Noninvasive diagnosis of carotid artery disease: the Oak Ridge experience in stroke prevention.
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Carotid Artery Diseases↗
Biomedical subjects
L Ryan
Publications and source records attributed to L Ryan.
Quantitative risk assessment for developmental toxicity.
Pharmaceutical companies and governmental regulatory agencies are becoming increasingly aware of the need for improved statistical methods for developmental toxicity experiments. Although a number of statisticians have become interested in this area, activity has centered mostly on the development of methods to analyze binary outcomes, such as malformations among live pups, while accounting appropriately for the correlation induced by the litter effect. In contrast, the topic of quantitative risk assessment has received relatively little attention. This paper addresses the specific question of how to assess risk appropriately when exposure causes a variety of adverse effects, including resorption and fetal death, in addition to malformations. It will be seen that risk assessments based on a single developmental outcome, such as malformation, may be conservative. A method is proposed for estimating an exposure level at which the overall risk of any adverse effect is acceptably low. The method is based on a continuation ratio formulation of a multinomial distribution, with an additional scale parameter to account for overdispersion. Comparisons are made with binary models on prenatal death and malformation, as well as a binary model that makes no distinction between death and malformation, but simply classifies each fetus as normal or abnormal. Data from several developmental toxicity studies illustrate the results and findings.
Abnormalities, Drug-Induced↗
Adjusting for age-related competing mortality in long-term cancer clinical trials.
Mortality related to causes other than the treated disease may have a significant impact on overall survival in long-term clinical trials. We present a model that adjusts for age-related competing mortality when cause of death is missing or only partially available. Through use of a piecewise exponential survival model, we extend relative survival methods to continuous follow-up data, allowing the competing mortality to differ from that of the general population by a scale parameter. An EM algorithm provides a simple way to compute the maximum likelihood estimators (MLEs) and to test hypotheses using widely available software. We compare the bias and relative efficiency of this model to a piecewise exponential Cox model for overall survival. Theoretical results are confirmed by simulations and illustrated with data from a clinical trial in colorectal cancer. This example also shows how age-related and disease-related mortality can be confounded in an analysis of overall survival. We conclude with a discussion of the advantages and disadvantages of the model.
Adolescent↗
Shutting the door on the watchdog.
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Community Health Services↗
Hyperviscosity-polycythemia syndrome: a case study.
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Humans↗
Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma.
The mesna, doxorubicin, ifosfamide, dacarbazine regimen produced a 47% response rate (including 10% complete responses) in 105 eligible adults with advanced sarcoma. The major dose-limiting toxicity was granulocytopenia. There was one toxic death from sepsis. Central nervous system and renal toxicity occurred infrequently, perhaps as a result of the continuous-infusion schedule. This regimen is being evaluated further in advanced disease, the adjuvant setting, and in combination with bone marrow colony-stimulating factors.
Adult↗
Ifosfamide and mesna: response and toxicity at standard- and high-dose schedules.
In two sequential trials, 154 patients were treated with dosages of ifosfamide, ranging between 8 and 18 g/m2 divided over 4 days, with mesna uroprotection. The first was a phase II efficacy trial in 125 advanced sarcoma patients (Antman et al: J Clin Oncol 7:126-131, 1989), while the second was a dose escalation trial involving 29 patients (Elias et al: J Clin Oncol 8:170-178, 1990). In the first trial, patients received 8 to 10 g/m2 ifosfamide either by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (P = .09). Of the 154 patients, 144 had sarcoma and had failed at least one previous regimen. Of these 144, 4% responded completely and 23% had a complete or partial response. The maximum tolerated dose of ifosfamide was 16 g/m2 in the second trial. Dose-limiting renal toxicity was observed at 18 g/m2 ifosfamide (Elias et al: J Clin Oncol 8:170-178, 1990). The duration of myelosuppression and the frequency and severity of mucositis and renal tubular acidosis were dose-dependent. A median of 11 days (range, 8 to 18) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion was not required. Severe central nervous system toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. The first four patients on the standard-dose study did not receive mesna because it was unavailable; three developed gross hematuria. In patients who received mesna, hematuria was uncommon. Hematuria in the group as a whole was significantly associated with a lack of uroprotection, but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus versus a continuous infusion schedule. Patients receiving ifosfamide with mesna uroprotection can tolerate considerable dose escalation over the usual prescribed doses before nonhematologic toxicity becomes dose-limiting. Ifosfamide, with its broad activity in solid tumors, may prove to be an important addition to high-dose combination-chemotherapy regimens (Elias et al: J Clin Oncol 8:170-178, 1990).
Adolescent↗
Survival analysis in natural history studies of disease.
