Clinical characteristics and prognosis of primary Waldeyer's ring and lymph node diffuse large B-cell lymphoma in the rituximab era.

This study was to compare the clinical characteristics and prognosis of Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) and lymph node DLBCL (LN-DLBCL) in the rituximab era. Before propensity score-matched (PSM), WR-DLBCL group shows more favorable clinical characteristics than LN-DLBCL group. After PSM, there was no significant difference in the response rate and survivals between them. The 5-year PFS and OS rates were 65.0% and 78.6% for WR-DLBCL group, respectively, and 53.7% and 66.1% for LN-DLBCL group, respectively. In WR-DLBCL group, ECOG score, Ann Arbor stage, B symptoms and IPI were associated with poor PFS and OS. In LN-DLBCL group, ECOG score, Ann Arbor stage, LDH, and IPI were significant factors to PFS and OS. Multivariate analysis showed that Ann Arbor stage was the only significant factor to PFS for WR-DLBCL group, for LN-DLBCL group, Ann Arbor stage and IPI were independent factors to PFS, LDH was the only significant factor to OS. WR-DLBCL was associated with more favorable clinical characteristics compared with LN-DLBCL, whereas, WR involvement itself did not have a real favorable prognostic significance. The PFS and OS of DLBCL were largely dependent on other prognostic factors such as Ann Arbor stage, LDH or IPI.

Efficacy and tolerance of pegaspargase, gemcitabine and oxaliplatin with sandwiched radiotherapy in the treatment of newly-diagnosed extranodal nature killer (NK)/T cell lymphoma.

Extranodal nature killer (NK)/T cell lymphoma (ENKL), nasal type, is a highly aggressive and heterogeneous disease. Here we report a retrospective study of 38 newly-diagnosed ENKL patients treated with pegaspargase, gemcitabine, oxaliplatin (P-Gemox) and sandwiched radiotherapy in our department during 2012-2016. A median of 4 (range, 2-6) (total=141) cycles of P-Gemox were administered. Interim restaging after at least 2 cycles showed complete remission (CR) rate of 23.68%, partial remission (PR) rate of 63.16%, giving an overall response rate (ORR) of 86.84%. On treatment completion, the ORR became 92.1% (CR=86.84%, PR=5.26%). Only one patient experienced disease progression during therapy. Multivariate analysis showed gender was a significant independent factor impacting on CR. Hematologic toxicity was common yet nonhematologic toxicity was mild, both of them can be well controlled by supportive treatments and only one treatment-related death was observed. At a median follow-up of 15.5 months, 4 patients (10.53%) experienced disease progression and died of disease. 1-year progression-free survival (PFS) rate and 1-year overall survival (OS) rate for the whole cohort were 86.7% and 86.6%. The P-Gemox regimen with sandwiched radiotherapy may be a promising option in the treatment of newly-diagnosed ENKL due to its high efficacy yet low toxicity.

Irradiation Response of Adipose-derived Stem Cells under Three-dimensional Culture Condition.

OBJECTIVE: Adipose tissue distributes widely in human body. The irradiation response of the adipose cells in vivo remains to be investigated. In this study we investigated irradiation response of adipose-derived stem cells (ASCs) under three-dimensional culture condition. METHODS: ASCs were isolated and cultured in low attachment dishes to form three-dimensional (3D) spheres in vitro. The neuronal differentiation potential and stem-liked characteristics was monitored by using immunofluoresence staining and flow cytometry in monolayer and 3D culture. To investigate the irradiation sensitivity of 3D sphere culture, the fraction of colony survival and micronucleus were detected in monolayer and 3D culture. Soft agar assays were performed for measuring malignant transformation for the irradiated monolayer and 3D culture. RESULTS: The 3D cultured ASCs had higher differentiation potential and an higher stem-like cell percentage. The 3D cultures were more radioresistant after either high linear energy transfer (LET) carbon ion beam or low LET X-ray irradiation compared with the monolayer cell. The ASCs' potential of cellular transformation was lower after irradiation by soft agar assay. CONCLUSION: These findings suggest that adipose tissue cell are relatively genomic stable and resistant to genotoxic stress.

