Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.     

Electrospray ionization mass spectrometry identification of fibrinogen Banks Peninsula (gamma280Tyr-->Cys): a new variant with defective polymerization

cis-Diamminedichloroplatinum (cisplatin) is an important anticancer drug used to treat solid tumors. The nephrotoxicity of cisplatin is recognized as the most important dose-limiting factor, but high doses of cisplatin also produce hepatotoxicity. However, little is known about cisplatin-induced liver injury and the role of metallothionein, a cysteine-rich, metal-binding protein, in modulating its hepatotoxicity. This study was designed to examine cisplatin hepatotoxicity in control and metallothionein-I/II knockout (MT-null) mice. Animals were given a single injection of cisplatin (50-200 mumol/kg i.p.), and liver injury was evaluated 3-16 h later. Cisplatin produced dose- and time-dependent liver injury, as evidenced by increased serum activity of alanine aminotransferase (ALT), as well as by histopathology. Apoptosis, rather than necrosis, predominates in cisplatin-induced liver injury, as indicated by increased numbers of apoptotic cells (hematoxylin and eosin staining), in situ apoptotic DNA detection, and DNA fragmentation on agarose gel electrophoresis. MT-null mice were more sensitive than controls to cisplatin-induced hepatotoxicity. Cisplatin (200 mumol/kg) was lethal to 12% of control mice, but 60% of MT-null mice died within 16 h. At the dose of 150 mumol/kg, serum ALT activities were increased 2-fold in control mice compared to 6.5-fold in MT-null mice. Apoptotic lesions were more pronounced in MT-null than in control mice. MT-null mice were also more susceptible than controls to cisplatin-induced nephrotoxicity, as evidenced by having higher blood urea nitrogen concentrations. Furthermore, cultured MT-null hepatocytes were more sensitive than control cells to the cytotoxicity of cisplatin (50-200 microM), as indicated by lactate dehydrogenase leakage into the medium. These results demonstrate that (1) high doses of cisplatin produce hepatotoxicity, with apoptosis as the major lesion, and (2) MT protects against cisplatin-induced liver injury.     

Personal performance profiles: a useful adjunct to quality assurance in cervical cytology

The purpose of this study was to determine whether the morphology of the midface differed in subjects with a retrognathic midfacial appearance (Class III malocclusions) using a combination of morphometric and cephalometric analyses. After obtaining appropriate consent, lateral cephalographs of 133 children of European-American descent, ages 5-11 years, were compared: 73 had Class III malocclusion, 60 had normal (Class I) occlusion. The cephalographs were traced and subdivided into seven age- and sex-matched groups. Average geometries based upon seven nodes (pterygoid point, PTS; rhinion, RO; posterior nasal spine, PNS; midpalatal point, MPP; anterior nasal spine, ANS; subspinale, A; prosthion, Pr), scaled to an equivalent size, were compared using a Procrustes routine. Euclidean distance matrix analysis (EDMA) was employed to localize differences in morphology. Bivariate analyses on unscaled data utilizing nine linear and six angular measurements were also undertaken. Results from Procrustes and EDMA analyses indicated that although the overall midfacial configurations differed statistically (P < 0.05), only about half of the seven age sub-groups maintained significance. Similarly, only four of the nine linear measures (PNS-MPP, MPP-ANS, A-Pr and PTS-RO) and two of the six angular parameters (PTS-RO-ANS and ANS-A-Pr) tested were significantly different (P < 0.05). Therefore, midfacial morphometric variability and morphological diversity may mask statistical differences. It is concluded that the midface may be the defining craniofacial component in the final appearance of Class III malocclusions compared to other craniofacial components, including the cranial base and mandible.     

Long-term regulation of leptin expression is correlated with adipocyte number in obese rats

OBJECTIVE: To investigate long-term regulation of leptin expression in adipose tissues of obese JCR:LA-corpulent rats, which have been shown to overexpress leptin. DESIGN: Manipulation of adipose tissue growth in obese rats by dietary restriction. INTERVENTIONS: Weanling female obese rats were maintained on 1 of 3 diets until 8 months old. One group was allowed to feed ad libitum, the second was pair-fed with lean rats, and the third had food intake restricted to maintain weights equal to those of age-matched lean rats. OUTCOME MEASURES: Body and fat pad weights, leptin messenger RNA (mRNA) levels, and size and number of adipocytes in retroperitoneal fat pads. RESULTS: Adipose tissue mass was increased 6-fold in the obese rats compared with the lean ones, despite equal body weight and intake restriction that was sufficient to impair growth. Although leptin mRNA level was down-regulated by intake restriction, it was still twice as elevated in the obese rats as in the lean ones, and was highly correlated with specific fat pad mass and adipocyte number, but not with size. CONCLUSIONS: These data suggest that leptin expression is correlated with adipocyte number within a fat pad, and that there is inappropriate hepatic de novo synthesis and storage of triacylglycerols in obese rats. A role for leptin in nutrient partitioning is proposed.     

