker that was significantly associated with a poor prognosis in terms of both overall survival (OS) and recurrence-free survival in the TCGA dataset (p < 0.05). Additionally, 202 resected SCC specimens were also subjected to an immunohistochemical analysis. Patients with the high expression of SLC38A7 (alternative name is SNAT7) protein showed significantly shorter OS in comparison to those with the low expression of SLC38A7 protein (median OS 3.9 years [95% CI, 2.4-6.4 years] vs. 2.2 years [95% CI, 1.9-4.1 years]; log rank test: p = 0.0021).

Conclusion: SLC38A7, which is the primary lysosomal glutamine transporter required for the extracellular protein-dependent growth of cancer cells, was identified as a candidate therapeutic target of SCC.
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http://dx.doi.org/10.1097/SLA.0000000000005001DOI Listing
June 2021

Programmed Death-Ligand 1 Expression and Tumor-Infiltrating Lymphocytes in Temporal Bone Squamous Cell Carcinoma.

Laryngoscope 2021 Jun 18. Epub 2021 Jun 18.

Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objectives/hypothesis: The tumor immune microenvironment in temporal bone squamous cell carcinoma (TBSCC), including the programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs), has not been established.

Study Design: Retrospective cohort study.

Methods: We performed immunohistochemistry analyses to retrospectively analyze 123 TBSCC cases for PD-L1 expression and TILs and their prognostic significance. We also evaluated the prognostic correlations between these immunomarkers and the therapeutic responses to chemoradiotherapy (CRT).

Results: PD-L1 expression (≥1%) was detected in 62 (50.4%) TBSCC cases and was significantly associated with worse prognosis: progression-free survival (PFS), P < .0001; overall survival (OS), P = .0009. A high density of CD8 TILs was significantly associated with better prognosis (PFS, P = .0012; OS, P = .0120). In contrast, a high density of Foxp3 TILs tended to be associated with an unfavorable prognosis (PFS, P = .0148; OS, P = .0850). With regard to the tumor microenvironment subtypes defined by CD8 TILs and PD-L1 expression, the CD8 /PD-L1 group showed significantly worse prognosis. Among the 36 neoadjuvant CRT-treated cases, PD-L1 expression was significantly associated with worse OS (P = .0132). Among the 32 CRT-treated cases without surgery, a high density of CD8 TILs tended to be more highly associated with complete response to CRT compared to a low density of CD8 TILs (P = .0702).

Conclusions: These results indicate that the evaluation of the tumor immune microenvironment may contribute to the prediction of prognoses and the selection of an individualized therapeutic strategy for patients with TBSCC.

Level Of Evidence: 4 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29689DOI Listing
June 2021

Lymphocyte-C-reactive protein ratio as a prognostic marker associated with the tumor immune microenvironment in intrahepatic cholangiocarcinoma.

Int J Clin Oncol 2021 Jun 12. Epub 2021 Jun 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Background: Changes in immune cell and inflammation-associated protein levels, either independently or in combination, are commonly used as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of LCR and its relationship to various aspects of the tumor immune microenvironment in patients with intrahepatic cholangiocarcinoma (ICC).

Methods: This was a single-center, retrospective study of patients who underwent surgical resection for ICC between 1998 and 2018. Patients were dichotomized into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. Tumor-infiltrating CD8+ and FOXP3s+ lymphocytes and tumor expression of CD34 and programmed death-ligand 1 were evaluated by immunohistochemical staining of resected tumors.

Results: A total of 78 ICC patients were enrolled and assigned to the high (n = 44)- and low (n = 34)-LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly higher serum CA19-9 level (median 20.6 vs. 77.3 U/mL, P = 0.0017) and larger tumor size (median 3.5 vs. 5.5 cm, P = 0.0018). LCR correlated significantly with tumor microvessel density (r = 0.369, P = 0.0009) and CD8+ T lymphocyte infiltration (r = 0.377, P = 0.0007) but not with FOXP3+ T lymphocyte infiltration or tumor PD-L1 expression. Low-LCR status was significantly associated with worse overall survival by multivariate analysis (P = 0.0348).

