The Prediction of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants through Clinical Indicators within 1 Hour of Delivery.

BACKGROUND: Despite the advances in neonatology, the incidence of bronchopulmonary dysplasia (BPD) is increasing. It is important to prevent the development of BPD in the first place. The online BPD outcome estimator from National Institute of Children Health and Human Development and Neonatal Research Network is available. However, it is not applicable for Asians. Moreover, limits are set for birth weight and gestational weeks excluding those who may still have BPD. The aim of this study was to develop a prediction model for BPD using first hour perinatal and neonatal factors in Korean very low birth weight infants (VLBWIs). METHODS: Data were collected for 8,022 VLBWIs with gestational age (GA) ≥ 22 weeks who were born between January 1, 2013 and December 31, 2016, and admitted to the neonatal intensive care units of the KNN. Multiple logistic regression models reanalyzed by stepwise selection with significant clinical indicators for BPD. PROC package was used to calculate the area under curve (AUC) and corresponding 95% confidence intervals. Moreover, it was used to search the best cut-off value. External validation was performed with the 2017 Korean neonatal network (KNN) data. RESULTS: After all missing data were excluded, 4,600 VLBWIs were included in the training dataset of the prediction model. Predictability of presence of BPD was 90.8% and prediction P value cut off was 0.550. Five-minute Apgar score, birth weight, GA, sex, surfactant use were significant indicators. Predictability of severe BPD was 81.5% and prediction P value cut off was 0.160. Five-minute Apgar score, birth weight, maternal PIH, chronic maternal hypertension, GA, sex, respiratory distress syndrome, need of resuscitation at birth were significant indicators. After external validation, sensitivity and specificity did not change significantly. CONCLUSION: From this study, high predictability was obtained using clinical parameters obtained within one hour of life. P value for prediction of each grade of BPD and equation for calculation was presented. It can be helpful for the early prediction of BPD in Korean VLBWI. This study will contribute to the prediction of BPD in Asians especially Korean VLBWIs, not currently included in the NICHD BPD online BPD predictor. In addition, the predictive power may be continuously increased with the cumulative data of KNN.

PELI1 expression is correlated with MYC and BCL6 expression and associated with poor prognosis in diffuse large B-cell lymphoma.

PELI is a family of E3 ubiquitin ligases that regulate protein activity through a post-translational modification, ubiquitination. While PELI1 has been found to play a pivotal role in inflammatory processes through the activation of Toll-like receptor signaling and the NF-kB pathway, the role of PELI1 in oncogenesis has not been the subject of much investigation. We aimed to explore PELI1 expression in various malignant lymphomas and identify clinicopathologic significance. Immunohistochemistry for PELI1 was performed on a total of 502 cases, including 406 B-cell, 76 T or NK-cell, and 20 Hodgkin lymphomas. High expression of PELI1 was found in high-grade B-cell lymphoma cases such as diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma, whereas low-grade B-cell lymphoma, T/NK-cell lymphoma, and Hodgkin lymphoma cases showed very low levels of expression. In vitro cell line studies, the results of western blot, and RT-PCR were concordant with those of the immunohistochemical results; RL7, Pfeiffer, SUDHL-2, DOHH2, and Ramos cell lines showed high levels of PELI1 protein and mRNA expression. In 182 diffuse large B-cell lymphoma, PELI1 expression was positively correlated with the expression of MYC, BCL6, BCL2, and MUM1 (Spearman's ρ=0.427, 0.507, 0.246, and 0.137, respectively; P<0.001, <0.001, 0.001, and 0.066, respectively). In diffuse large B-cell lymphoma, high expression of PELI1 was associated with frequent bone marrow involvement (P=0.013) and shorter relapse-free survival (P=0.002). Our results suggest that PELI1 might participate in B-cell maturation or oncogenic activation of aggressive B-cell lymphomas, both during and after germinal center stages.

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

AIMS: We aimed to investigate MYC expression and chromosomal aberration in mantle cell lymphoma (MCL), and the clinical significance of these factors. METHODS AND RESULTS: Sixty-five patients with MCL, including 54 classic, nine blastoid and two pleomorphic variants, were enrolled. Expression of MYC, Ki67 and p53 was assessed by immunohistochemistry. MYC amplification or translocation was examined by fluorescence in-situ hybridization. MYC expression was higher in blastoid/pleomorphic MCL variants (mean, 19.0%) than in classic MCL (mean, 1.9%; P < 0.001). Expression of p53 and Ki67 was also significantly higher in these variants. MYC amplification was found in two of 53 cases tested, both of which were blastoid variants with high MYC expression (29.7% and 20.4%). MYC translocation was found in two of 52 cases tested, both of which were pleomorphic variants with remarkably high MYC expression (68.5% and 71.0%). High MYC or p53 expression was significantly associated with shortened overall survival and progression-free survival in univariable and multivariable analyses (all P < 0.05). CONCLUSIONS: MYC overexpression is a negative predictor of MCL patient outcomes. MYC gene amplification or translocation might be related to the pathogenesis of MCL, particularly in blastoid/pleomorphic variants.

Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study.

BACKGROUND: Regulation of tumor microenvironment is closely involved in the prognosis of Hodgkin lymphoma (HL). Indoleamine 2,3-dioxygenase (IDO) is an enzyme acting as immune modulator through suppression of T-cell immunity. This study aims to investigate role of IDO in the microenvironment of HL. METHODS: A total of 121 cases of HL were enrolled to do immunohistochemistry for IDO, CD163, CD68, CD4, CD8, and FoxP3. Positivity was evaluated from area fractions or numbers of positive cells using automated image analyzer. Correlations between IDO expression and various cellular infiltrates and clinicopathologic parameters were examined and survival analyses were performed. RESULTS: IDO was expressed in histiocytes, dendritic cells and some endothelial cells with variable degrees, but not in tumor cells. IDO positive cells were more frequently found in mixed cellularity type than other histologic types, and in cases with EBV+, high Ann Arbor stages, B symptoms, and high IPS (all p < 0.05). High IDO expression was associated with inferior survival (p < 0.001) and reflects an independent prognostic factor in nodular sclerosis HL. CONCLUSIONS: This is the first study suggesting that IDO is the principle immunomodulator and is involved to adverse clinical outcomes of HL.

Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen: a report of six cases with increased IgG4-positive plasma cells.

Inflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma is a rare neoplasm typically occurring in the spleen or liver. We present six cases of EBV(+) IPT-like FDC sarcoma of the spleen among Koreans along with their clinicopathologic features and IHC results. Most patients presented with an asymptomatic, incidentally detected single splenic mass and were successfully managed by splenectomy alone. Concomitant disease was found in one case, showing EBV(+) gastric carcinoma with lymphoid-rich stroma. Histologic features showed fibro-inflammatory lesions that were often accompanied by necrosis and epithelioid histiocytic collection, which are barely distinguishable from IPT. Tumor cells did not frequently express conventional FDC markers, including CD21 (3/6 positive cases), clusterin (4/6), and D2-40 (2/6), but showed uniform positivity for smooth muscle actin (SMA). Noticeably, significant numbers of IgG4(+) plasma cells were found within all six tumors. We suggest that the diagnosis of IPT-like FDC sarcoma should be made by the application of a panel of FDC markers, and CD21 negativity or SMA positivity cannot be the criterion for exclusion of IPT-like FDC sarcoma. Relationship of IPT-like FDC sarcoma of the spleen and IgG4-related sclerosing disease should be investigated in further studies.

Prognostic implications of FGFR1 and MYC status in esophageal squamous cell carcinoma.

AIM: To investigate the clinicopathological features and prognostic implications of combined MYC and fibroblast growth factor receptor 1 (FGFR1) status in esophageal squamous cell carcinomas (ESCCs). METHODS: All patients with ESCC (n = 180) underwent surgical resection at Seoul National University Hospital sometime between 2000 and 2013. A tissue microarray was constructed using cores obtained from representative tumor areas of formalin-fixed, paraffin-embedded tissue blocks. FGFR1 and MYC copy numbers were quantified using fluorescence in situ hybridization. The level of MYC expression was determined using immunohistochemistry. FGFR1 and MYC amplification status was compared between primary and metastatic lymph nodes. Univariate and multivariate survival analyses were performed according to adjuvant therapy status. RESULTS: FGFR1 and MYC amplifications were observed in 21.4% (37/173) and 54.2% (91/168) of patients, respectively, while MYC expression was observed in 58.9% (106/180) of patients. There was a positive correlation between MYC amplification and overexpression (P = 0.002). Although FGFR1 amplification was not associated with MYC amplification or expression, 12.3% (20/163) of patients exhibited both FGFR1 amplification and MYC expression. There was also a correlation in FGFR1 amplification status between matched primary tumors and metastatic lymph nodes (P < 0.001). MYC expression was higher in ESCCs with pT1 (P < 0.001) and in those with no lymph node metastasis (P = 0.023). MYC expression was associated with prolonged disease-free survival (P = 0.036) and overall survival (OS) (P = 0.017) but was not an independent prognostic factor. FGFR1 amplification was an independent predictor for prolonged OS in all patients (P = 0.029) and in those who did not receive adjuvant therapy (P = 0.013). Combined FGFR1 amplification and MYC expression predicted better OS in patients who did not receive adjuvant therapy (P = 0.034) but not in those who did receive adjuvant therapy. CONCLUSION: FGFR1 amplification and MYC expression have prognostic implications in resected ESCCs with respect to adjuvant therapy. The role of FGFR1-targeted therapy in ESCC remains to be explored.