Computer-assisted analysis of biopsy specimen microvessels predicts the outcome of esophageal cancers treated with chemoradiotherapy.

PURPOSE: A computer-assisted microvessel analysis system was developed to evaluate correlations between the architecture of biopsy specimen microvessels and the outcome for patients with esophageal cancer treated with chemoradiotherapy. EXPERIMENTAL DESIGN: Biopsy specimens from 51 patients with esophageal cancer (T(2-3), any N, M0) treated with chemoradiotherapy were immunostained with an anti-CD31 antibody and quantified using computerized image analysis. We evaluated the association of several microvessel factors with overall survival, including the ratio of total microvessel perimeter to total tumor area (TP/TA), the tumor hypoxic ratio, and the ratio of total microvessel number to total tumor area (TN/TA). Results from traditional manual microvessel density (MVD) hotspot count and computerized hotspot count were compared and the relation between hotspot MVD count and survival rate was evaluated. RESULTS: The median follow-up time was 32 months. Both univariate and multivariate analyses revealed that computer-counted hotspot MVD and TN/TA and TP/TA ratios correlated significantly with the outcome of chemoradiotherapy. Kaplan-Meier survival curves showed that patients with high computer-counted hotspot MVDs and high TN/TA and TP/TA ratios had better overall survival rate than patients with low MVDs or ratios (P = 0.025, 0.008, and 0.031, respectively). Combining computer-counted MVD or TN/TA ratio with TP/TA ratio proved more predictive than any single factor. Two researcher-counted hotspot MVDs had no significant relation with outcome. CONCLUSION: Computer-assisted tumor microvessel analysis is a powerful tool in predicting the outcome for patients with esophageal cancer treated with chemoradiotherapy because intraobserver and interobserver variability is minimized.

Inhibition of bone-derived insulin-like growth factors by a ligand-specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse.

Multiple myeloma (MM) is a fatal disease that affects plasma cells. Patients with MM have 1 or more osteolytic lesions in their bone tissues, where insulin-like growth factors (IGFs; IGF-I and IGF-II) are mainly stored. The role of bone-derived IGFs in the development of MM has not been extensively studied because reliable animal models are lacking. We established an animal model using a human MM cell line, RPMI8226, in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice implanted with human adult bone (HAB) fragments. Treatment with an anti-human IGF-neutralizing monoclonal antibody, KM1468, inhibited the IGF-I-stimulated phosphorylation of type-I IGF receptors (IGF-IR) in RPMI8226 cells and the activation of the downstream PI3-K/Akt signaling pathway in vitro. KM1468 inhibited IGF-I-mediated RPMI8226 cell growth in a dose-dependent manner. In the NOD/SCID-HAB model, treatment with KM1468 significantly inhibited the growth of RPMI8226 cells (p<0.02). These results indicated that the growth of MM cells was predominantly stimulated not by serum-derived IGFs, but by bone-derived IGFs. Furthermore, the targeting of bone-derived IGFs, using a neutralizing antibody, may offer a new therapeutic strategy for MM.

Laminin 5 expression protects against anoikis at aerogenous spread and lepidic growth of human lung adenocarcinoma.

Adenocarcinoma of the lung is characterized by frequent aerogenous spread (AE) and advancement along the alveolar wall (BAC growth). To elucidate the mechanism of AE metastasis and BAC growth in human lung adenocarcinoma, we established an in vivo orthotopic animal model and an in vitro culture. Investigation of expression levels of integrins, laminins and Type IV collagens, which are the major regulating molecules for cell attachment and anoikis was carried out and a clear correlation between the expression level of laminin 5 (LN5) and the BAC growth was observed using an orthotopic animal model. Introduction of LN5 cDNA to A549 cells increased anoikis resistance in an expression dependent manner. Cells with LN5 overexpression resisted with anoikis after treatment with PI3K-Akt and ERK inhibitors. The amount of phosphorylated focal adhesion kinase (FAK) was also higher in LN5 overexpressing cells. Major tyrosine residues of the EGF receptor at 1068, 1086 and 1173, except at 1148, remained phosphorylated only in the LN5 overexpressing cells even without EGF stimulation, that indicates the ligand independent activation of EGF receptor. BAC growth ratio and AE was confirmed to be significantly correlated with LN5 expression in surgically resected human lung adenocarcinomas by immunohistochemistry. Our results indicate that the activation of the EGF receptor by overexpressing LN5-integrin-FAK signaling pathway may play a crucial role in BAC growth and AE metastasis in human lung adenocarcinoma.