Conclusions: Low-LCR status may reflect a poor anti-tumor immune response and predict worse outcomes in ICC patients.
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http://dx.doi.org/10.1007/s10147-021-01962-4DOI Listing
June 2021

Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Jun 5. Epub 2021 Jun 5.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our goal was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME).

Methods: Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients' clinicopathological factors.

Results: A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P < 0.001), more numbers of tumors (P = 0.003), higher α-fetoprotein levels (P = 0.001), higher des-γ-carboxy prothrombin levels (P = 0.022), microvascular invasion (P < 0.001), and poor differentiation (P = 0.010). Overall survival (OS) of patients with VETC was significantly lower than those with VETC (P = 0.021; 5-year OS rates, 72.0% vs. 87.1%). Furthermore, the ratio of CD3 cells was significantly lower in VETC group (P = 0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC/CD3 was an independent risk factor for mortality (hazard ratio 2.760, 95% confidence interval 1.183-6.439, P = 0.019). Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome.

Conclusions: Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.
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http://dx.doi.org/10.1245/s10434-021-10209-5DOI Listing
June 2021

Quantification of HER family dimers by proximity ligation assay and its clinical evaluation in non-small cell lung cancer patients treated with osimertinib.

Lung Cancer 2021 Aug 25;158:156-161. Epub 2021 May 25.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objectives: The epidermal growth factor receptor (EGFR, also known as Her1) is a member of the human epidermal growth factor receptor (HER) family of proteins and a target of tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) positive for activating mutations ofEGFR. Signal transduction by HER family proteins is dependent on their homo- or heterodimerization, but little is known of the relation between the relative proportions of such dimers of Her1 and sensitivity to EGFR-TKIs. We here investigated the feasibility of assessing this relation with the in situ proximity ligation assay (PLA) technique, which is able to detect the interaction of two proteins of interest when they are in close proximity.

Materials And Methods: In situ PLA was applied to detect Her1 homodimers and Her1 heterodimers in NSCLC cell lines and tissue specimens positive for EGFR activating mutations.

Results: In situ PLA allowed visualization and quantitative assessment of Her1 homodimers as well as of Her1 heterodimers with Her2, Her3, or Her4 not only in NSCLC cell lines but also in NSCLC tissue specimens obtained from various anatomic sites and by different collection methods. Treatment of NSCLC cell lines with EGFR-TKIs resulted in a decrease in the number of Her1 dimers, with the effect on homodimers being greater than that on heterodimers. A high ratio of Her1 heterodimers to homodimers was associated with poor progression-free survival in NSCLC patients treated with osimertinib.

Conclusion: In situ PLA allows the detection of HER family dimers in NSCLC tissue, and quantitative assessment of Her1 homo- and heterodimers may prove informative for prediction of the response of NSCLC patients to EGFR-TKI treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.023DOI Listing
August 2021

The effects of ARID1A mutations on colorectal cancer and associations with PD-L1 expression by stromal cells.

Cancer Rep (Hoboken) 2021 May 27:e1420. Epub 2021 May 27.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro.

Aim: To clarify the role of ARID1A mutation in CRC.

Method And Results: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS).

Conclusion: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.
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http://dx.doi.org/10.1002/cnr2.1420DOI Listing
May 2021

Clinical significance of signal regulatory protein alpha (SIRPα) expression in esophageal squamous cell carcinoma.

Cancer Sci 2021 May 19. Epub 2021 May 19.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47-SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death-ligand 1 (PD-L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8 T cells, and PD-L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD-L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD-1-PD-L1 blockade.
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http://dx.doi.org/10.1111/cas.14971DOI Listing
May 2021

Prognostic implications of the coexisting precursor lesion types in invasive gallbladder cancer.

