Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.

PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.     

Kappa 3 receptors and levorphanol-induced analgesia.

Levorphanol is a widely used opiate analgesic. Although structurally related to morphine, levorphanol has high affinity for a number of receptor subtypes, including both kappa 1 and kappa 3. Prior reports had implicated a kappa component of levorphanol-induced antinociception. Evidence is now presented suggesting that levorphanol-induced analgesia is produced by a mixture of mu and kappa 3 mechanisms. Levorphanol was a potent analgesic in the tail-flick assay, when given systemically, spinally or supraspinally. Isobolographic analysis of the combined administration of levorphanol, spinally and supraspinally implied synergistic interactions. Naloxonazine reduced levorphanol-induced analgesia, implicating a role for mu1 receptors. The kappa 1 antagonist nor-binaltorphimine at a dose which reversed analgesia induced by U50,488H did not antagonize levorphanol-induced analgesia. Additional studies revealed no cross tolerance in either direction, between levorphanol with the kappa 1 analgesic U50,488H. Together, these results strongly argue against a role for kappa 1 receptors in levorphanol-induced analgesia. However, mice tolerant to the kappa 3 analgesic, naloxone benzoylhydrazone (NalBzoH), showed cross tolerance to levorphanol, implying a role of kappa 3 mechanisms in levorphanol-induced analgesia.     

Increased sensitivity of virus-infected cells to inhibitors of protein synthesis does not correlate with changes in plasma membrane permeability

Semliki Forest virus-infected BHK cells or herpes simplex virus-infected Vero cells were incubated with the protein synthesis inhibitors hygromycin B and gougerotin. Infected cells take up no more [3H]hygromycin or [3H]gougerotin than do mock-infected cells, at a time p.i. at which either compound is more inhibitory to protein synthesis in infected, than in mock-infected cells. The concentrations of hygromycin and gougerotin required to inhibit protein synthesis in intact cells (irrespective of whether they are infected or not) are several orders of magnitude higher than those required in either permeabilized cells or in cell-free systems. Infected cells take up 86Rb+ at the same rate as mock-infected cells, their intracellular content of K+ is the same, and the activity of the Na+ pump is the same. It is concluded that the increased efficacy of hygromycin and gougerotin in virus-infected cells is a consequence of altered intracellular compartmentation and that increases in permeability of the plasma membrane, if any, are so small as to be undetectable by direct methods.     

Is 18F-FDG PET/CT useful for imaging and management of patients with suspected occult recurrence of cancer?

Rising serum tumor markers may be associated with negative imaging in the presence of cancer. CT and (18)F-FDG PET may yield incongruent results in the assessment of tumor recurrence. The present study evaluates the incremental role of (18)F-FDG PET/CT for the diagnosis and management of cancer patients with increasing levels of tumor markers as the sole indicator of potential recurrence after initial successful treatment. METHODS: Thirty-six cancer patients with increasing levels of tumor markers during follow-up and negative CT underwent (18)F-FDG PET/CT, which showed 111 sites of increased tracer uptake. PET/CT was compared with PET results on a site-based analysis for characterization of (18)F-FDG foci and on a patient-based analysis for diagnosis of recurrence. The clinical impact of PET/CT on further patient management was evaluated. RESULTS: Thirty patients (83%) had recurrence in 85 malignant sites (77%). For the site-based analysis, PET had a sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 96%, 50%, 85%, 85%, and 82%, respectively, as compared with the performance indices of PET/CT of 100%, 89%, 97%, 97%, and 100%, respectively. There was a statistically significant difference between the specificity (P < 0.05) and accuracy (P < 0.001) of PET and PET/CT for precise characterization of suspected lesions. For the patient-based analysis, PET had a sensitivity, specificity, and accuracy of 93%, 50%, and 86%, respectively, as compared with PET/CT with values of 93%, 67%, and 89%, respectively (P = not significant). PET/CT was the single modality that directed further management and treatment planning in 12 patients (33%). CONCLUSION: The results of this study indicate that PET/CT may improve the accuracy of occult cancer detection and further lead to management changes in patients with increasing levels of tumor markers as the sole suspicion of recurrent malignancy.     

In vitro bioactivities of various forms of GnRH in relation to their susceptibility to degradation at the pituitary level in the rainbow trout, Oncorhynchus mykiss.

In vitro potencies of native and modified forms of salmon and mammalian gonadotropin-releasing hormone (GnRH) were studied in relation with their susceptibility to degradation by intact pituitary cells maintained in culture. The kinetics of degradation and the origin of the proteases involved in this process were examined. All the molecules tested (native and modified forms) were equipotent at doses between 10(-6) and 10(-7) M in inducing GtH release by cultured pituitary cells. On the other hand, their effectiveness differed at 10(-9) and 10(-8) M leading to the establishment of the following hierarchy of bioactivity: the native forms, LHRH and sGnRH, were the less potent, the fish analogues (DAla6Pro9Net)sGnRH and (DArg6Pro9Net)sGnRH were the more potent, and mammalian analogues with substitutions at position 6 and/or 10 were intermediate in potency. The native form sGnRH was weakly degraded while no degradation of the modified molecules was observed. The degradation of the native sGnRH occurred after 12 and 24 hr of incubation and the results indicate that the peptidases involved are released from the cells into the incubation medium.     

Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder.

BACKGROUND: Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS: Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS: Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS: The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.     

A statistically significant sex difference in the number of colony-forming cells from human peripheral blood

 The number of colony-forming cells (CFC) in the peripheral blood (PB) of 43 volunteers was examined using a semisolid clonogenic culture assay. In all, 22 male (age 21–39 years) and 21 female individuals (age 21–39 years) were tested, ten of each group twice to examine the intraindividual variability of colony-forming cells in PB. A statistically significant sex difference in the number of CFC, erythroblastic colonies (BFU-E), and granulocyte/macrophage colonies (CFU-GM) in PB was detected in favor of male individuals. No significant difference between female and male PB was found for the number of CFU-GEMM. The intraindividual variability of CFC and BFU-E was significantly higher in female donors. These results support previous reports by others on a potential influence of sex steroids on hematopoiesis. Received: 8 November 1996 / Accepted: 4 April 1997     

Chronic lithium treatment increases the phosphorylation of a 64-kDa protein in rat brains

Despite the wide clinical use of lithium in the treatment of manic depressive illness there is no adequate explanation for its mechanism of action. In the light of lithium's suggestive effects on the second messenger system in the brain, we studied the effects of chronic dietary lithium treatment (achieving blood levels in the therapeutic range) on protein phosphorylation in different areas of rat brain. An increase in the phosphorylation of a 64-kDa membrane-associated protein was evident in the lithium-treated rats compared to controls. This increase was observed only under basal phosphorylating conditions and was abolished when the phosphorylation was performed in the presence of Ca²⁺ or Ca²⁺ and calmodulin. The possibility that this 64-kDa protein affected by lithium is the beta-subunit of the calmodulin-dependent protein kinase or a different protein which co-migrates with it is discussed.