Citations

Abstract Purpose: Although metastasis is the primary determinant of poor survival of patients with osteogenic sarcoma, some patients live much longer than others, indicating metastatic heterogeneity underlying survival outcome. The purpose of the investigation was to identify genes underlying survival outcome of patients with osteogenic sarcoma metastasis. Experimental Design: We have used microarray to first compare mRNA expression between normal bone and osteogenic sarcoma specimens, identified genes overexpressed in osteogenic sarcoma, and compared expression of the selected gene between a poorly metastatic (SAOS) and two highly metastatic cell lines (LM8 and 143B). Finally, expression of the selected gene was assessed by immunostaining of osteogenic sarcoma samples with known survival outcome. Results: Microarray analysis revealed 5.3-fold more expression of WT1 mRNA in osteogenic sarcoma compared with normal bone and >2-fold overexpression in 143B and LM8 cells compared with SAOS. Furthermore, WT1 mRNA was absent in normal bone (10 of 10) by reverse transcription-PCR but present in osteogenic sarcoma–derived cell lines (5 of 8). One hundred percent (42 of 42) of low-grade osteogenic sarcoma specimens expressed no WT1 as determined by immunostaining; however, 24% (12 of 49) of the high-grade specimens showed intense staining. Mean survival of patients with high-grade metastatic osteogenic sarcoma but low WT1 staining (27 of 37) was 96.5 ± 129.3 months, whereas mean survival of patients with high-grade metastatic osteogenic sarcoma having intense staining (10 of 37) was 18.3 ± 12.3 months (P > 0.0143). All splice variants of WT1 mRNA, including a hitherto unknown variant (lacking exons 4 and 5), were found to be expressed in osteogenic sarcoma. Conclusion: WT1 seems to be associated with very poor survival of patients with osteogenic sarcoma metastasis.

Abstract Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors—CHIR258, PD173074, and SU5402—and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1α) was the single most differentially altered gene. MIP-1 α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 α is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.

Purpose Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade ≥ 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. Patients and Methods The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. Results Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. Conclusion FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

PurposeTo determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors.MethodsChildren 21 years of age or younger received daily doses from 350 mg/m2to 3,300 mg/m2(divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose.ResultsFifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m2with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2and 800 mg/m2. There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 μmol/L at MTD.ConclusionThe pediatric MTD of oral capsular fenretinide was 2,475 mg/m2per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.

Abstract Much of the ability of the MUC1 oncoprotein to foster tumorigenesis and tumor progression likely originates from the interaction of its cytoplasmic tail with proteins involved in oncogenic signaling. Many of these interactions are regulated by phosphorylation, as the cytoplasmic tail contains seven highly conserved tyrosines and several serine/threonine phosphorylation sites. We have developed a cell line–based model system to study the effects of tyrosine phosphorylation on MUC1 signaling, with particular emphasis on its effects on gene transcription. COS-7 cells, which lack endogenous MUC1, were stably infected with wild-type MUC1 or a MUC1 construct lacking all seven tyrosines (MUC1 Y0) and analyzed for effects on transcription mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) pathways. COS.MUC1 Y0 cells showed heightened active ERK1/2 with increased activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) transcriptional activity; there was also a simultaneous decrease in NF-κB transcriptional activity and nuclear localization. These changes altered the phenotype of COS.MUC1 Y0 cells, as this line displayed increased invasion and enhanced [3H]thymidine incorporation. Analysis of the three lines also showed significant differences in their cell cycle profile and bromodeoxyuridine incorporation when the cells were serum starved. These data support the growing evidence that MUC1 is involved in transcriptional regulation and link MUC1 for the first time to the NF-κB pathway. (Mol Cancer Res 2006;4(7):489–97)

Background— In the elderly, mitral regurgitation (MR) is frequent, but surgery risks are considered high. Benefits and indications of MR surgery are uncertain in the elderly. Methods and Results— Baseline characteristics, outcome, and trends for surgical results improvement were analyzed in elderly patients (≥75 years of age; n=284) operated on for MR in 1980 to 1995 compared with younger patients (65 to 74 years of age, n=504; and <65 years of age, n=556). Preoperatively, class III to IV symptoms, atrial fibrillation, coronary disease, creatinine, and comorbidity index were more severe in elderly patients (all P <0.002). In the long term after surgery, observed survival stratified by age (≥75, 65 to 74, <65 years) was lower in elderly than in younger patients (at 5 years, 57±3%, 73±2%, and 85±2%, respectively; P <0.001), but ratios of observed to expected survival were similar (83%, 85%, and 88%, respectively). In multivariate analysis adjusted to expected survival, elderly patients showed no difference in life expectancy restoration compared with younger patients (adjusted hazard ratio, 0.89; 95% confidence interval, 0.73 to 1.30; P =0.54). Temporal trends showed that risk of operative mortality, although higher in elderly patients ( P <0.001), declined markedly for all ages (27% to 5% in those ≥75 years of age, P <0.01; 21% to 4% in those 65 to 74 years of age, P <0.01; and 7% to 2% in those <65 years of age, P =0.06), with a parallel decline in low cardiac output and length of hospital stay. Over time, valve repair feasibility increased in all age groups (30% to 84% overall and 31% to 93% in degenerative MR; P <0.0001). Conclusions— Elderly patients undergoing MR surgery display more severe preoperative characteristics and incur higher operative risks than younger patients. However, restoration of life expectancy after surgery is similar in elderly and younger patients, and outstanding recent surgical improvements particularly benefited elderly patients. Thus, elderly patients with MR can now carefully be considered for surgery before refractory heart failure is present.