Hum Pathol 2021 May 11;114:44-53. Epub 2021 May 11.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P < 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.
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http://dx.doi.org/10.1016/j.humpath.2021.05.001DOI Listing
May 2021

Endometrial endometrioid carcinoma, grade 1, is more aggressive in the elderly than in the young.

Histopathology 2021 May 13. Epub 2021 May 13.

Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims: The aim of this study was to characterise grade 1 (G1) endometrioid carcinoma in the elderly, by using clinicopathological features and immunohistochemical features of surrogate markers of molecular subtypes.

Methods And Results: We retrospectively analysed tumour samples from 268 patients with G1 endometrioid carcinoma (<40 years, n = 24; 40-59 years, n = 169; ≥60 years, n = 75) for whom long-term clinical follow-up data were available. G1 endometrioid carcinoma in the elderly (≥60 years) was characterised by frequent deep myometrial invasion, less frequent endometrioid intraepithelial neoplasia (EIN), lack of benign hyperplasia (BH), less frequent squamous differentiation, and occasional aberrant p53 expression. In contrast, this condition in the young (<40 years) was characterised by frequent EIN, BH, and squamous differentiation. Univariate analysis revealed that elderly status (≥60 years), International Federation of Obstetrics and Gynecology (FIGO) 2009 stage and aberrant p53 expression were significantly associated with shorter progression-free survival, and multivariate analysis revealed that elderly status and FIGO 2009 stage were independently associated with a poor prognosis.

Conclusions: G1 endometrioid carcinoma in the elderly is more aggressive than that in the young, and elderly status is an independent predictor of shorter progression-free survival in this condition. We propose that type 1 tumours can be subdivided into type 1a (young age at onset and indolent) and type 1b (old age at onset and relatively aggressive).
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http://dx.doi.org/10.1111/his.14400DOI Listing
May 2021

Histological background of dedifferentiated solitary fibrous tumour.

J Clin Pathol 2021 May 11. Epub 2021 May 11.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs.

Methods: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed.

Results: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%).

Conclusions: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.
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http://dx.doi.org/10.1136/jclinpath-2020-207311DOI Listing
May 2021

Expression of CD44 variant 9 induces chemoresistance of gastric cancer by controlling intracellular reactive oxygen spices accumulation.

Gastric Cancer 2021 May 8. Epub 2021 May 8.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: CD44 variant 9 (CD44v9) has been reported to suppress reactive oxygen spices (ROS) in association with antioxidant factors such as glutathione (GSH) and glutathione peroxidase 2 (GPx2), resulting in promoted tumor growth.

Methods: CD44v9 and GPx2 expression were investigated by immunohistochemistry in resected specimens from 193 gastric cancer (GC) patients without preoperative chemotherapy and in pretreatment biopsy specimens from 29 GC patients with preoperative chemotherapy. We analyzed the relationship between CD44v9 expression and clinicopathological factors, prognosis, and pathological response to chemotherapy. In GC cell lines, we examined the relationship between CD44v9 expression and chemotherapeutic sensitivity.

Results: In patients without preoperative chemotherapy, CD44v9 expression was significantly associated with depth of invasion, lymphatic permeation, vascular invasion, distant metastasis and GPx2 expression. In multivariate analysis, CD44v9 expression was an independent poor prognosis factor for overall survival and recurrence-free survival. In patients with preoperative chemotherapy, CD44v9 expression was significantly associated with worse pathological response and GPx2 expression. In GC cell lines, downregulation of CD44v9 expression enhanced chemotherapeutic sensitivity to 5-fluorouracil with changing GSH and ROS levels.

Conclusions: CD44v9-positive expression was associated with chemotherapeutic resistance by controlling intracellular accumulated ROS, suggesting that CD44v9 may be a predictive biomarker for chemotherapy in GC.
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http://dx.doi.org/10.1007/s10120-021-01194-5DOI Listing
May 2021

Myxoepithelioid tumour with chordoid features: a clinicopathological, immunohistochemical and genetic study of 14 cases of SMARCB1/INI1-deficient soft-tissue neoplasm.

