Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies.

BACKGROUND: Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression-free survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a prognostic role in patients with mRCC. METHODS: Adipose tissue, skeletal muscle, and skeletal muscle density (SMD) were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues and mean muscle Hounsfield units (HU). A high level of mean HU indicates a high SMD and high quality of muscle. OS and PFS were estimated using the Kaplan-Meier method and compared with the log-rank test. The multivariable Cox proportional hazards model was adjusted for Heng risk score and treatment. RESULTS: In the 149 patients studied, the median OS was 21.4 months and was strongly associated with SMD; the median OS in patients with low SMD was approximately one-half that of patients with high SMD (14 months vs 29 months; P = .001). After adjustment for Heng risk score and treatment, high SMD was associated with longer OS (hazards ratio, 1.85; P = .004) and longer PFS (hazards ratio, 1.81; P = .002). Adding SMD will separate the intermediate-risk and favorable-risk groups into 3 groups, with different median OS periods ranging from 8 months (95% confidence interval [95% CI], 6 months-12 months) for an intermediate-risk Heng score/low SMD to 22 months (95% CI, 14 months-27 months) for an intermediate-risk Heng score/high SMD and a favorable-risk Heng score/low SMD to 35 months (95% CI, 24 months-43 months) for a favorable-risk Heng score/high SMD. CONCLUSIONS: High muscle density appears to be independently associated with improved outcome and could be integrated into the prognostic scores thereby enhancing the management of patients with mRCC.

Reappraisal of treatment-induced renal dysfunction in patients receiving antiangiogenic agents in phase I trials.

BACKGROUND: Several phase I trials are currently evaluating new antiangiogenic compounds. While hypertension and proteinuria have been largely reported as a class side effect of these agents, data on renal function [i.e. the glomerular filtration rate (GFR)] in patients (pts) treated with new antiangiogenic compounds in phase I trials are much scarcer. PATIENTS AND METHODS: Between November 2005 and March 2008, we identified 72 pts with solid tumors who had been included in four Phase I trials testing antiangiogenic or related compounds. Thirty-two pts had received a pan-HER/VEGFR inhibitor (A), 29 had received a vascular-disrupting agent (B) and 11 had received a pan-VEGFR inhibitor in combination with CPT11 (C). For each patient, we retrospectively analyzed the serum creatinine level (SCr), Cr clearance (CrCl) calculated by both the Cockcroft and Gault and aMDRD equations at baseline, during treatment and at the end of treatment. Acute renal failure (ARF) was defined as a decrease of >25% in CrCl, and severe renal failure (SRF) as a decrease of >50% in CrCl. Chronic renal failure (CRF) was defined according to the KDOQI-KDIGO classification. Renal dysfunction was defined as Cl <60 ml/min with a normal Cr level (<125 µmol/l). RESULTS: Each pt had received an average of 4 cycles of treatment (1 to 12). During treatment, the incidence of ARF ranged from 40.2% to 44.4% (A = 11/32, B = 19/29, C = 2/11). Seven to 9.7% of these cases were severe (A = 1/32, B = 6/29, C = 0/11). Moreover, 26.4 to 27.7% of the pts had exhibited persistent renal insufficiency at the end of the study (A = 5/32, B = 15/29, C = 0/11). From the start till the end of treatment, ARF had been documented in 20.8% to 22.2% of the pts. The average reduction in clearance was 9.8 to 11.6 ml/min/1.73 m2 between baseline and the end of treatment. CONCLUSION: The incidence of renal toxicity in phase I pts treated with antiangiogenic compounds was much higher than expected. Simple screening of Cr levels appears to be insufficient and careful nephrologic monitoring at baseline and during treatment should be implemented in early clinical trials assessing the risk/benefit ratio of new antiangiogenic compounds.

Clinical implications of body composition assessment by computed tomography in metastatic renal cell carcinoma.

According to computed tomography image analysis, skeletal muscle (SM) and adipose tissue areas vary widely in patients with the same body mass index or the same body surface area. Body composition variables such as SM mass, SM density and subcutaneous and visceral adipose tissue have shown value as potential independent predictive factors for survival in cancer patients, although data for patients with renal cell carcinoma (RCC) undergoing targeted therapy remain relatively scarce. Confirmation of their prognostic value is required before they can be considered useful adjuncts to conventional predictive models of survival in RCC patients. In addition, variability in SM mass might affect drug toxicity, with patients with a low rather than high SM mass being at a higher risk of toxicity. A dose tailored to the individual patient's SM mass might lower toxicity in RCC patients, enable completion of the treatment plan and thus impact favorably on treatment effectiveness.

[Cell cycle, mitosis and therapeutic applications]. / Cycle cellulaire, mitose et applications thérapeutiques.

Genomic DNA is constantly under stress of endogenous and exogenous DNA damaging agents. Without proper care, the DNA damage causes an alteration of the genomic structure and can lead to cell death or the occurrence of mutations involved in tumorigenesis. During the process of evolution, organisms have acquired a series of response mechanisms and repair of DNA damage, thereby ensuring the maintenance of genome stability and faithful transmission of genetic information. The checkpoints are the major mechanisms by which a cell can respond to DNA damage, either by actively stopping the cell cycle or by induction of apoptosis. Two parallel signalling pathways, ATM and ATR respond to genotoxic stress by activating their downstream target proteins including the two effectors kinases CHK1 and CHK2. Promising preliminary data render these proteins potential targets for therapeutic development against cancer.