Sonic hedgehog signalling proteins are frequently expressed in retinoblastoma and are associated with aggressive clinicopathological features.

AIMS: This study aimed to examine the expression of Sonic hedgehog (SHH) signalling proteins in retinoblastoma and to evaluate its clinical significance. METHODS: Seventy-nine enucleated retinoblastoma tumours were investigated immunohistochemically using antibodies against SHH pathway proteins, such as SHH, glioma-associated oncogene homologue (GLI) 1, GLI2, GLI3 and ABC binding cassette G2 (ABCG2). Western blotting of SHH signalling proteins was performed in two retinoblastoma cell lines. RESULTS: SHH was expressed in most retinoblastoma cases (78 of 79, 98.7%), with 21 cases (26.6%) showing strong expression. GLI1 and GLI2 were also frequently expressed: 67 of 78 cases (85.9%) and 71 of 77 cases (92.2%), respectively. GLI3, a transcriptional repressor, was expressed at low levels in 23 of the 78 cases (29.5%). High ABCG2 expression was found in 23 of the 78 cases (29.5%). High expression levels of these proteins in retinoblastoma cell lines were confirmed by western blotting. The expression of SHH was associated with advanced stages, local invasion and metastasis (all p<0.05). CONCLUSIONS: SHH signalling molecules were frequently expressed in retinoblastoma tumour cells, and high SHH expression was closely related to an advanced disease status. Our results suggest that the SHH signalling pathway may play a role in the progression of retinoblastoma.

Expression of cancer stem cell markers is more frequent in anaplastic thyroid carcinoma compared to papillary thyroid carcinoma and is related to adverse clinical outcome.

BACKGROUND: Thyroid cancer is one of the most commonly detected cancers worldwide, and papillary thyroidal carcinoma (PTC) accounts for the majority of thyroid cancers. In contrast to the indolent nature of PTC, anaplastic thyroid carcinoma (ATC) shows an extremely poor prognosis and has not responded to any therapeutic modalities. Many researchers postulate that the dedifferentiation of thyroid follicular cells into primitive cells might be related to the pathogenesis of ATC because several cases of ATC have revealed pre-existing PTC lesions. Additionally, the cancer stem cell (CSC) theory has been widely accepted in the pathogenesis of ATC. OBJECTIVE: To explore the expression of various CSC markers in thyroid carcinoma tissues and analyse their clinical significance. METHODS: 133 patients with PTC and 25 patients with ATC were enrolled. Immunohistochemistry for aldehyde dehydrogenase 1 (ALDH1), CD133, CXCR4, ATP-binding cassette (ABC)G2, multidrug resistance associated protein-1 (MRP1), lung resistance protein-1 (LRP), P-glycoprotein 1 (P-Gp1), SOX2, SOX9 and Oct4 was performed using tissue microarray. RESULTS: CSC marker expression was significantly high in ATC, particularly chemoresistance markers such as ABCG2, MRP1, LRP and CXCR4. In PTC, ABCG2 was highly positive in more advanced pathological stages and was associated with lymph node involvement, with borderline significance. In ATC, high expression of CXCR4 correlated with distant metastasis, and LRP showed a tendency to correlate with lymph node metastasis. High expression of CSC markers was related to shorter overall survival in patients with ATC. CONCLUSIONS: These results provide strong evidence that CSCs are related to the pathogenesis of ATC and can explain the frequent treatment failure and aggressiveness of ATC.

Expression of c-Met Is Different along the Location and Associated with Lymph Node Metastasis of Head and Neck Carcinoma.

BACKGROUND: Activation of the c-Met pathway is involved in cancer progression and the prognosis. We aimed to identify any association of c-Met protein expression with a number of clinicopathologic variables including infection of human papillomavirus and Epstein-Barr virus (EBV) in head and neck carcinomas (HNCa). METHODS: Eighty-two cases were enrolled in this study. Expression of c-Met and p16 was investigated immunohistochemically. EBV was detected by in situ hybridization and amplification of the c-Met gene by fluorescence in situ hybridization. RESULTS: The c-Met protein was expressed in 41.5% (34/82), and gene amplification was found in 1.4% (1/71). High expression of c-Met was associated with the primary location of the tumor; the hypopharynx showed the highest expression, followed by the oral cavity, larynx, and nasal cavity. Squamous cell carcinoma expressed c-Met more frequently than undifferentiated carcinoma. Also, p16 immunoreactivity or EBV infection was associated with the tumor location and well-differentiated histologic type, but were not linked to c-Met expression. The patients with positive c-Met expression showed frequent lymph node metastasis. CONCLUSIONS: Activation of the c-Met pathway might be involved in a subset of HNCa. Cases showing positive c-Met expression should be carefully monitored because of the high probability of lymph node metastasis.