The tea leaves of small trials.
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Antidotes↗
Biomedical subjects
D P Harrington
Publications and source records attributed to D P Harrington.
Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission.
BACKGROUND: In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the long-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneic marrow transplantation during the first remission of acute myeloid leukemia. METHODS: Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemia received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplantation. The end points were survival from the time of complete remission and disease-free survival. RESULTS: In an intention-to-treat analysis, we found no significant differences in disease-free survival among patients receiving high-dose chemotherapy, those undergoing autologous bone marrow transplantation, and those undergoing allogeneic marrow transplantation. The median follow-up was four years. Survival after complete remission was somewhat better after chemotherapy than after autologous marrow transplantation (P=0.05). There was a marginal advantage in terms of overall survival with chemotherapy as compared with allogeneic marrow transplantation (P=0.04). CONCLUSIONS: A postinduction course of high-dose cytarabine can provide equivalent disease-free survival and somewhat better overall survival than autologous marrow transplantation in adults with acute myeloid leukemia.
Acute Disease↗
Ionized and total magnesium concentrations in blood from dogs with naturally acquired parvoviral enteritis.
OBJECTIVE: To determine whether pretreatment total and ionized blood magnesium concentrations were associated with outcome for dogs with parvoviral enteritis and whether ionized magnesium concentration was related to total magnesium concentration or other laboratory values. DESIGN: Prospective cohort study. ANIMALS: 61 healthy dogs and 72 dogs with parvoviral enteritis. PROCEDURE: Total, ionized, and pH-normalized ionized magnesium concentrations, ionized and pH-normalized ionized calcium concentrations, pH, sodium and potassium concentrations, and Hct were measured prior to treatment. chi 2 Analyses were used to test for associations between outcome and age and between outcome and treatment with antiendotoxin antibody. Pearson's correlation coefficients were calculated to determine whether ionized magnesium concentration was linearly associated with other laboratory values. RESULTS: Total and ionized magnesium concentrations were not significantly different between healthy dogs and dogs with parvoviral enteritis or between dogs surviving and those not surviving parvoviral enteritis. The only laboratory value strongly correlated with ionized magnesium concentration was pH-normalized ionized magnesium concentration. Of the factors tested, none were significantly associated with outcome, except that dogs 16 weeks old or less treated with antiendotoxin antibody were significantly more likely to die than were dogs 16 weeks old or less that were not treated with antiendotoxin antibody. CLINICAL IMPLICATIONS: Total and ionized blood magnesium concentrations cannot be used to consistently predict outcome for dogs with parvoviral enteritis. Antiendotoxin antibody should be used with caution in dogs 16 weeks old or less.
Age Factors↗
Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.
BACKGROUND: The Eastern Cooperative Oncology Group (ECOG) performed a Phase III comparison of melphalan and prednisone (MP) with vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) in an attempt to determine which of these regimens should be the standard treatment for multiple myeloma. METHODS: Four hundred seventy-nine previously untreated patients with multiple myeloma from 23 ECOG institutions were enrolled. Treatment, assigned by randomization, consisted of either 4-week cycles of MP or 5-week cycles of VBCMP. After 1 year of induction therapy, patients received MP or VBMCP maintenance therapy at 6- and 8- week intervals, respectively, until relapse. Patients who experienced treatment failure with MP were eligible for crossover therapy with VBMCP. RESULTS: Objective responses were obtained for 51% of patients receiving MP, as compared with 72% of patients receiving VBMCP (P < 0.001). Response duration was also longer with VBMCP (median, 18 months with MP vs. 24 months with VBMCP; P = 0.007). Overall survival was not significantly different between MP and VBMCP (P = 0.30). The 5-year survival for VBMCP was 26%, as compared with 19% for MP. VBMCP was associated with more nausea, peripheral nerve toxicity, alopecia, and neutropenia, but the infection rate was equal to that observed with MP. Both regimens were generally well tolerated. The main exception was that elderly patients who were confined to bed had a higher risk of death with VBMCP. The two regimens produced a similar incidence of late secondary myelodysplastic syndrome and acute leukemia. Crossover VBMCP for patients failing with MP was only minimally effective, with an objective response rate of 20% and median survival of 11 months after crossover. CONCLUSIONS: VBMCP is more effective than MP in producing and sustaining remission of multiple myeloma. It is associated with a marginal survival advantage and an apparently greater chance of surviving 5 years for patients who can tolerate moderately intensive combination chemotherapy. Cancer 1997;79:1561-7. 1997 American Cancer Society.
