Chan-Kum Park

Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray.

The signal transducer and activator of the transcription (Stat)‐family of proteins are latent cytoplasmic transcription factors that transmit signals from cytokines and growth‐factor receptors to the nucleus. Stat proteins, especially Stat3 and Stat5, are constitutively activated in various solid tumors and hematological malignancies. However, the role of Stat3 signaling in gastric carcinoma has not yet been fully determined. This study was conducted to investigate the clinical value of phospho‐Stat3 expression in gastric carcinoma. Expression of phospho‐Stat3 (Tyr705), vascular endothelial growth factor (VEGF), p53, and Bcl‐2 was determined by immunohistochemical staining of tissue microarrays from 137 cases of resected gastric cancer specimens. We evaluated the relationships among phospho‐Stat3, VEGF, p53, and Bcl‐2 expression and the correlation between expression of these proteins and various clinicopathological factors, including overall survival. Phospho‐Stat3 nuclear expression was observed in 18.2% of the cases. Of the total number of cases, 68.6% were positive for VEGF, 40.1% for p53, and 11.7% for Bcl‐2. Phospho‐Stat3 expression correlated with VEGF (p=0.021) and Bcl‐2 (p=0.005) expression. Positive phospho‐Stat3 staining was significantly associated with poor pathological grade. However, there was no significant difference in other clinicopathological parameters, such as tumor stage (T, N, M), pathological type, relapse‐free survival, and overall survival between the phospho‐Stat3‐positive and ‐negative groups. Co‐expression of phospho‐Stat3 and VEGF was found in many patients with N3 and Stage IV disease. These results suggest that phospho‐Stat3 expression might be associated with angiogenesis, anti‐apoptosis, and tumor progression. Further studies are needed to determine the role of phospho‐Stat3 in gastric cancer.

Prognostic evaluation of nodal diffuse large B cell lymphoma by immunohistochemical profiles with emphasis on CD138 expression as a poor prognostic factor.

Recently diffuse large B cell lymphoma (DLBCLs) was reported to be subdivided into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subgroups by using cDNA microarray and immunohistochemical markers. Tissue microarray blocks were created from 51 nodal DLBCLs with c ntrol tissue. Immunohistochemical staining for the above markers were performed. The median follow-up period was 26 months. Nodal DLBCLs were subclassified into GCB [CD10+ or CD10-/Bcl-6+/MUM1-, n=17 (33%)] and non-GC subgroups [CD10-/Bcl-6- or CD10-/Bcl- 6+/MUM1+, n=35 (67%)], and were alternatively subclassified into pattern A [+ for GCB marker only, n=12 (23%)], B [Co-positive for both markers, n=13 (33%)], C [+ for activation marker only, n=18 (35%)], and D [- for both markers, n=9 (17%)]. Upon survival analysis, the GCB groups showed a relatively better survival than non-GC groups (p=0.0748). Also, pattern C (p=0.0055) and CD138+ (p=0.0008) patients had significantly lower survival rates. By multivariate analysis, CD138 expression alone was considered as an independent risk factor (p=0.031). In summary, our results add to the registration of prognostic implications for previously reported DLBCL subgroups. CD138 may play an important role as a poor prognostic marker. By using immunohistochemistry, a prognostically important subclassification of DLBCLs is possible.

Expression of p63 in Reactive Hyperplasias and Malignant Lymphomas

p63 is a recently described p53 homologue. It is involved in survival and differentiation of reserve/stem cells in epithelia. To obtain new insights into the role of p63 in malignant lymphomas (MLs), immunohistochemical staining for p63 and p53 was performed in 126 cases of MLs. p63 was expressed in 38 cases of MLs (30.2%) including 32/61 cases (52.5%) of diffuse large B-cell lymphoma (DLBCL), 1/8 cases (12.5%) of precursor T-lymphoblastic lymphoma (T-LBL), 4/14 cases (28.6%) of follicular lymphoma, 1/6 cases (16.7%) of T/NK cell lymphoma. Among p63 positive cases, p63 was strongly expressed in 15/32 cases of DLBCL and 1/1 case of T-LBL. p63 was not expressed in mantle cell lymphomas, peripheral T-cell lymphomas, marginal zone B-cell lymphomas, plasma cell myelomas and Hodgkins lymphomas. p63 was coexpressed with p53 in 18/38 p63 positive cases in which only 4 cases were strongly coexpressed. All p63+/p53+ cases were DLBCL. p63 overexpression (above 30%) cases showed significant poor survival (p=0.0228) in DLBCL. However, there was no statistically significant correlation between p63 expression and IPI score on Multivariate analysis. We could speculate that p63 could act indirectly as an oncogene by inhibiting p53 functions. Stage of differentiation of neoplastic lymphocytes appears to have a correlation with p63 expression in MLs.

