27Moderate physical exercise does not cause any changes in the plasma levels of the catabolic hormone cortisol and the anabolic hormone testosterone compared with the concentrations during a control day. In studies on army recruits, however, fit compared to unfit men tended to have smaller mean decreases in plasma testosterone and free testosterone index during the day both during a control day and during a day with submaximal marching exercise. After 4 months training, the mean plasma testosterone and free testosterone index tended to decrease less during both control and marching exercise days, and this was more evident in the well-conditioned subjects. However, very fit male athletes, who have been training for many years, and sedentary men have identical plasma testosterone levels and serum sex hormone binding globulin binding capacities (SHBG). Intense physical exercise invariably leads to an increase in plasma cortisol and a decrease in plasma testosterone compared with the concentrations during a control day. However, the percentage of free testosterone seems to increase cornpensatorily, which in many individuals keeps the absolute free testosterone level constant or even higher despite no change or slight increase in SHBG. Prolonged exhaustive physical exercise in men results in a decrease in plasma testosterone even down to normal female levels, and there is a constant increase in SHBG resulting in very low free testosterone concentrations. It is known from studies in rats that a low level of androgens results in an increase in the binding of cortisol in muscle tissue probably due to an increase in the number of cortisol receptors. This in combination with the high level of cortisol during prolonged exhaustive physical exercise may lead to a situation in which the protein catabolic events in the muscle cells supersedes the anabolic ones. Rats trained on a treadmill and sedentary rats have identical plasma and testicular testosterone concentrations, identical plasma LH levels, and training has no effect on Leydig cell LH and prolactin receptors. When these rats ran until exhaustion, the trained rats were able to run much longer (up to 3 h) than the untrained rats. In this experiment, the decrease in plasma testosterone was greater in the trained rats compared with the untrained ones, and also the testicular concentration of testosterone, androstenedione, and progesterone fell to lower levels in the trained rats after the exhaustive exercise. The plasma LH levels remained unchanged. This suggests that the decrease in plasma testosterone is due to a reduction in testicular testosterone production and a depletion of the testosterone stores and that the testosterone-LH feedback mechanism is no longer functioning in these exhausted animals. However, when the Leydig cells were incubated in vitro with HCG at different concentrations, it could be shown that in trained rats Leydig cell testosterone and cyclic AMP production was significantly greater than in sedentary rats. All these results are in good agreement w...

Autologous hematopoietic stem cell transplantation was used for treatment of 384 patients with multiple myeloma in 37 centers during the years 1986-1994. An analysis of prognostic factors was performed in 207 of these patients. One hundred forty one were males and 66 females, and median age was 49 years (range, 24-68). Actuarial survival at 78 months is 45%. Factors associated with a good prognosis were: response on chemotherapy immediately pretransplant, administration of only one treatment regimen, a low serum-beta 2-Microglobulin value at diagnosis and the use of a conditioning regimen including melphalan. In a multivariate analysis, response status pretransplant, age < 45 years, melphalan conditioning and non-TBI conditioning were independently predictive for longer survival, while transplantation after only one line of primary treatment and isotype other than light-chain were of borderline significance. Post-transplant alpha-interferon treatment was associated with improved survival in responsive patients. Eighteen patients treated in one center (Huddinge) passed a double autograft program, and 14 are in continuous complete remission ([CR]; n = 10) or good partial remission (n = 4) at a median time of 17 months after the first transplant (range, 2-38). In five CR patients, polymerase chain reaction (PCR)-analysis of the clone-specific immunoglobulin-rearrangement was performed, and four are PCR-negative up to 33+ months after the first transplantation. We conclude that autografting in myeloma is most effective when applied early in the course of disease in younger, chemotherapy-reponsive patients. Alpha-interferon maintaince treatment seems to be beneficial with respect to improved survival.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of ursodeoxycholic acid (UDCA) in the prevention of hepatic complications after allogeneic stem cell transplantation was studied in a prospective randomized open-label multicenter trial. A total of 242 patients were allocated to receive (n ‫؍‬ 123) or not to receive (n ‫؍‬ 119) UDCA in the dose of 12 mg/kg/d orally from the day preceding the conditioning until day 90 after transplantation. In the UDCA-treated group a significantly smaller proportion of patients developed a serum bilirubin level exceeding 50 M (18 of 123 versus 31 of 119, P ‫؍‬ .04), and similarly a smaller proportion of patients exceeded the alanine aminotransferase level of 100 U/L. There was no difference in the incidence of veno-occlusive disease of the liver. Compared to the control group, in the UDCA-treated group there was a nonsignificant trend toward a lower overall incidence of acute graft-versushost disease (GVHD) and a significantly lower incidence of grade III to IV acute GVHD (5 of 123 versus 17 of 119, P ‫؍‬ .01), stage II to IV liver and intestinal GVHD, and stage III to IV skin GVHD. There was no difference in the incidence of chronic GVHD or in the relapse rate. Among the patients given UDCA, the survival at 1 year was significantly better, 71% versus 55% (P ‫؍‬ .02), and the nonrelapse mortality rate was lower, 19% versus 34% (P ‫؍‬ .01), than in the control group. There were significantly more deaths in GVHD in the control group. In conclusion, UDCA administration reduced hepatic problems and severe acute GVHD and improved survival. These results suggest a role for UDCA in the prevention of transplantrelated complications in allogeneic transplantation.

Biologic and clinical observations suggest that combining imatinib with IFN-␣ may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN␣2b (Peg-IFN-␣2b) 50 g weekly and imatinib 400 mg daily (n ‫؍‬ 56) or to receive imatinib 400 mg daily monotherapy (n ‫؍‬ 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-␣2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-␣2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P ‫؍‬ .002). The MMR rate increased with the duration of Peg-IFN␣2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-␣2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-␣2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent. (Blood. 2011;118(12):3228-3235)