Soon Auck Hong

Expression of Programmed Death Receptor Ligand 1 with High Tumor-Infiltrating Lymphocytes Is Associated with Better Prognosis in Breast Cancer

Purpose The interaction of programmed death receptor 1 (PD-1) and its ligand, programmed death receptor ligand 1 (PD-L1), negatively regulates immune responses. This study aimed to clarify PD-L1 expression levels in breast cancer through immunohistochemistry (IHC) and to evaluate associations between these findings and clinicopathologic variables, including prognosis. Methods PD-L1 expression was analyzed using IHC on tissue microarrays of 465 invasive breast carcinomas. Results High PD-L1 expression was demonstrated in 63 of 465 tumors (13.5%). High PD-L1 expression was significantly associated with high histologic grade (p<0.001), negative lymph nodes (p=0.011), early pathologic stage (p=0.025), high tumor-infiltrating lymphocyte (TIL) (p<0.001) counts, negative estrogen receptor (p<0.001) and progesterone receptor (p=0.002) expression, positive human epidermal growth factor receptor 2 (HER2) (p=0.003), cytokeratin 5/6 (p=0.011), epidermal growth factor receptor (p<0.001), and p53 (p<0.001) expression, and high Ki-67 proliferating index (p<0.001). Based on intrinsic subtypes, high PD-L1 expression and high TIL counts were significantly associated with the HER2 and triple-negative basal type (p<0.001). PD-L1 expression was significantly associated with better disease-free survival (DFS) (p=0.041) and overall survival (OS) (p=0.026) in the univariate analysis, but not in the multivariate analysis. Higher TIL levels was an independent prognostic factor for decreased disease progression (hazard ratio [HR], 2.389; 95% confidence interval [CI], 1.284–4.445; p=0.006) and overall death (HR, 3.666; 95% CI, 1.561–8.607; p=0.003). Conclusion PD-L1 protein expression in breast cancer is associated with better DFS and OS, but is not an independent prognostic factor. High PD-L1 expression was significantly associated with high TIL levels. This finding has important implications for antibody therapies targeting the PD-1/PD-L1 signaling mechanism in breast cancer.

DICOM-based intravascular ultrasound signal intensity analysis: an Echoplaque Medical Imaging Bench study.

BackgroundMost intravascular ultrasound (IVUS) data are stored digitally using the Digital Imaging and Communications in Medicine (DICOM) standard. This allows random access to studies and improves on the major limitation of conventional grayscale IVUS. MethodsWe harvested 129 coronary arteries from 43 autopsied cases. Grayscale IVUS and virtual histology-IVUS imaging were performed beginning 30 mm distal to the ostium of each coronary artery. Grayscale IVUS was processed; and the signal intensity was determined from DICOM-stored images using a new Medical Imaging Bench system (Echoplaque-MIB). We compared 436 regions of interest. The accuracy rate was expressed using the interpolation method and 95% confidence interval (CI). ResultsPatients’ mean age was 49±9 years and 82% were men. Four patients succumbed to sudden cardiac death and 39 to noncardiac death. Grayscale IVUS signal intensity of dense calcium was 215±21.1 (95% CI: 207–223), that of fibrotic plaque was 75±17.8 (95% CI: 72–79), and that of fibrofatty plaque was 55±11.3 (95% CI: 52–59); however, the signal intensity of the necrotic core was between fibrotic plaque and dense calcium of 161±27.4 (95% CI: 153–168). Using the interpolation method, the cutoff values were as follows: fibrofatty plaque 0–65, fibrotic plaque 66–105, necrotic core 106–187, and dense calcium of at least 188. Overall, MIB grayscale had a 78.1% sensitivity and a 91.9% specificity versus histopathology. ConclusionPlaque characterization using DICOM-based grayscale IVUS signal intensity analysis may improve on the major limitation of conventional grayscale IVUS: its inability to assess plaque composition.

Pulmonary sclerosing pneumocytoma of the lung: CT characteristics in a large series of a tertiary referral center.

AbstractThe purpose of this study is to describe the detailed clinical, chest computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography (FDG PET) characteristics of the tumor boundary for the diagnosis and investigate the outcome of pulmonary sclerosing pneumocytoma (PSP) using confirmed large data of a tertiary referral center.Confirmed 76 patients were included. We evaluated the findings of CT including 4 CT signs, FDG PET, and histopathology.Most patients had a single lesion (92.1%), smooth boundary (65.8%), and oval shape (65.8%) and the mean diameter was 22.7 mm. The CT signs included marginal pseudocapsule (50%), overlying vessel (26.3%), air gap (2.6%), and halo sign (17.1%). A predominantly solid was the most common histopathologic type. The mean maximum standardized uptake value on FDG PET of 17 patients was 1.8 (range, near 0 or normal tissue metabolism ∼2.9).PSP should be considered in middle-aged women whose CT features show incidental nodule(s), commonly with surrounding ground-glass opacity and characteristic CT signs of the tumor boundary, and hypometabolic uptake on FDG PET. Outcome of patients is excellent.

