Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein ...cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.
Abstract only Extended-release niacin (ERN) produces improvements across the lipid profile in patients with dyslipidemia, but is underutilized due to flushing, a process primarily mediated by ...prostaglandin D 2 (PGD 2 ). The PGD 2 receptor antagonist, laropiprant (LRPT), reduces ERN-induced flushing in patients with dyslipidemia. This study tested the hypothesis that, after 20 weeks of the fixed-dose combination ERN/LRPT, patients who continued on ERN/LRPT would have less flushing than patients who had LRPT withdrawn, but continued on ERN alone. After a 2-week placebo run-in, 1152 patients with dyslipidemia were randomized 2:2:1 to one of three daily treatment groups: (1) ERN/LRPT 1g/20mg from 0 to 4 weeks, then ERN/LRPT 2g/40mg for the remainder of the study; (2) ERN/LRPT 1g/20mg from 0 to 4 weeks, then ERN/LRPT 2g/40mg from 5 to 20 weeks, then ERN 2g without laropiprant from 21 to 32 weeks; or (3) placebo for the duration of the study. The key endpoints were based on the Global Flushing Severity Score (GFSS) from the previously validated Flushing Symptom Questionnaire: the number of days/week with moderate or greater GFSS ≥4 (primary) and the percentage of patients with maximum GFSS ≥4 (secondary) during the post-withdrawal period of the study (weeks 21 to 32). ERN/LRPT produced significantly less flushing relative to ERN alone during the post-withdrawal period, as measured by the number of days/week with GFSS ≥4 (p<0.001; see fig) and the percentage of patients with maximum GFSS ≥4 (ERN/LRPT: 19.6%; ERN: 48.9%; Placebo: 9.2%). There were fewer drug related adverse experiences during the post-withdrawal period comparing the ERN/LRPT to the ERN treatment groups. In summary, following 20 weeks of stable maintenance therapy, dyslipidemic patients treated continuously with ERN/LRPT experienced less flushing than patients who had LRPT withdrawn, and continued with ERN alone. This study supports the long-term efficacy (> 24 weeks) of ERN/LRPT in reducing flushing symptoms.
We reviewed a 45-year experience with 459 patients who had previously untreated minor salivary gland neoplasms, 378 (82%) of which were malignant. Data were adequate for retrospective clinical ...staging in 353 of the 378 patients with malignant tumors using criteria identical to those for squamous carcinoma in the same sites. Five-, 10-, and 15-year survival rates for the patients with malignant tumors treated after 1966 were 75%, 62%, and 56%, respectively, a significant improvement compared with results reported previously. Multivariate analysis confirms that survival was significantly influenced by the clinical stage and the histologic grade, but the applicability of grading was limited to patients with mucoepidermoid carcinoma or adenocarcinoma. Ten-year overall survival was 83%, 53%, 35%, and 24% for patients with stage I through stage IV, respectively. Results in these patients are similar to those we have recently reported in patients with major salivary gland carcinomas, but we are unable to demonstrate that postoperative radiotherapy improved survival.
Primary CNS lymphoma (PCNSL), formerly rare, is being seen with increased frequency among apparently immunocompetent patients. Conventional treatment has consisted of whole-brain radiotherapy (RT) ...and corticosteroids, with a median survival of 15 to 18 months and a 3% to 4% 5-year survival. Chemotherapy has been useful in the treatment of recurrent PCNSL. In 1985 we began a treatment protocol using chemotherapy and cranial irradiation for the initial therapy of non-AIDS PCNSL.
Thirty-one patients (group A) completed the combined modality regimen. All had placement of an Ommaya reservoir and received pre-RT systemic methotrexate, 1 g/m2, plus six doses of intra-Ommaya methotrexate at 12 mg per dose. A full course of cranial RT (4,000-cGy whole-brain RT plus a 1,440-cGy boost) was followed by two cycles of high-dose cytarabine (ara-C), with each course consisting of two doses of 3 g/m2 ara-C separated by 24 hours and infused over 3 hours. During this period, 16 additional patients (group R) were treated with RT alone, either because patients refused chemotherapy or RT was initiated before our consultation; all would have been eligible to participate in the protocol. Follow-up extended through April 1, 1991.
Group A had a significantly prolonged time to recurrence (median, 41 months) compared with group R (median, 10 months; P = .003). Although median survival was doubled from 21.7 months for group R to 42.5 months for group A, this was not statistically significant because of small sample size. More importantly, group R patients received systemic chemotherapy for recurrent PCNSL, which improved survival.
The addition of chemotherapy to cranial RT for initial treatment of PCNSL significantly improved disease-free survival and contributed to overall survival; all non-AIDS patients with newly diagnosed PCNSL should be considered for combined modality therapy.
The effects of the aminobisphosphonate alendronate sodium on bone mass and markers of bone remodeling were investigated.
