A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer.

BACKGROUND: Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies METHODS: Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test. RESULTS: Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity. CONCLUSIONS: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.

Single dose cefazolin prophylaxis for postcesarean infections: before vs. after cord clamping.

The objective of this study was to test the hypothesis that 1 g of cefazolin administered preoperatively is no more effective than the same dose administered after cord clamping in preventing postcesarean infectious morbidity. Ninety consecutive laboring subjects undergoing cesarean delivery at > or = 37 weeks gestation were randomized by computer to receive 1 g of cefazolin intravenously preoperatively or after cord clamping in a double-blinded, placebo-controlled study. The 2 groups were compared for differences in maternal and neonatal demographics, and intrapartum and operative characteristics associated with postcesarean infection. Primary maternal outcome variables were endometritis or wound infection. Secondary outcomes included intra-abdominal abscess formation, septic pelvic thrombophlebitis, pneumonia, or urinary tract infection. Neonatal outcomes included sepsis screens, sepsis, pneumonia, and meningitis. Subjects were followed 6 weeks postoperatively for late complications. Subjects receiving cefazolin preoperatively or after cord clamping had similar maternal and neonatal demographics, and intrapartum and operative characteristics. One patient in the former group experienced both endometritis and wound infection. In the latter group, 2 wound infections and 1 case of endometritis occurred (P = 0.35). There were no secondary maternal infections. Two infants treated for pneumonia and 2 other infants readmitted with febrile illnesses were born to mothers receiving cefazolin preoperatively. Overall, 8 neonates were evaluated for suspected sepsis and all had negative studies. Six of these infants' mothers received cefazolin preoperatively (P = 0.28). In conclusion, 1 gram of cefazolin preoperatively is no more effective than the same dose administered after cord clamping in preventing postcesarean infectious morbidity, but is associated with a trend toward increased suspected sepsis in the newborn. However, this trend may be related to differences between the study groups' risk factors for infection.

In utero hypoxic ischemia decreases the cholinergic agonist-stimulated poly-phosphoinositide turnover in the developing rat brain.

Perinatal hypoxic-ischemic (HI) insult is known to cause cellular and molecular disturbances leading to functional and behavioral abnormalities during brain development. In this study, we examined the effects of an in utero HI insult on poly-phosphoinositide turnover in vivo in the cerebrum and cerebellum as well as cholinergic-stimulated turnover in cortical slices from developing rat brain. In utero HI treatment was carried out by clamping the uterine blood vessels of near-term fetuses for 5, 10 and 15 min followed by resuscitation of the newborn pups. The in vivo protocol for examining poly-PI signaling activity in 2 week-old pup brain involved intracerebral injection of [3H]inositol for 16 hr and subsequent intraperitoneal injection with lithium (8 meq/kg) for 4 hr prior to decapitation. In the control pups, lithium elicited a 2.6 fold increase in labeled inositol phosphate (IP) in the cerebrum as compared to a 1.3 fold increase in the cerebellum. In utero HI insult (5 to 15 min) resulted in a small increase in labeled IP in the cerebrum but not in the cerebellum. Carbachol stimulation of poly-PI turnover was examined in brain slices prelabeled with [3H]inositol in vivo. Incubation of the prelabeled slices with carbachol in the presence of LiCl (10 mM) resulted in a time-, dose- and age-dependent increase in labeled IP. Brain slices from 2 week-old pups that experienced in utero HI-treatment for 10 and 15 min (but not 5 min) showed a significant decrease in carbachol-stimulation of labeled IP as compared with control pups. These results indicate the effects of in utero HI on the choninergic-stimulated poly-PI signaling pathway and its implication on related functional deficits in the developing brain.

Intrauterine hypoxia-ischemia increases N-methyl-D-aspartate-induced cGMP formation and glutamate accumulation in cultured rat cerebellar granule cells.

Effects of intrauterine hypoxia-ischemia (HI) on brain functional development in the term rat were examined in cerebellar granule cell cultures obtained from an in utero HI model. On gestation d 17, HI conditions were achieved by complete clamping of the uterine vasculature for designated durations followed by removal of the clamps to permit reperfusion. Sham operation (surgery without vasculature clamping) was performed as the control. After surgery, the uterine horns were returned to dam's abdomen to let the pups deliver naturally. Severe HI insult from the surgical manipulation was evident in that the lactate levels of fetal brain increased, and fetal blood pH decreased with the duration of vasculature clamping up to 1 h. The experimental HI insult up to 1 h did not affect fetal survival rate, but retarded growth of fetuses or newborns was observed in the 1 h HI group. N-Methyl-D-aspartate (NMDA)- and kainate (KA)-stimulated cGMP formation and glutamate accumulation were measured in cerebellar granule cell cultures from 8-d-old pups suffering from various durations of antenatal HI insult. NMDA (100 microM)-induced elevation of cGMP was further augmented by a 10-35-min HI insult as compared with the control cells (62.4-78.2 versus 49 pmol/mg protein). In the presence of L-NG-monomethyl-arginine (L-NMMA, 150 microM), a nitric oxide synthase inhibitor, NMDA-induced cGMP formation was blocked, and the blockade of cGMP formation by L-NMMA (10 microM) could be reversed by simultaneous application of 1 mM arginine in both control and HI cells.(ABSTRACT TRUNCATED AT 250 WORDS)