Identification of Downstream Genes of the mTOR Pathway that Predict Recurrence and Progression in Non-Muscle Invasive High-Grade Urothelial Carcinoma of the Bladder

Microarray analysis was used to investigate the lack of identified mammalian target of rapamycin (mTOR) pathway downstream genes to overcome cross-talk at non-muscle invasive high-grade (HG)-urothelial carcinoma (UC) of the bladder, gene expression patterns, gene ontology, and gene clustering by triple (p70S6K, S6K, and eIF4E) small interfering RNAs (siRNAs) or rapamycin in 5637 and T24 cell lines. We selected mTOR pathway downstream genes that were suppressed by siRNAs more than 2-fold, or were up-regulated or down-regulated by rapamycin more than 2-fold. We validated mTOR downstream genes with immunohistochemistry using a tissue microarray (TMA) of 125 non-muscle invasive HG-UC patients and knockout study to evaluate the synergistic effect with rapamycin. The microarray analysis selected mTOR pathway downstream genes consisting of 4 rapamycin up-regulated genes (FABP4, H19, ANXA10, and UPK3A) and 4 rapamycin down-regulated genes (FOXD3, ATP7A, plexin D1, and ADAMTS5). In the TMA, FABP4, and ATP7A were more expressed at T1 and FOXD3 was at Ta. ANXA10 and ADAMTS5 were more expressed in tumors ≤ 3 cm in diameter. In a multivariate Cox regression model, ANXA10 was a significant predictor of recurrence and ATP7A was a significant predictor of progression in non-muscle invasive HG-UC of the bladder. In an ATP7A knock-out model, rapamycin treatment synergistically inhibited cell viability, wound healing, and invasion ability compared to rapamycin only. Activity of the ANXA10 and ATP7A mTOR pathway downstream genes might predict recurrence and progression in non-muscle invasive HG-UC of the bladder. ATP7A knockout overcomes rapamycin cross-talk.

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer.

Purpose Transducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. We investigated the prognostic significance of TLE1 protein expression in breast cancers by using immunohistochemistry and explored the relationship of TLE1 with clinicopathological parameters. Methods Immunohistochemistry was performed on 456 cases of breast cancer tiled on tissue microarrays. The relationship between TLE1 expression in normal breast specimens and ductal carcinoma in situ (DCIS) was also analyzed. Results TLE1 was highly expressed in 57 of 456 (12.5%) carcinoma samples. TLE1 was more frequently expressed in DCIS and invasive breast cancers than in normal breast tissue (p=0.002). High expression of TLE1 significantly correlated with negative lymph node (LN) metastasis (p=0.007), high histologic grade (p<0.001), estrogen receptor negativity (p<0.001), progesterone receptor negativity (p<0.001), human epidermal growth factor receptor 2 (HER2) positivity (p<0.001), and high Ki-67 proliferation index (p<0.001). Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease-free survival (DFS) (p=0.167) or overall survival (OS) (p=0.286). In subgroup analyses, no correlation was found between TLE1 expression and DFS or OS according to LN status or intrinsic subtype. Conclusion High TLE1 expression is significantly associated with the HER2+ and TNBC subtypes. This is the first study documenting immunohistochemical expression of TLE1 in invasive breast cancer and its association with clinicopathological parameters, prognosis, and intrinsic subtype.

Overexpression of YAP1 in EGFR mutant lung adenocarcinoma prior to tyrosine kinase inhibitor therapy is associated with poor survival

EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination. Expression of YAP1 protein was evaluated using immunohistochemistry. Fifteen paired cases (36.6%) with high nuclear YAP1 expression were detected in the pre-EGFR TKI LADC group and 21 paired cases (52.5%) after treatment with EGFR TKI. Nuclear YAP1 expression was significantly upregulated after EGFR TKI therapy (P = .002). Fifteen paired cases with high nuclear YAP1 expression before EGFR TKI LADCs showed poorer overall survival (OS) (P = .023) and progression-free survival (PFS) (P = .041). Among the 63 patients under study, those with high nuclear YAP1 expression before EGFR TKI showed shorter OS (P = .038) and PFS (P < .001). High nuclear YAP1 expression in cases with acquired EGFR exon 20 T790 M mutant LADCs showed poorer OS (P < .001). We demonstrated that YAP1 burden before clinical application of EGFR TKI plays a crucial role in prognosis of EGFR mutant LADC treated using EGFR TKI.