Absence of Clinical Prognostic Value of Vascular Endothelial Growth Factor and Microvessel Density in Multiple Myeloma

Vascular endothelial growth factor (VEGF) is considered a potent stimulator of angiogenesis. In multiple myeloma (MM), it has been reported that bone marrow angiogenesis parallels tumor progression and correlates with a poor prognosis. To investigate the role of angiogenesis in MM, we investigated VEGF expression and microvessel density (MVD) in the bone marrow of 75 MM patients by immunohistochemical methods. VEGF expression was observed in 87.3% (62 of 71) of patients. MVD was 69.42 ± 9.67 (mean ± SE) compared with the normal control values of 26.81 ± 2.85. MVD values were 73.98 ± 11.27 and 36.04 ± 6.99 in the VEGF-positive and VEGF-negative groups, respectively. The MVD of patients in the VEGF-positive group was significantly higher than in the VEGF-negative group (P = .045). However, there were no significant differences in various clinical parameters, such as age, sex, hemoglobin, platelet count, serum levels of albumin, calcium, creatinine, and β2-microglobulin, and bone marrow plasma cell percentage, between the VEGF-positive and VEGF-negative groups. Multivariate analysis revealed that age, hemoglobin, platelet count, serum levels of albumin and creatinine, and bone marrow plasma cell percentage were correlated with overall survival, whereas VEGF expression or MVD was not. In conclusion, our results suggest that VEGF is highly expressed and that MVD is increased in MM, indicating that angiogenesis may play a role in MM. Although MVD in the bone marrow of the VEGF-positive group is significantly higher compared with the VEGF-negative group (P = .045), VEGF is not correlated with overall survival. Further studies that include other angiogenic factors are needed to determine the functional role of angiogenesis in MM. Int J Hematol. 2002;76:460-464.

Thymidylate Synthase, Thymidine Phosphorylase, VEGF and p53 Protein Expression in Primary Colorectal Cancer for Predicting Response to 5-fluorouracil-based Chemotherapy

PURPOSE In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival. MATERIALS AND METHODS The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated. RESULTS Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy. CONCLUSION These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.

Early-onset Childhood Sarcoidosis with Incidental Multiple Enchondromatosis

The triad of rash, arthritis, and uveitis seems to be characteristic for early-onset childhood sarcoidosis. We describe an interesting case of early-onset childhood sarcoidosis coexisting enchondromatosis, which clinically masquerade as Langerhans cell histiocytosis. A 33 months old girl presented with skin rash, subcutaneous nodules with polyarthritis, and revealed the involvement of lymph nodes as well as spleen during work-up. She also presented with multiple osteolytic lesions which pathologically proven enchondromatosis. Oral prednisone was prescribed at 2 mg/kg/day for 2 months until when subcutaneous nodules and joint swellings almost disappeared, and then slowly tapered over a period of 5 months. We report an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis.

Heat Transfer to a Composite Material Under Ice Particle Impacts

This paper examines what would happen if a supersonic vehicle flies through an atmosphere laden with ice particles.Inpreviousresearchofthepresentauthors,anexperimentwasperformedtodetermine thecharacteristics of ice-particle impact phenomenon. Therein, the mass loss from the vehicle’s surface material by the impacts was measured and the fragments’ behavior was studied. In the present work, the trajectories of fragments from the stagnation region were calculated at the experimental conditions. It was surmised that the flow in the stagnation region is turbulent. Turbulent flow increases the heat transfer rate to the surface, and consequently the mass loss increases.Todeterminetheextentofheattransferrateincrease,thenewturbulencemodel,tentativelynamedcraterinducedturbulencemodel,wasproposed.Therein,anassumptionwasintroducedthattheturbulentmixinglengthis proportional to the depth of the impact craters. The constant of proportionality was determined from the existing experimental data taken in wind-tunnel tests. It is shown that heat transfer rate may increase up to 14 times that without ice-particle impacts. Nomenclature