Soo Jeong Nam

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1+ and CD8+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P<0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P=0.006), smokers (P=0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P<0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P=0.054) and expression of EGFR and MET (P<0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P=0.052), and expression of MET (P<0.001) and ERBB2 (P=0.013). The numbers of CD8+ and programmed cell death-1+ lymphocytes were higher in smokers (P=0.012 and 0.016) and MET-expressing adenocarcinomas (P<0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1+/CD8+ lymphocytes showed shorter disease-free survival (P=0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

Abstract Tumor-associated macrophages (TAMs) and regulatory T-cells (Tregs) play an important role in the tumor microenvironment. Here, we investigated the prognostic implications of TAMs and Tregs in 165 diffuse large B-cell lymphomas (DLBCLs) using immunohistochemistry. Survival analysis was performed among 109 DLBCLs treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). An increase in CD68 (+) cells was related to improved overall survival (OS) (p = 0.033). By contrast, an increased number of CD163 (+) cells and a higher ratio of CD163/CD68 (+) cells were significantly associated with shorter OS (p = 0.041 and 0.003) and progression-free survival (PFS) (p < 0.001 and 0.002). Patients with increased Tregs tended to have a better prognosis. In multivariate analysis, an increased ratio of CD163/CD68 (+) cells was an independent predictor of shorter OS and PFS. These results suggest that M2 macrophages might have a lymphoma-promoting function in DLBCL and predict poor clinical outcome. Therapeutic approaches targeting M2 macrophages would be valuable for the management of DLBCL in the R era.

Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma according to treatment modalities

Abstract Extranodal natural killer/T-cell lymphoma (NKTCL) has aggressive behaviors and poor clinical outcomes. A monomethyl auristatin E-conjugated anti-CD30 antibody (brentuximab vedotin) was recently introduced to treat CD30-positive lymphomas. Thus we investigated the clinicopathological features and prognostic implications of CD30 expression in 72 patients with NKTCL. CD30-positive cases, defined as cases with CD30 expression in more than 1%, 5% and 25% of tumor cells as cut-off values (COVs), accounted for 40 (56%), 27 (38%) and 16 (22%) cases of NKTCL, respectively. CD30 expression was significantly higher in large/anaplastic cell-predominant NKTCL than in small/medium cell-predominant cases. CD30-positive NKTCL showed better responses to non-anthracycline-based therapy. CD30-positive NKTCL with COV of 25% showed a lower rate of relapse. Moreover, in patients treated with non-anthracycline-based chemotherapy, CD30 positivity with COV of 5% was significantly and independently associated with longer overall survival. CD30 may be useful as a prognostic factor and therapeutic target in NKTCL.

MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma.

We aimed to investigate MYC expression and chromosomal aberration in mantle cell lymphoma (MCL), and the clinical significance of these factors.

Decreased PBRM1 expression predicts unfavorable prognosis in patients with clear cell renal cell carcinoma

AIMS PBRM1 is one of the histone and chromatin regulators. A mutation in PBRM1 was recently identified in clear cell renal cell carcinoma (ccRCC). The aim of this study was to determine the clinicopathologic and prognostic significance of PBRM1 expression in ccRCC. METHODS AND RESULTS Immunohistochemistry was performed for PBRM1 in 657 ccRCC cases. The number of positive cells was determined using image analyzer after virtual microscope scanning. There was a strong correlation between decreased PBRM1 expression and old age, increased tumor size, higher Fuhrman grade, higher pT stage, and higher stage (all P <0.001). Patients with decreased PBRM1 expression showed significantly worse cancer-specific survival (CSS) and progression-free survival (PFS) (both P<0.001). In multivariate analysis, PBRM1 expression was an independent predictor of shorter PFS (P = 0.007). In lower-stage group (stages I and II), decreased expression of PBRM1 exhibited significantly worse CSS and PFS (both P<0.001) but not in higher-stage group (stages III and IV). In multivariate analysis of lower-stage group, decreased expression of PBRM1 was significantly associated with both poor CSS and PFS (P = 0.038 and 0.003, respectively). CONCLUSIONS Decreased expression of PBRM1 predicts unfavorable clinical outcome in patients with ccRCC.

