Unexplained elevated maternal serum alpha-fetoprotein is not predictive of adverse perinatal outcome in an indigent urban population.

OBJECTIVE: The null hypothesis of this study is that in an urban, indigent obstetric population at high risk for adverse perinatal outcome, unexplained elevations of maternal serum alpha-fetoprotein are not an additional predictor of adverse perinatal outcome. STUDY DESIGN: Perinatal outcomes of 72 patients from a clinic for indigent patients with unexplained elevated maternal serum alpha-fetoprotein levels were compared with those of matched controls from the same population with normal maternal serum alpha-fetoprotein levels. Subjects and controls were matched for age, race, parity, and presence or absence of Hollister risk factors. The frequency of adverse perinatal outcome in the two groups was subjected to matched-pair chi 2 analysis. RESULTS: Adverse perinatal outcome occurred in 38.9% (28 of 72) of subjects with unexplained elevated maternal serum alpha-fetoprotein levels greater than or equal to 2.5 multiples of the median, compared with 31.9% (23 of 72) of controls with normal maternal serum alpha-fetoprotein levels (p = 0.5). No statistically significant difference in adverse perinatal outcomes was found. CONCLUSIONS: Elevated maternal serum alpha-fetoprotein levels offer little if any additional predictive value for adverse perinatal outcome in populations already at high risk for such outcomes on the basis of obstetric or socioeconomic criteria.     

Pradigastat disposition in humans: in vivo and in vitro investigations

1.?Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients.

2.?Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans.

3.?In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma.

4.?In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed.

5.?Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.     

Phase II study of carboplatin in recurrent ovarian cancer: severe hematologic toxicity in previously treated patients

Summary Carboplatin (CBDCA) is a second-generation cisplatin analog that has shown activity in early clinical trials. Its spectrum of toxicity is quantitatively and qualitatively different from that of the parent compound. Between November 1984 and September 1986 we conducted a phase II trial of CBDCA in 46 women with epithelial ovarian cancer. All patients had undergone at least one prior chemotherapy regimen; 41 (89%) had previously received cisplatin (mean cumulative dose, 540 mg/m²). The CBDCA dose was based on renal function and was injected i. v. once every 4 weeks. Patients were stratified on the basis of baseline creatinine clearance: those with a baseline creatinine clearance of 60 ml/min received 400 mg/m² CBDCA; those with a creatinine clearance between 30 and 60 ml/min received an initial dose calculated according to a previously published formula [2, 3] that corrected for renal insufficiency and projected nadir platelet counts of 75,000/mm³. Of 41 evaluable patients, 6 (15%) had an objective response [2 complete responses (CRs); 4 partial responses (PRs)]; 5 of the 6 responders had previously responded to cisplatin treatment. No responses were observed in 12 patients who had not responded to prior cisplatin therapy. Significant hematologic toxicity was seen. Of 18 patients with a creatinine clearance of 60 ml/min (dose, 400 mg/m²), 6 had nadir platelet counts of <25,000/mm³, 4 with symptomatic bleeding. Of the 21 evaluable patients for whom the dose-modification formula was applied, 10 had nadir platelet counts of <75,000/mm³; 5 had counts of <50,000/mm³. CBDCA has activity even in patients who have previously undergone extensive cisplatin therapy; however, its toxicity is variable and thrombocytopenia is dose-limiting. We did not confirm the ability of the above-mentioned formula to calculate the CBDCA dose and accurately predict the nadir platelet count for all patients. Other factors, such as prior radiotherapy, may also be important in the dosing of CBDCA in pretreated patients.Supported in part by a grant from Bristol Myers Company Pharmaceutical Research and Development Division, CRU CA 16087 and CRU-96.N. Colombo is the recipient of a fellowship from the American Italian Foundation for Cancer Research.     

The "natural history" of ulcerative colitis: an analysis of the placebo response

We have attempted to elucidate the "natural history" of ulcerative colitis by studying the placebo groups of 11 controlled trials of 185 patients with active disease. Most (182) of the patients were mild to moderately ill, but 3 had severe colitis. They were studied by endoscopic, pathologic, and/or clinical criteria and followed for 15-42 days. Up to 52% improved clinically and 59% sigmoidoscopically. Relapses commonly occurred within 2 months of these "spontaneous" improvements. In another six trials of 174 patients in remission receiving only placebo therapy (134 followed for 6 months and 40 for 12 months), up to 51% remained in remission. Favorable predictive factors for continued remission included a normal rectal mucosa on sigmoidoscopy, limited extent of colitis, and remission recently achieved by active therapy or maintained by therapy for at least 1 year before study entry. Thus, patients can get and stay better with no "specific" therapy. We have clarified advantageous predictive factors.     

Preoperative chemo-radiotherapy in advanced head and neck cancer

In a prospective evaluation, two preoperative courses of methotrexate, bleomycin, and cisplatin combined with 2,000 rad/10 fractions ("chemo-radiotherapy") yielded 78% responses rates in previously untreated advanced head and neck cancer. Similarly staged patients receiving preoperative irradiation of 5,000 rad alone had a 67% response rate. Treatment-related mortality in the chemo-radiotherapy patients was equal to that seen with standard combinations of surgery and preoperative or postoperative irradiation. At 24 months, disease-free survival is 47% with chemo-radiotherapy vs 33% with standard therapy; however, patients benefiting most from the former approach were those with T4 primary lesions or N3a neck nodes.