Compared with the general population, members of Li-Fraumeni syndrome families have an exceptionally high risk of developing multiple primary cancers. The excess risk of additional primary cancers is mainly for cancers that are characteristic of Li-Fraumeni syndrome, with the highest risk observed for survivors of childhood cancers. Cancer survivors in these families should be closely monitored for early manifestations of new cancers.

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Inhibition of Ca 2؉ mobilization by cyclic nucleotides is central to the mechanism whereby endothelial-derived prostacyclin and nitric oxide limit platelet activation in the intact circulation. However, we show that ϳ 50% of the Ca 2؉ response after stimulation of glycoprotein VI (GPVI) by collagen, or of Toll-like 2/1 receptors by Pam 3 Cys-Ser-(Lys) 4 (Pam 3 CSK 4 ), is resistant to prostacyclin. At low agonist concentrations, the prostacyclinresistant Ca 2؉ response was predominantly because of P2X1 receptors activated by ATP release via a phospholipase-C-coupled secretory pathway requiring both protein kinase C and cytosolic Ca 2؉ elevation. At higher agonist concentrations, an additional pathway was observed because of intracellular Ca 2؉ release that also depended on activation of phospholipase C and, for TLR 2/1, PI3-kinase. Secondary activation of P2X1-dependent Ca 2؉ influx also persisted in the presence of nitric oxide, delivered from spermine NONOate, or increased ectonucleotidase levels (apyrase). Surprisingly, apyrase was more effective than prostacyclin and NO at limiting secondary P2X1 activation. Dilution of platelets reduced the average extracellular ATP level without affecting the percentage contribution of P2X1 receptors to collagenevoked Ca 2؉ responses, indicating a highly efficient activation mechanism by local ATP. In conclusion, platelets possess inhibitor-resistant Ca 2؉ IntroductionPlatelet activation is the initial required event during the physiologic process of hemostasis. With increasing age, the onset of atherosclerosis lowers the threshold for platelet reactivity and consequently the risk of thrombosis. In the intact circulation, there are inhibitors of platelet reactivity that serve to maintain blood fluidity. These inhibitors include endothelial-derived prostacyclin (PGI 2 ) and nitric oxide (NO) that elevate intraplatelet cyclic AMP (cAMP) and cyclic GMP (cGMP), respectively. 1 cAMP-and cGMP-dependent kinases target several platelet signaling pathways, particularly mobilization of the key second messenger Ca 2ϩ . 1,2 Degradation of nucleotides by enzymes in the plasma and on the surface of endothelium and leukocytes represents a further important inhibitory influence. The dominant ectonucleotidase CD39 converts the platelet agonists ATP and ADP to inert AMP, and AMP is subsequently degraded by CD73 to adenosine and therefore further inhibits platelets through stimulation of G scoupled A 2a and A 2b receptors. [3][4][5] After breach of vascular integrity, disruption of the endothelial layer leads to local loss of these inhibitory pathways that will facilitate platelet activation by adhesive macromolecules such as collagen and diffusible agonists such as ADP, thromboxane A 2 (TxA 2 ), and thrombin. 6 In identifying potential strategies to manage thrombosis, it is therefore important to consider the relative effectiveness of natural platelet inhibitory influences on various platelet activation pathways.Platelets possess multiple mechanisms whereby agonists can generate an incre...

To determine the predictive values of using different sizes on CT as criteria for the detection of retroperitoneal lymph-node metastases in patients with early-stage (nodes 5 cm or lass in diameter) primary nonseminomatous testicular cancer, we performed a retrospective analysis of 51 patients. Measurements oflymph-node transaxial diameters on CT were correlated with histologic findings at lymph-node dissection or with response to initial chemotherapy. All patients had normal serum markers(alpha-fetoprotein, human chorionic gonadotropin) after orchiectomy. The frequency of lymph-node metastases in this population was 51%. When a CT criterion of 5 mm was used, the negative predictive value was 79%; the posftive predictive value, 62%; the specificity, 44%; and the sensitivity, 88%. With a criterion of 15 mm, the negative predictive value was 63%; the posftive predictive value, 71%; the specificity, 76%; and the sensitivity, 58%. Metastases in retroperitoneal lymph nodes that appeared within normal limits (i.e., had normal transaxial diameters) on CT were the limiting factor in the abllfty of CT to exclude the presence of metastases.We conclude that using smaller sizes on CT scans as the criteria for detection of