Application of image-guided surface coil P-31 MR spectroscopy to human liver, heart, and kidney

Localized phosphorus-31 magnetic resonance (MR) spectroscopy in humans has previously been accomplished with surface coils by means of depth-resolved surface coil spectroscopy or rotating frame experiments, in which the extent of tissue sampled critically depends on surface coil placement. The authors' goal was to modify the surface coil image-selected in vivo spectroscopy (ISIS) experiment to accomplish three-dimensional volume selection through application of selective pulses in the presence of B0 gradients. Advantages of ISIS include the ability to use proton images to define the volume of interest (VOI) and reduced dependence on exact positioning of the surface coil. However, rapid replication of the surface coil ISIS experiment can cause spectral contamination from signals originating outside the VOI. A modified version of the ISIS experiment was developed to alleviate contamination under conditions of rapid replication. Applications of localized P-31 MR spectroscopy for observation of high-energy phosphorus metabolites are presented in human liver, heart, and transplanted and normal kidney.     

Inhibition of hepatitis C replicon RNA synthesis by beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine: a specific inhibitor of hepatitis C virus replication

beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is a cytidine analogue with potent and selective anti-hepatitis C virus (HCV) activity in the subgenomic HCV replicon assay, 90% effective concentration (EC90)=4.6 +/- 2.0 microM. The spectrum of activity and cytotoxicity profile of PSI-6130 was evaluated against a diverse panel of viruses and cell types, and against two additional HCV-1b replicons. The S282T mutation, which confers resistance to 2'-C-methyl adenosine and other 2'-methylated nucleosides, showed only a 6.5-fold increase in EC90. When assayed for activity against bovine diarrhoea virus (BVDV), which is typically used as a surrogate assay to identify compounds active against HCV, PSI-6130 showed no anti-BVDV activity. Weak antiviral activity was noted against other flaviviruses, including West Nile virus, Dengue type 2, and yellow fever virus. These results indicate that PSI-6130 is a specific inhibitor of HCV. PSI-6130 showed little or no cytotoxicity against various cell types, including human peripheral blood mononuclear and human bone marrow progenitor cells. No mitochondrial toxicity was observed with PSI-6130. The reduced activity against the RdRp S282T mutant suggests that PSI-6130 is an inhibitor of replicon RNA synthesis. Finally, the no-effect dose for mice treated intraperitoneally with PSI-6130 for six consecutive days was > or =100 mg/kg per day.     

Radiation therapy for consolidation of metastatic or recurrent sarcomas in children treated with intensive chemotherapy and stem cell rescue. A feasibility study.

PURPOSE: To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma. METHODS AND MATERIALS: Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4-24.7 years). Primary histologies included Ewing's (12), PNET (3), and other soft tissue sarcomas (6). Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2). TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2). Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20-60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8-20) with 25% of patients having been followed for more than 20 months. RESULTS: The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13). Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Nonamenable sites were: multiple lung metastases (13) and bone marrow (2). Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) (p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response (p = 0.002) and extent of surgical resection (p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy (p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response (p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS (p = 0.032) as well as for OS (p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival (p = 0.05). CONCLUSION: Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.     

Endothelium: from cellophane to orchestral maestro

Endothelial cells from human umbilical veins were first cultured nearly four decades ago, initiating explosive growth in research in vascular biology and leading to major insights into angiogenesis, vasculogenesis, and tumor biology. Recent studies now promise to open new horizons in regenerative medicine as well as organ engineering.