Histopathology 2021 May 1. Epub 2021 May 1.

Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity.

Methods And Results: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases.

Conclusion: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours.
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http://dx.doi.org/10.1111/his.14393DOI Listing
May 2021

A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy.

Sci Rep 2021 Apr 19;11(1):8454. Epub 2021 Apr 19.

Department of Pathology, Kurume University School of Medicine, Kurume, 830-0011, Japan.

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.
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http://dx.doi.org/10.1038/s41598-021-87748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055968PMC
April 2021

Serum NT-proBNP levels and histopathological myocardial fibrosis in autopsied cases from a Japanese community: The Hisayama Study.

J Cardiol 2021 Apr 13. Epub 2021 Apr 13.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Background: natriuretic peptide is associated with myocardial fibrosis in animal models and among patients with heart disease. However, it remains unclear whether serum N-terminal pro-B-type peptide (NT-proBNP) levels are associated with histopathologically proven myocardial fibrosis among individuals without apparent heart disease. This study aimed to evaluate the association between serum NT-proBNP levels and the histopathologically estimated myocardial fibrotic area in autopsied samples from a community.

Methods: we selected 63 cases without apparent heart disease with available data of serum NT-proBNP concentrations within six years before death (average age: 82 years; male: 52%) from autopsied cases in a community, and evaluated the percentage areas of myocardial fibrosis in four cardiac segments from each case (i.e. 252 cardiac segments in total). The association between serum NT-proBNP levels and the percentage area of myocardial fibrosis was estimated using a linear mixed model for repeated measures.

Results: serum NT-proBNP levels were positively correlated with myocardial fibrotic area [Pearson's correlation coefficient: r = 0.49 (95% confidence interval: 0.28-0.66), p <0.001]. Serum NT-proBNP levels were significantly associated with the percentage areas of myocardial fibrosis after adjusting for potential confounding factors. There was no evidence of heterogeneity in the association between the subgroups with and without reduced estimated glomerular filtration rate (<60 mL/min/1.73 m).

Conclusions: the present study demonstrated that elevated serum NT-proBNP levels were associated with the histopathologically measured myocardial fibrotic area in autopsied cases from a community. These findings may help clarify the association between elevated serum NT-proBNP levels and myocardial fibrosis and their influence on prognosis.
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http://dx.doi.org/10.1016/j.jjcc.2021.03.014DOI Listing
April 2021

ARID1A Deficiency Is Associated With High Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma.

Hepatol Commun 2021 Apr 30;5(4):675-688. Epub 2020 Dec 30.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy.
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http://dx.doi.org/10.1002/hep4.1659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034578PMC
April 2021

Morphological, immunohistochemical, and genomic analyses of papillary renal neoplasm with reverse polarity.

Hum Pathol 2021 Jun 1;112:48-58. Epub 2021 Apr 1.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently proposed entity of renal tumor. It shows a far better prognosis than papillary renal cell carcinoma (PRCC) and frequently has KRAS missense mutation. In this study, we compared 14 cases of PRNRP and 10 cases of PRCC type 1 (PRCC1) and type 2 (PRCC2) from clinical, morphological, immunohistochemical, and molecular biological perspectives. We subjected all PRNRP and PRCC cases to immunohistochemical analysis. Whole-exome sequencing using next-generation sequencing (NGS) was performed for six cases of PRNRP, three cases of PRCC1, and four cases of PRCC2. A search for KRAS gene mutation in the remaining eight cases of PRNRP was performed by polymerase chain reaction (PCR) sequencing. The results showed that all cases of PRNRP were pT1N0M0, none of which followed a course of recurrence or tumor-related death. Immunohistochemical analysis revealed diffuse staining of CK7, EMA, PAX8, and GATA3 but weak or negative staining of CD10, CD15, and AMACR in PRNRP. By NGS and PCR, KRAS missense mutation was detected in 11 of 14 PRNRP cases, although pathogenic KRAS mutation was not observed in PRCC1 and PRCC2. NGS analysis revealed less tumor mutation burden in PRNRP than in PRCC. PRNRP also showed no specific chromosomal copy number abnormalities, including gains of 7 and 17. In conclusion, we propose that PRNRP is a distinct condition from PRCC.
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http://dx.doi.org/10.1016/j.humpath.2021.03.009DOI Listing
June 2021

The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma.