In a multicenter, randomized, double-blind, placebo-controlled, 2-year study, ...188 postmenopausal women, aged 42 to 75 years, with low bone mineral density (BMD) of the lumbar spine were randomly assigned to 1 of 6 daily treatment groups: placebo for 2 years, alendronate 5 or 10 mg for 2 years, alendronate 20 or 40 mg for 1 year followed by placebo for 1 year, or alendronate 40 mg for 3 months followed by 2.5 mg for 21 months. All subjects were given 500 mg/d of elemental calcium as calcium carbonate.
At each dose, alendronate produced significant reductions in markers of bone resorption and formation, and significantly increased bone mass at the lumbar spine, hip, and total body, as compared with decreases (significant at lumbar spine) in subjects receiving placebo. In the 10-mg group, mean urinary deoxypyridinoline/creatinine had declined by 47% at 3 months, and mean serum osteocalcin by 53% at 6 months. Mean changes in BMD over 24 months with 10 mg alendronate were +7.21% +/- 0.49% for the lumbar spine, +5.27% +/- 0.70% for total hip, and +2.53% +/- 0.68% for total body (each P < 0.01) compared to changes of -1.35% +/- 0.61%, -1.20% +/- 0.64% and -0.31% +/- 0.44% at these sites, respectively, with placebo treatment. Progressive increases in BMD of both lumbar spine and total hip were observed in the second year of treatment with 10 mg alendronate (both P < 0.05).
Alendronate, a potent inhibitor of bone resorption, reduces markers of bone remodeling and significantly increases BMD at the lumbar spine, hip, and total body, and is well tolerated at therapeutic doses (5 or 10 mg daily) in the treatment of osteoporosis in postmenopausal women.
Oral alendronate sodium is a potent, specific inhibitor of osteoclast-mediated bone resorption. To assess its efficacy and safety, a 3-year, randomized, double-blind, multicenter study of 478 ...postmenopausal women with Osteoporosis was conducted.
Subjects received either placebo, alendronate 5 or 10 mg/day for 3 years, or 20 mg/day for 2 years followed by 5 mg/day for 1 year (20/5 mg). All subjects received 500 mg/day of supplemental calcium. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA).
After 3 years, alendronate 10 mg induced marked increases in BMD of the lumbar spine (9.6 ± 0.4%), femoral neck (4.7 ± 0.7%) and trochanter (7.4 ± 0.6%) (mean ± SE; each P ≤ 0.001) versus decreases of 0.8 to 1.6% with placebo. Progressive increases at these sites in the alendronate 10 mg group were significant during both the second and third years. Alendronate 10 mg increased total body BMD (1.6 ± 0.3%,
P < 0.001), and prevented loss but did not increase BMD at the 1/3 forearm site. Alendronate 20/5 mg was no more effective, whereas alendronate 5 mg was significantly less effective than 10 mg at all sites. Bone turnover decreased to a stable nadir over 3 months for resorption markers (urine deoxypyridinoline) and over 6 months for formation markers (alkaline phosphatase and osteocalcin). Mean loss of stature was reduced by 41% in alendronate treated subjects (
P = 0.01).
The safety profile of alendronate was similar to that of placebo. At 10 mg, there were no trends toward increased frequency of any adverse experience except for abdominal pain, which was usually mild, transient, and resolved with continued treatment. Thus, alendronate appears to be an important advance in the treatment of Osteoporosis in postmenopausal women.
This study was conducted to evaluate clinical prognostic factors predictive of the probability of recurrence of desmoid tumor (DT).
Sixty-three patients with histologically confirmed diagnosis of DT ...were retrospectively studied. Median age at diagnosis was 13 years. Patient distribution by site was as follows: 61% extremities, 18% head and neck, 13% trunk (including 5% intraabdominal), and 8% multicentric lesions. All patients had partial or complete resections; 20 patients also received radiotherapy and/or chemotherapy.
At a median follow-up time of 6 years since first treatment, the overall actuarial probability of having one or more recurrences was 75%. Age, sex, site, size, or number of previous recurrences had no significant impact on the likelihood of recurrence. The only factor associated with an increased proportion of recurrence-free patients was a negative margin of resection (70% v 15% with positive margins; P = .006). Of the four patients with more than 3 years follow-up since chemotherapy, two recurred, and of the 11 patients with the same follow-up after radiotherapy, four recurred, including two of five patients who received a dose of 50 Gy or more. No deaths directly related to tumor invasion were observed.
A surgical approach aiming at clear margins is presently the best treatment option. When this cannot be accomplished without severe disfigurement or function impairment, partial resection is an acceptable alternative, but one associated with a high risk of regrowth. Whether adjuvant strategies should be used in this situation remains to be addressed.
Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D..., which leads to poor patient compliance and suboptimal dosing. This phase ...II dose-ranging study was designed to assess whether the prostaglandin D... receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients. (ProQuest: ... denotes formulae/symbols omitted.)
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