Clinicians often wish to use data from clinical trials or hospital databases to study disease natural history. Of particular interest are estimated survival and prognostic factors. In this context, it may be appropriate to measure survival from diagnosis or some other time origin, possibly prior to study entry. We describe the application of methods for truncated survival data, and compare these with the standard product limit estimator and proportional hazards models in the measurement of survival from entry. Theoretical considerations suggest that analysis of survival from entry may under- or overestimate the survival distribution of interest, depending on the shape of the true underlying hazard. Analogous results hold for the coefficients from a proportional hazards model. We illustrate our findings with data from a multicenter clinical trial and a hospital database.
Actuarial Analysis↗
Factors associated with severity of symptoms in patients with chronic unexplained muscular aching.
Subjects with chronic, diffuse, unexplained muscular aching were recruited--21 from a primary care practice, nine from a rheumatology practice, and two from a pain clinic. No additional criteria were used to select subjects. Subjects with mild or moderate symptoms differed from those with severe symptoms with respect to the following characteristics: the presence of fatigue on awakening, the number of tender points, difficulty in sleeping, and the degree of tenderness in typical fibromyalgia areas as measured by a dolorimeter. These findings suggest that muscular aching is likely to be of greater severity if other symptoms or signs of fibromyalgia are also present.
Adult↗
Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma.
European and American investigators have reported response rates of 38% to 83% for ifosfamide alone in pretreated sarcomas. In a phase II trial of ifosfamide 2.0g/m2 days 1 to 4 with mesna uroprotection in 124 patients with previously failed sarcomas, four (3%) responded completely (95% exact confidence interval, 1% to 8%) and 26 (21%) had a complete or partial response (95% exact confidence interval, 14% to 29%). The median time to progression was 5 and 9 months for partial and complete responders, respectively. In the subset of soft tissue sarcomas, the response rate for the patients receiving bolus administration was 26%, compared with 9% for the patients receiving a continuous infusion schedule (P = .03). The response rates among patients with soft tissue and bony sarcomas with a performance score of 0-2 and 0-1 prior to chemotherapy administration were 20% and 40%, respectively. Somnolence or confusion developed in 19%. Neurotoxicity was significantly associated with poor performance status (P less than .01), elevated creatinine (P less than .01), and low bicarbonate levels (P = .05). A serum bicarbonate less than 20 developed in 31% of the patients and was significantly associated with older age (P = .01), elevated creatinine (P = .02), and female sex (P = .06). Hematuria was significantly associated with no uroprotection (the first four patients did not receive mesna because it was unavailable), but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus v continuation infusion schedule. Thus, ifosfamide is active in failed sarcomas and warrants further study in previously untreated patients with sarcoma.
Adolescent↗
Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy.
In this phase II trial, 105 eligible patients with no prior chemotherapy and advanced sarcoma received doxorubicin, ifosfamide, and dacarbazine (DTIC) with mesna uroprotection (MAID). Starting doses of these drugs were 60, 7,500, and 900 mg/m2 divided over 72 hours by continuous infusion, respectively. Mesna was given for 84 to 96 hours at 2,500 mg/m2/d. Myelosuppression was dose limiting, causing the only toxic death (sepsis). Nonhematologic toxicity consisted predominantly of anorexia and vomiting. Severe mucositis, macroscopic hematuria, renal tubular acidosis, renal failure, and CNS toxicity occurred in less than 5% of cycles. No cardiotoxicity was detected. The overall response rate (10% complete response [CR]) was 47% (95% confidence intervals, 5% to 18% and 37% to 57%, respectively). Most responses (approximately 70%) were observed within two cycles. Median times to progression were 10 and 9 months, respectively. Histologic high tumor grade, lesions less than 5 cm, and less than 1 year from diagnosis to study entry correlated with the probability of response. The median survival was 16 months. Time from diagnosis to study entry, performance status, and extent of disease, but not histologic grade, correlated with survival. Following CR, two patients remain disease-free at 32 and 16 months. Of the 15 additional patients rendered disease-free with surgery, two remain disease-free at 30 and 18 months with no further therapy. While most relapses occurred in sites of prior involvement, death from CNS metastases occurred in 11 of the 80 patients with high-grade sarcomas, of whom seven were still responding systematically (three complete responders). Because of its substantial response in this phase II trial, the MAID regimen is being compared with doxorubicin and DTIC alone in advanced sarcomas and to observation in the adjuvant treatment of high-grade sarcomas in randomized trials.
Actuarial Analysis↗
A clinical study of 2.5 liter exchange volumes.
