Arithmetic versus harmonic mean values for cyclosporin-A pharmacokinetic parameters.

The harmonic and arithmetic mean values for volume of distribution at steady state, half-life, and clearance of intravenous cyclosporin-A were calculated using an index set of 22 renal transplant candidates to determine if harmonic mean values provide a less biased estimate of central tendency than arithmetic mean values. Cyclosporin-A was measured using a nonspecific radioimmune assay method. The arithmetic mean value for volume of distribution was 16% larger than calculations by the harmonic mean method. Similarly, the arithmetic mean half-life and clearance values were larger than harmonic mean values by 10% and 15%, respectively. However, 95% confidence intervals for these pharmacokinetic parameters overlapped. When these mean pharmacokinetic parameter values were used to predict actual values in a test group of 22 renal transplant candidates receiving cyclosporin-A, similar levels of precision were demonstrated by either method. Both methods produced positively biased predictions for volume of distribution and clearance. However, these differences were not significant. These findings suggest there is little practical value for the use of harmonic mean calculations to describe the central tendency of pharmacokinetic parameters of cyclosporin-A under the conditions studied. The value of harmonic mean values for pharmacokinetic parameters in other patient populations or with other assay methods for cyclosporin remain to be studied.     

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.     

Survival in Chronic Lymphocytic Leukemia

Survival of 839 chronic lymphocytic leukemia patients has been reviewed in relationto a number of patient and disease characteristics. Over-all, the relative 5-yr survival rate was 44%. Studying survival byage and sex led to the following observations: Dividing age into intervals < 50,50-59, 60-69, 70-79, and 80 yr and over,relative survival declined with increasingage; relative 5-yr survival for females washigher than that for males-50% versus 41%.This pattern of superior survival of femalesover males was noted in all but one of theage intervals. Survival was negatively associated with the presence of recordedclinical signs and symptoms, hematologicalabnormalities, and pathological bone marrow findings. Differences in survival werealso found by treatment category and interval from diagnosis to initiation of treatment. Adjustment for differences in distribution of each of these variables did notmaterially diminish the survival differencesnoted by age and sex. An unexpected pattern of survival in relation to white bloodcount level was noted. Survival increasedwith increasing white blood count at diagnosis, peaking in the interval at 25,000-49,000, and decreasing after that. Whensurvival by white blood count was adjustedfor some variables which were found to beassociated with survival, the gradient wasstill noted, though somewhat reduced.

Submitted on June 12, 1972 Revised on February 12, 1973 Accepted on February 16, 1973     

Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer

Sulf-2 is an endosulfatase with activity against glucosamine-6-sulfate modifications within subregions of intact heparin. The enzyme has the potential to modify the sulfation status of extracellular heparan sulfate proteoglycan (HSPG) glycosaminoglycan chains and thereby to regulate interactions with HSPG-binding proteins. In the present investigation, data mining from published studies was employed to establish Sulf-2 mRNA upregulation in human breast cancer. We further found that cultured breast carcinoma cells expressed Sulf-2 mRNA and released enzymatically active proteins into conditioned medium. In two mouse models of mammary carcinoma, Sulf-2 mRNA was upregulated in comparison to its expression in normal mammary gland. Although mRNA was present in normal tissues, Sulf-2 protein was undetectable; it was, however, detected in some premalignant lesions and in tumors. The protein was localized to the epithelial cells of the tumors. In support of the possible mechanistic relevance of Sulf-2 upregulation in tumors, purified recombinant Sulf-2 promoted angiogenesis in the chick chorioallantoic membrane assay.