Vismodegib was recently approved for the treatment of locally advanced or metastatic BCC that is refractory to standard treatments or if patients are not candidates for surgery or radiation. Vismodegib may have little effect on the treatment of BCC, given its high cost, the high cure rates achieved with standard therapies, and its unacceptable toxicity profile in patients with a non-life-threatening disease. However, vismodegib's novel mechanism of action, oral dosage form, preliminary efficacy, and tolerability compared with cytotoxic chemotherapy may make it an attractive candidate for the treatment of other cancers.

<b><i>Background:</i></b> A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. <b><i>Methods:</i></b> The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. <b><i>Results:</i></b> Cell senescence (p16^INK4A, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (<i>p</i> &#x3c; 0.05–0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16^INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16^INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16^INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16^INK4A, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss. <b><i>Conclusions:</i></b> The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16^INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

An experimental study was conducted in the rat to evaluate the sensitivity of the liver to hyperthermia and ischemia. A 15-min asanguineous isolated hyperthermic in vivo perfusion of the liver was done in rats with a normal liver and in rats with an hepatocarcinoma induced by chronic 3’-diethylaminoazobenzene intoxication. The perfusion was made using various ranges of temperature of the perfusate. In normal rats, the in vivo perfusion was well tolerated as long as the mean intrahepatic temperature remained under 38 °C. Postoperative evolution of serum transaminase level was similar whatever the temperature of the perfusate. Histological lesions of the hepatic parenchyma were as severe as the temperature of the perfusate was elevated. In rats with tumors, the mortality rate was elevated in the animals with large tumors. A moderate decrease in the serum α-fetoprotein level was observed during the first days after liver perfusion. In all cases, death occurred apparently as a direct consequence of liver injury. This study defines the sensitivity of the normal or neoplastic rat liver to hyperthermia and ischemia using a model of isolated in vivo perfusion of the liver. It provides a basis for further investigations on the effect of hyperthermia on experimental liver tumors.

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