Low levels of insulin-like growth factor type 1 receptor expression at cancer cell membrane predict liver metastasis in Dukes' C human colorectal cancers.

PURPOSE: The aim of this study was to evaluate the prognostic significance of insulin-like growth factor type 1 receptor (IGF-1R) expression in Dukes' C human colorectal cancers (CRCs). EXPERIMENTAL DESIGN: Immunohistochemical staining for IGF-1R was done on formalin-fixed, paraffin-embedded specimens from 161 patients with curatively resected Dukes' C CRC and at least 5-year follow-up periods. We investigated the association between the levels of IGF-1R expression and the clinicopathologic parameters. To evaluate the accurate prognostic value of IGF-1R expression, we investigated two patterns of recurrence-free survival (RFS) according to the mode of recurrence, the hepatic-RFS (H-RFS), and the nonhepatic-RFS (nH-RFS). The influence of the pattern of IGF-1R immunostaining (membranous or cytoplasmic) on RFS was also estimated. RESULTS: High (diffuse staining) and low (focal staining) levels of IGF-1R expression were found in 45 (28%) and 116 (72%) specimens, respectively. The recurrence rate was significantly higher in the latter group (49 of 116) than the former group (9 of 45; P = 0.01). H-RFS was significantly longer for the former group than the latter group (P = 0.021), whereas no difference was found in nH-RFS between the two groups (P = 0.121). In multivariate analysis, the level of IGF-1R expression was an independent factor for H-RFS (P = 0.015) as were the depth of invasion and lymph vessel invasion (P = 0.006 and 0.022, respectively). Using a combination of the level of IGF-1R expression and these two factors, the prognostic value was further increased. When IGF-1R staining patterns (membranous or cytoplasmic) were compared, membrane staining of IGF-1R possessed prognostic significance. CONCLUSIONS: In Dukes' C CRC, focal membrane expression of IGF-1R in the primary tumor can predict a high risk of recurrence, especially liver metastasis. Understanding the mechanisms involved could lead to new therapeutic approaches for advanced CRC.

Intratumor microvessel density in biopsy specimens predicts local response of hypopharyngeal cancer to radiotherapy.

BACKGROUND: The aim of this retrospective study was to identify reliable predictive factors for local control of hypopharyngeal cancer (HPC) treated by radiotherapy. METHODS: A cohort of 38 patients with HPC treated by radical radiotherapy at the National Cancer Center Hospital East between 1992 and 1999 were selected as subjects for the present study. Paraffin-embedded pre-therapy biopsy specimens from these patients were used for immunostaining to evaluate the relationships between local tumor control and expression of the following previously reported predictive factors for local recurrence of head and neck cancer treated by radiotherapy: Ki-67, Cyclin D1, CDC25B, VEGF, p53, Bax and Bcl-2. The predictive power of microvessel density (MVD) in biopsy specimens and of clinicopathologic factors (age, gender and clinical tumor-node-metastasis stage) was also statistically analyzed. RESULTS: Twenty-five patients developed tumor recurrence at the primary site. Univariate analysis indicated better local control of tumors with high microvessel density [MVD >or= median (39 vessels/field)] than with low MVD (< median, P = 0.042). There were no significant associations between local control and expression of Ki-67 (P = 0.467), Bcl-2 (P = 0.127), Bax (P = 0.242 ), p53 (P = 0.262), Cyclin D1 (P = 0.245), CDC25B (P = 0.511) or VEGF (P = 0.496). Clinicopathologic factors were also demonstrated to have no significant influence on local control (age, P = 0.974; gender, P = 0.372; T factor, P = 0.602; N factor, P = 0.530; Stage, P = 0.499). CONCLUSION: Microvessel density in biopsy specimens was closely correlated with local control of HPC treated by radiotherapy.