J Cancer Res Clin Oncol 2021 Jul 3;147(7):2003-2011. Epub 2021 Apr 3.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease.

Materials And Methods: Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data.

Results: TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival.

Conclusions: UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.
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http://dx.doi.org/10.1007/s00432-021-03616-4DOI Listing
July 2021

Nectin Cell Adhesion Molecule 4 (NECTIN4) Expression in Cutaneous Squamous Cell Carcinoma: A New Therapeutic Target?

Biomedicines 2021 Mar 30;9(4). Epub 2021 Mar 30.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is rising because of the aging population. Nectin cell adhesion molecule 4 (NECTIN4) is involved in the progression of tumors and has attracted interest as a potential therapeutic target. However, little is known about the expression and significance of NECTIN4 in cSCC. The aim of this study was to determine the expression and function of NECTIN4 in cSCC. Immunohistological NECTIN4 expression was investigated in tissues from 34 cSCC patients. Using an A431 human SCC cell line, the role of NECTIN4 in the regulation of cell-cell attachment and migration and proliferation was assessed. NECTIN4 was expressed in most cSCC tissues and on the plasma membrane of A431 cells. Silencing of NECTIN4 prevented cell-cell attachment and induced the expression migration-related molecules, leading to an increase in cell migration. Knockdown of NECTIN4 downregulated extracellular signal-regulated kinase signaling, decreased cyclin D1 expression, and inhibited cell proliferation. These results show that NECTIN4 is expressed in cSCC and functions in the regulation of cell-cell interactions, as well as in the migration and proliferation of SCC cells. NECTIN4-targeted therapy may serve as a novel and promising treatment for cSCC.
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http://dx.doi.org/10.3390/biomedicines9040355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067104PMC
March 2021

Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy: a case report.

Int Cancer Conf J 2021 Apr 3;10(2):96-99. Epub 2021 Jan 3.

Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan.

Salvage radical prostatectomy is a therapeutic option for the biochemical recurrence of prostate cancer after radiotherapy. However, only one case report of salvage radical prostatectomy after carbon ion radiotherapy has been reported. We report a case of salvage robot-assisted radical prostatectomy for local recurrence of prostate cancer after carbon ion radiotherapy with surgical video. Owing to adhesion and degeneration after radiotherapy, difficulties in surgery and post-operative complications have been anticipated. However, surgery was feasible without severe peri- and post-operative complications. Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy may be a reasonable therapeutic option.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-020-00464-w.
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http://dx.doi.org/10.1007/s13691-020-00464-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947102PMC
April 2021

Cytolytic activity score as a biomarker for antitumor immunity and clinical outcome in patients with gastric cancer.

Cancer Med 2021 05 26;10(9):3129-3138. Epub 2021 Mar 26.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients.

Materials And Methods: We evaluated the correlations between tumor-infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)-quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti-PD-1 therapy in 7 GC samples from Kyushu University Hospital.

Results: The CYT score positively correlated with the proportions of tumor-infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein-Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti-PD-1 therapy compared to nonresponders.

Conclusion: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients.
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http://dx.doi.org/10.1002/cam4.3828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085935PMC
May 2021

Brachyury expression in intracranial SMARCB1-deficient tumors: important points for distinguishing poorly differentiated chordoma from atypical teratoid/rhabdoid tumor.

Hum Pathol 2021 Jun 17;112:1-8. Epub 2021 Mar 17.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.
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http://dx.doi.org/10.1016/j.humpath.2021.03.001DOI Listing
June 2021