Citations

Abstract Purpose: Chronic lymphocytic leukemia (CLL) is incurable with current chemotherapy treatments. Curcumin (diferuloylmethane), an active ingredient in the spice turmeric, inhibits tumor metastasis, invasion, and angiogenesis in tumor cell lines. We evaluated the effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection. Experimental Design: The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated. Results: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 μmol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor κB. Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection. Conclusions: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion. Additional evaluation of curcumin as a potential therapeutic agent for treatment of CLL seems warranted.

Abstract Purpose: Atypical protein kinase Cι (PKCι) is an oncogene in non–small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCι in lung adenocarcinoma (LAC), the most prominent form of NSCLC. Experimental Design: Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCι in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediated knockdown of PKCι and the target genes was used to determine whether expression of the identified genes was regulated by PKCι, and whether these target genes play a role in anchorage-independent growth and invasion of LAC cells. Results: Meta-analysis identified seven genes whose expression correlated with PKCι in primary LAC. Subsequent QPCR analysis confirmed coordinate overexpression of four genes (COPB2, ELF3, RFC4, and PLS1) in an independent set of LAC samples. RNAi-mediated knockdown showed that PKCι regulates expression of all four genes in LAC cells, and that the four PKCι target genes play an important role in the anchorage-independent growth and invasion of LAC cells. Meta-analysis of gene expression data sets from lung squamous cell, breast, colon, prostate, and pancreas carcinomas, as well as glioblastoma, revealed that a subset of PKCι target genes, particularly COPB2 and RFC4, correlate with PKCι expression in many tumor types. Conclusion: Meta-analysis of public gene expression data are useful in identifying novel gene targets of oncogenic PKCι signaling. Our data indicate that both common and cell type–specific signaling mechanisms contribute to PKCι-dependent transformation.

Abstract Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

To compare the radiation dose to normal cardiac tissue for 3Dimensional (3D) conformal external beam partial breast irradiation (PBI) and standard whole breast irradiation (WBI), and examine the effect of tumor bed location.For 14 patients with left breast tumors randomized on the National Surgical Adjuvant Breast and Bowel Project B‐39 protocol, computer‐generated radiotherapy treatment plans were devised for WBI and PBI. Tumor bed location was designated according to whether more than 50% of the excision cavity was medial or lateral to the nipple line. The volume of heart receiving doses of 2.5, 5, 10, and 20 Gy was calculated for all PBI and WBI plans. Dose to 5% of the heart volume (D5) and mean heart dose were also calculated. The biologically‐equivalent dose (BED) was calculated to account for the different fractionation used in PBI and WBI.Of the 14 patients, 8 had lateral tumor beds, and 6 had medial tumor beds. The volumes of heart receiving 2.5, 5, 10, and 20 Gy were significantly lower for lateral PBI compared with WBI. For medial PBI, significant cardiac sparing was only seen at a dose of 20 Gy. The difference of D5 values was significant for lateral PBI compared with WBI , but not for medial PBI compared with WBI . The mean dose was also significantly lower for lateral PBI compared with WBI , but not for medial PBI . The results from BED calculations did not change this outcome.Both 3D conformal PBI and standard WBI can deliver relatively low doses to the heart. For patients with lateralized tumor beds, PBI offers significant cardiac sparing compared with WBI. Patients with medial lesions have relatively similar heart dosimetry with PBI and WBI. 3D conformal PBI is an emerging treatment modality and continued participation on clinical trials is encouraged. Patients with left‐sided lesions and lateralized tumor beds warrant special consideration for PBI, given the significant cardiac dose sparing.PACS numbers: 87.53.Tf

Abstract Background Portal vein–superior mesenteric vein resection is frequently required after surgical resection of tumours of the pancreas head. The ideal graft for portal vein reconstruction (PVR) remains undefined. Methods Between May 2000 and July 2007, 28 patients had portal vein–superior mesenteric vein resection and PVR during pancreaticoduodenectomy. Their clinical reports were reviewed retrospectively with specific attention to the methods of PVR and outcomes. Results Ten patients had PVR with primary anastomosis, seven had PVR with autologous vein, one had a polytetrafluoroethylene (PTFE) patch, one did not have PVR and nine had PVR with a PTFE interposition graft. There was no infection after PTFE grafting. Six patients had PVR thrombosis after surgery: four after primary anastomosis, one after interposition PTFE and one after vein repair. Conclusion PTFE appeared to be an effective and safe option as an interposition graft for portomesenteric venous reconstruction after pancreaticoduodenectomy.