Comparisons of peritoneal clearances, hematologic and biochemical assays were performed on eleven CAPD patients using 2 liter and 2.5 liter daily exchanges. Group 1 consisted of 8 patients substituting all four daily 2 liter exchanges. These patients experienced statistically significant increases in urea and creatinine clearance (an average of 15% and 10% respectively). Corresponding reductions in serum levels occurred (8% and 9% respectively). Ultrafiltrate volume increased by an average of 12%. Group II consisted of 3 patients that substituted one 2 liter exchange. These patients also experienced increases in urea and creatinine clearance (8% and 11% respectively) and decreases in corresponding serum levels (1% and 4% respectively). Ultrafiltrate volume increased an average of 12%. After one month on the 2.5 liter regimen, patients were surveyed for their reactions to larger exchange volumes. Ninety-one percent of patients decided to continue using the 2.5 liter volume. Reasons cited included feeling better and having better weight and fluid control. None of the patients demonstrated complications such as catheter leakage or hernias. The use of four daily 2.5 liter exchanges can provide over 20% more clearance for many CAPD patients currently using 2 liter exchanges. This survey demonstrates most patients tolerate 2.5 liters, and they feel better. A 2.5 liter regimen may be indicated for patients who could benefit from more dialysis and for those at risk of dropping out of CAPD due to inadequate dialysis.
Blood Urea Nitrogen↗
Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression.
An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.
Adolescent↗
Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985.
All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.
Boston↗
Hydrophobic surfactant-associated proteins: electrophoretic and immunologic analyses and cellular localization in human lung.
Pulmonary surfactant isolated from a number of animal species contains a protein of molecular weight 38,000 and several very hydrophobic proteins soluble in solvents often used to extract lipids. Although found to be intimately associated with surfactant lipids, localization of the very hydrophobic proteins to alveolar epithelial type II cells, the cells involved in the synthesis and secretion of pulmonary surfactant, has not been demonstrated. Hydrophobic proteins were extracted along with lipids from human surfactant, and, after extraction with deoxycholate, were used to raise an antiserum. The antiserum was characterized by the immunoblotting ("Western") technique, using blots of pulmonary surfactant, and of hydrophobic proteins prepared by deoxycholate extraction and by Sephadex LH-20 chromatography. The antiserum shows reactivity to a 6.5- to 18-kDa surfactant-associated hydrophobic protein, which appears to be the major component of deoxycholate extracted proteins, and has Phe as the N-terminal amino acid. In addition, 28-kDa, 40-kDa, 50-kDa, and 70-kDa bands (chemically unreduced) are seen in human pulmonary surfactant. Whether these bands represent precursors of the major surfactant-associated hydrophobic proteins, different proteolytic cleavage products of the precursor protein, distinct proteins, or associated forms of the same protein is not yet clear. When used in the immunoperoxidase staining of human lung sections, the antiserum yielded a staining pattern identical to that obtained by the use of an antiserum to the 35-kDa surfactant protein. The number, size, and location of the stained cells are consistent with their being the alveolar epithelial type II cells.
Chromatography, Gel↗
Neurophysiological consequences of amphetamine administration.
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Amphetamines↗
Leishmaniasis in Brazil. XXIV. Natural flagellate infections of sandflies (Diptera: Psychodidae) in Pará State, with particular reference to the rôle of Psychodopygus wellcomei as the vector of Leishmania braziliensis braziliensis in the Serra dos Carajás.
Between July 1983 and December 1984 natural flagellate infections were found in 114 (1%) of 11,586 female phlebotomine sandflies (Diptera: Psychodidae) of 21 species. A further 1084 females of 17 other species were not infected. Identification of the organisms on a number of occasions confirms the exclusive parasite/vector relationship of Leishmania mexicana amazonensis/Lutzomyia flaviscutellata and Le. braziliensis braziliensis/Psychodopygus "wellcomei". Undescribed or unidentified Leishmania spp. were isolated from Lu. shawi, Lu. ubiquitalis, Lu. whitmani, Ps. hirsutus, Ps. paraensis Ps. "wellcomei", and trypanosomes from Lu. nordestina and Lu. trinidadensis. Flagellate infections were recorded in 8 of 21 species examined for the first time, and some were isolated directly from insects into cultures. Le. b. braziliensis was transmitted to a hamster by the bite of a wild-caught, naturally infected Ps. "wellcomei". 7 of the 35 infected Ps. "wellcomei" were allowed to oviposit and the eggs were reared to adults. Four produced Ps. wellcomei males only, confirming the rôle of this species as the major vector of Le. b. braziliensis.
Animals↗
Leishmaniasis in Brazil: XXIII. The identification of Leishmania braziliensis braziliensis in wild-caught neotropical sandflies using monoclonal antibodies.
Using the indirect immunofluorescence test natural flagellate infections of wild-caught sandflies, from the Serra dos Carajás region of Pará State, Brazil, were identified by sequentially staining smears made from the infected flies with monoclonal antibodies. With normal methods of isolation 30% of the infections were identifiable, but when monoclonal antibodies specific to Leishmania braziliensis braziliensis were used a further 26% were identified. The staining of organisms in smears of natural infections was different from that seen with culture forms and with forms from experimentally infected wild flies. A monoclonal antibody previously thought to be specific for Leishmania did not react with culture forms of Endotrypanum, but did react with those of monoxenous insect parasites.
Animals↗