Sarcomatoid carcinoma in the trachea: A case report and literature review

Tracheal sarcomatoid carcinoma is an extremely infrequent neoplasm with unclear pathogenesis and clinical outcomes. To date, only two cases have been described in English literature. We report a case of a 37‐year‐old patient complaining of hemoptysis, dyspnea, and cough. An intraluminal polypoid mass in the trachea was found and ultimately diagnosed as tracheal sarcomatoid carcinoma in the cervical trachea with both carcinomatous and sarcomatoid morphology. The patient is alive without recurrence after segmental resection of the trachea. We also present a comparative analysis of our case with a prior tracheal sarcomatoid carcinoma case.

Changes in PD-L1 expression according to tumor infiltrating lymphocytes of acquired EGFR-TKI resistant EGFR-mutant non-small-cell lung cancer

Backgrounds EGFR-mutant non-small cell lung cancer (NSCLC) that developed acquired resistance to EGFR-tyrosine kinase (TKI) are potential candidates for programmed death 1 (PD1) inhibitor. Results TPS≥1% for PD-L1 and low CD8+ TIL in post-TKI tumor showed a trend for a lower PFS of EGFR-TKIs (14.2 vs 9.9 months; P = 0.060) (cohort A). Only 2 of 22 specimens (9.1%) with an acquired EGFR exon 20 T790M mutation exhibited in post-TKI TPS≥50% for PD-L1. The degree in post-TKI tumor of PD-L1 expression was varied in 19 patients (40.5%), with 10 (21.2%) showing higher levels in the resistant biopsy (cohort B). Among the post-TKI high TPS groups, median PFS with low post- TKI CD8+ TIL scores treated with EGFR-TKIs (6.6 months) was significantly lower than that for the other patients (14.2 months; P = 0.015). Conclusions The change of PD-L1 expression was accompanied by dynamic change in CD8+ TILs and might reflect diverse mechanism of resistance to EGFR-TKI therapy. Material and Methods We identified 69 patients (cohort A) with sufficient post-TKI tumor tissues and 47 patients (cohort B) with paired tumor tissues available. TPS for PD-L1 expression of tumor cells and CD8+ TILs score in tumor specimens were determined by immunohistochemistry.

A role of human beta defensin-1 in predicting prostatic adenocarcinoma in cases of false-negative biopsy

The purpose of this study was to clarify the role of human beta defensin‐1 (hBD‐1) in predicting PAC in morphologically normal prostate glands. In total, 25 patients with a negative initial biopsy for PAC and diagnosed as PAC positive in subsequent biopsies performed within 1 year of the initial biopsy were included. As a control group, 22 patients negative for PAC in at least three consecutive histologic examinations were selected. Expression of hBD‐1 was analyzed separately via immunohistochemistry in paired cores of non‐neoplastic gland and PAC in the false‐negative group and control group. Loss of hBD‐1 expression was observed in 95.6% and 90.0% PAC cases with Gleason Patterns 3 and 4 in repeat biopsies, respectively. hBD‐1 loss of basal cells in 40 (85.1%) previous non‐neoplastic biopsy cores in the false‐negative group was observed, in contrast to preserved basal cell expression of hBD‐1 in 64 (72.7%) biopsy cores in the control group (p = 0.001). Multivariate logistic regression analysis showed that hBD‐1 basal cell loss (≥20% of prostatic glands in total cores) is an independent factor for predicting PAC (odds ratio: 4.739, confidence interval: 1.093–20.554, p = 0.038). hBD‐1 loss of basal cells is a useful indicator to identify extremely high‐risk patients with initially negative biopsy.

DNA Methylation-Mediated Downregulation of DEFB1 in Prostate Cancer Cells.

Epigenetic aberrations play crucial roles in prostate cancer (PCa) development and progression. The DEFB1 gene, which encodes human ß-defensin-1 (HBD-1), contributes to innate immune responses and functions as a potential tumor suppressor in urological cancers. We investigated whether differential DNA methylation at the low CpG-content promoter (LCP) of DEFB1 was associated with transcriptional regulation of DEFB1 in PCa cells. To identify distinct CpG loci within the DEFB1 LCP related to the epigenetic regulation of DEFB1, we performed an in vitro methylated reporter assay followed by bisulfite sequencing of the DEFB1 promoter fragment. The methylation status of two adjacent CpG loci in the DEFB1 LCP was found to be important for DEFB1 expression in PCa cells. Paired epithelial specimens of PCa patients (n = 60), which were distinguished as non-tumor and tumor tissues by microdissection, were analyzed by bisulfite pyrosequencing of site-specific CpG dinucleotide units in the DEFB1 LCP. CpG methylation frequencies in the DEFB1 LCP were significantly higher in malignant tissues than in adjacent benign tissues across almost all PCa patients. These results suggested that methylation status of each CpG site in the DEFB1 promoter could mediate downregulation of DEFB1 in PCa cells.