Statistical design of REACT (Rapid Early Action for Coronary Treatment), a multisite community trial with continual data collection

Unusual problems in statistical design were faced by Rapid Early Action for Coronary Treatment (REACT), a multisite trial testing a community intervention to reduce the delay between onset of symptoms of acute myocardial infarction (MI) and patients' arrival at a hospital emergency department. In 20 pair-matched U.S. communities, hospital staff members recorded delay time throughout a 4-month baseline period and the subsequent 18-month intervention period, during which one randomly selected community of each pair received a campaign of public and professional education. To exploit the continual nature of its data-collection protocol, REACT estimated the trend of delay time separately in each community by linear regression, adjusting for age, sex, and history of MI, and compared the ten adjusted slopes from intervention communities with those from control communities by a paired t-test. Power calculations based on the analytical model showed that with K=600-800 cases per community, REACT would have 80% power to demonstrate a differential reduction of 30 min in mean delay time between intervention and control communities, as well as effects on a variety of secondary outcomes. Sensitivity analysis confirmed that the number of communities was optimal within constraints of funding and that the detectable effect depended weakly on the effectiveness of matching but strongly on K, helping the investigators set operational priorities. The methodologic strategy developed for REACT should prove useful in the design of similar trials in the future.     

Outcome of coronary bypass surgery versus coronary angioplasty in diabetic patients with multivessel coronary artery disease

The coloration of cells of the cyanobacterium Synechococcus sp. PCC 7002 changed from normal blue-green to yellow-green when cells were grown at 15 degrees C in a medium containing nitrate as the sole nitrogen source. This change of coloration was similar to a general response to nutrient deprivation (chlorosis). For the chlorotic cells at 15 degrees C, the total amounts of phycobiliproteins and chlorophyll a decreased, high levels of glycogen accumulated, and growth was arithmetic rather than exponential. These changes in composition and growth occurred in cells grown at low (50 microE m-2 s-1) as well as high (250 microE m-2 s-1) light intensity. After a temperature shift-up to 38 degrees C, chlorotic cells rapidly regained their normal blue-green coloration and normal exponential growth rate within 7 h. When cells were grown at 15 degrees C in a medium containing urea as the reduced nitrogen source, cells grew exponentially and the symptoms of chlorosis were not observed. The decrease in photosynthetic oxygen evolution activity at low temperature was much smaller than the decrease in growth rate for cells grown on nitrate as the nitrogen source. These studies demonstrate that low-temperature-induced chlorosis of Synechococcus sp. PCC 7002 is caused by nitrogen limitation and is not the result of limited photosynthetic activity or photodamage to the photosynthetic apparatus, and that nitrogen assimilation is an important aspect of the low-temperature physiology of cyanobacteria.     

Initial experience with endovascular aneurysm repair: comparison of early results with outcome of conventional open repair

PURPOSE: To determine the safety, effectiveness, and problems encountered with endovascular repair of abdominal aortic aneurysm (AAA). Initial experience with endoluminal stent grafts was examined and compared with outcome for a matched concurrent control group undergoing conventional operative repair of AAA. METHODS: Over a 3-year period, 30 patients underwent attempts at endovascular repair of infrarenal AAA. Of the 28 (93%) successfully implanted endografts, 8 were tube endografts, 8 bifurcated grafts, and 12 aortouniiliac grafts combined with femorofemoral bypass. Most of the procedures were performed in the past year because the availability of bifurcated and aortoiliac endografts markedly expanded the percentage of patients with AAA who might be treated with endoluminal methods. The follow-up period ranged from 1 to 44 months, with a mean value of 11 months. RESULTS: Endovascular procedures demonstrated significant advantages with respect to reduced blood loss (408 versus 1287 ml), use of an intensive care unit (0.1 versus 1.75 days), length of hospitalization (3.9 versus 10.3 days), and quicker recovery (11 versus 47 days). Although the total number of postoperative complications was identical for the two groups, the nature of the complications differed considerably. Local and vascular complications characteristic of endovascular repair could frequently be corrected at the time of the procedure and tended to be less severe than systemic or remote complications, which predominated among the open surgical repair group. On an intent-to-treat basis, 23 (77%) of the 30 AAAs were successfully managed with endoluminal repair. The seven (23%) failures were attributable to two immediate conversions caused by access problems, three persistent endoleaks, one late conversion caused by AAA expansion, and one late rupture. CONCLUSIONS: Although less definitive than those for conventional operations, these early results suggest that endovascular AAA repair offers considerable benefits for appropriate patients. The results justify continued application of this method of AAA repair, particularly in the treatment of older persons at high risk.     

Met-enkephalin Arg-Phe-immunoreactive neurons in the central nervous system of the pond snail Lymnaea stagnalis

The distribution of an opioid peptide related to YGGFMRF was determined in the CNS and other organs of the pond snail, Lymnaea stagnalis, by RIA and immunocytochemistry. RIA revealed the highest levels in the CNS (1 pmol/organ) and penis (400 fmol/organ). There were also significant levels in the haemolymph, most of which was not associated with haemocytes (580 fmol/ml). Both serial section and whole-mount immunocytochemistry of the CNS revealed immunoreactive cells in every ganglion with the majority in the cerebral and pedal ganglia. In the pedal ganglia some of the immunoreactive cells were close to the cells of the A-cluster, which are known to respond to opioids, and could innervate them. In the cerebral ganglia the immunoreactive cells included a group of neurosecretory cells, the caudo dorsal cells (CDCs) and the terminals of these cells in the cerebral commissure were also stained. The CDCs secrete peptides into the haemolymph and so could be the source of the YGGFMRF immunoreactivity. Immunoreactivity (including the CDCs) was observed in locations that correspond to those reported for other fragments of proenkephalin, such as Met- and Leu-enkephalin, suggesting that they may share a common precursor, a Lymnaea proenkephalin. A map of the 358 YGGFMRF-immunoreactive cells in the CNS is presented, many of which have not been previously identified.     

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)