Expression of the promyelocytic leukemia zinc-finger in T-lymphoblastic lymphoma and leukemia has strong implications for their cellular origin and greater association with initial bone marrow involvement

The promyelocytic leukemia zinc-finger (PLZF) is essential for the development of innate T cells (as represented by natural killer T cells) for acquisition of their unique innate immune properties. We evaluated the PLZF protein expression in a variety of immature and mature lymphoid malignancies. PLZF was preferentially expressed in T-lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) in 50% of the 54 cases. Among 51 cases of peripheral T-cell lymphoma not otherwise specified, only one (2%) expressed PLZF. One mycosis fungoides case expressed PLZF in lymph node involved by tumor. Otherwise, PLZF was not detected in any other type of lymphoma. In T-LBL/ALL, PLZF expression was more common in CD4/CD8 double-negative (67%) or CD8 single-positive subtypes (73%) than in CD4/CD8 double-positive (13%) and CD4 single-positive subtypes (0%) (P=0.001). Importantly, PLZF and CD1a expression were mutually exclusive in T-LBL/ALL (P=0.001). This was also the case for T-cell receptor βF1 expression (P=0.000). Most (96%) of the PLZF-positive T-LBL/ALL cases showed initial bone marrow involvement compared with 39% of PLZF-negative cases (P=0.000). Based on these findings, we suggest that T-LBL/ALLs that express PLZF arise from early immature double-negative thymocytes when the T-cell receptor β chain has not yet expressed or innate T-cell precursors, and strongly imply bone marrow involvement.

Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non–Small Cell Lung Cancer

EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy has achieved favorable clinical outcomes in non–small cell lung cancer (NSCLC) patients with EGFR mutations. However, patients eventually develop resistance to EGFR-TKIs by several mechanisms. Adenine nucleotide translocase-2 (ANT2) is an oncogenic mitochondrial membrane–associated protein. We investigated the therapeutic potential of ANT2 inhibition to EGFR-TKI resistance in NSCLC using gefitinib-sensitive (PC9 and HCC827) and gefitinib-resistant (H1975 and HCC827/GR) NSCLC cell lines. ANT2 was inhibited by transfecting cells with an ANT2-specific shRNA. ANT2 expression was elevated in the H1975 and HCC827/GR cells compared with the PC9 and HCC827 cells. ANT2 upregulation in gefitinib-resistant cells was associated with increased SP1 binding to the ANT2 promoter. ANT2-specific shRNA decreased NSCLC cell viability. Moreover, ANT2-specific shRNA sensitized the H1975 and HCC827/GR cells to gefitinib, accompanied by HSP90 and EGFR downregulation. ANT2-specific shRNA also inactivated the PI3K/Akt signaling pathway in the H1975 and HCC827/GR cells, which was mediated by the suppression of miR-221/222 levels and by the subsequent restoration of PTEN. In EGFR-TKI–treated NSCLC patients, ANT2 expression was higher in patients exhibiting poor responses compared with patients showing excellent responses. Furthermore, ANT2 expression increased in tumor tissues biopsied after acquiring gefitinib resistance compared with tissues before gefitinib treatment. These findings suggest that ANT2 overexpression contributes to EGFR-TKI resistance in NSCLC and that ANT2 targeting may be considered a novel strategy for overcoming this resistance. Mol Cancer Ther; 15(6); 1387–96. ©2016 AACR.

An increase in indoleamine 2,3-dioxygenase-positive cells in the tumor microenvironment predicts favorable prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone

Soo Jeong Nam, Sehui Kim, Jin Ho Paik, Tae Min Kim, Dae Seog Heo, Chul Woo Kim and Yoon Kyung Jeon Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; The Tumor Immunity Medical Research Center, Cancer Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University Bundang Hospital, Seongnam-Si, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

VEGF and Ki-67 Overexpression in Predicting Poor Overall Survival in Adenoid Cystic Carcinoma

Purpose The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). Materials and Methods A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS). Results In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. Conclusion High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.

Aberrant expression of napsin A in a subset of malignant lymphomas.

BACKGROUND Napsin A is commonly expressed in pulmonary adenocarcinomas and some renal cell carcinomas. However, napsin A expression in lymphoid neoplasms has never been reported. METHODS Glycoproteomic analyses of lymphoma-derived cell lines revealed napsin A expression in anaplastic large cell lymphoma (ALCL) cells. We thus investigated napsin A expression in lymphoid neoplasms. A variety of lymphomas (n=672) and histiocytic tumors (n=55) was immunostained for napsin A using patient tissues. RESULTS In reactive lymphoid tissues, only a few histiocytes were positive for napsin A. ALK-positive ALCLs most frequently expressed napsin A (34.4%, 11/32 cases) at a rate that was significantly higher compared with ALK-negative ALCL (8.6%, 3/35; P=0.015). Napsin A expression was also observed in 13.4% (20/149) of diffuse large B-cell lymphomas (DLBCL), 11.1% (15/134) of Hodgkin lymphomas, 4.9% (2/41) of follicular lymphomas, 6% (4/67) of peripheral T-cell lymphomas, and 3.8% (1/26) of plasma cell neoplasms. Otherwise, napsin A was not detected in any other types of lymphomas or histiocytic neoplasms. Napsin A expression in systemic ALCL was associated with a higher international prognostic index. ALCL and DLBCL patients with napsin A expression tended to have poor prognosis. CONCLUSION These results demonstrated that napsin A is aberrantly expressed in a subset of lymphomas. The biological significance of napsin A in lymphomas warrants further study.