Adult↗
Effectiveness of extreme discordant sib pairs to detect oligogenic disease loci.
A method for the genomic screening of quantitative traits using extreme discordant sib pairs (EDSPs) has recently been described by Risch and Zhang [1995; 1996]. For many models relevant to common, genetically complex diseases, EDSPs are the most powerful siblings for detecting linkage. Thus, if such siblings can be identified and collected, powerful studies with reasonable genotyping budgets can be conducted. Using a subset of the GAW10 data, we have simulated a genomic screen using EDSPs. From the 4,780 total families in the first 20 replicates of 239 families, there were 100, 104, 155, 107, and 180 EDSP families for Q1, Q2, Q3, Q4, and Q5, respectively. EDSP data were analyzed for each trait using a modified version of MAPMAKER/SIBS capable of handling extreme discordant sib pairs. Four regions, one for Q1, one for Q2, and two for Q4, were able to exceed a threshold for linkage corresponding to a 0.001 pointwise significance level. In three cases, maximum lod score (MLS) peaks occurred within 3.8 cM of a major gene. In the fourth case, the MLS peak occurred 28.4 cM from a major gene. Omission of parents and an alternative definition of EDSP were also investigated.
Chromosome Mapping↗
The inversion of the exponential Radon transform for quantitative brain SPECT.
The mathematical derivation for the inversion of the exponential Radon transform is presented and the implementation of the inversion is detailed. The inversion can be verified and implemented by the readers for practical applications, such as for quantitative reconstruction of brain SPECT (single-photon emission computed tomography).
Brain↗
Revascularization for femoropopliteal disease. A decision and cost-effectiveness analysis.
OBJECTIVE: To evaluate the relative benefits and cost-effectiveness of revascularization for femoropopliteal disease using percutaneous transluminal angioplasty or bypass surgery. DESIGN: Decision analysis using a multistate transition simulation model (Markov process) and cost-effectiveness analysis from the perspective of the health care system. SETTING: Based on mortality, morbidity, patency, and cost data from a literature review. PATIENTS: Hypothetical cohort of patients with chronic femoropopliteal disease who desire revascularization. Subgroup analysis for patients defined by age, sex, indication, lesion type, and graft type. INTERVENTIONS: Percutaneous transluminal angioplasty, bypass surgery, and a strategies combining the two treatments. MAIN OUTCOME MEASURES: Five-year patency results, quality-adjusted life expectancy, lifetime costs, and incremental cost-effectiveness ratios. RESULTS: For 65-year-old men with disabling claudication and a femoropopliteal stenosis or occlusion and for 65-year-old men with chronic critical ischemia and a femoropopliteal stenosis, initial angioplasty increased quality-adjusted life expectancy by 2 to 13 months and resulted in decreased lifetime expenditures compared with bypass surgery. For patients with chronic critical ischemia and a femoropopliteal occlusion, initial bypass surgery increased quality-adjusted life expectancy by 1 to 4 months and resulted in decreased lifetime expenditures compared with angioplasty. Sensitivity analysis demonstrated that angioplasty would always be the preferred initial treatment if the angioplasty 5-year patency rate exceeds 30%. CONCLUSION: Angioplasty is the preferred initial treatment in patients with disabling claudication and a femoropopliteal stenosis or occlusion and in those with chronic critical ischemia and a stenosis. Bypass surgery is the preferred initial treatment in patients with chronic critical ischemia and a femoropopliteal occlusion.
Aged↗
Fulminant human herpesvirus six encephalitis in a human immunodeficiency virus-infected infant.
Self-limited involvement of the central nervous system (CNS) is a relatively common complication of primary infection with human herpesvirus six (HHV-6) in normal children. We describe an HIV-infected infant who developed fulminant encephalitis as a complication of HHV-6 infection. Immunohistochemical staining of CNS tissue demonstrated productive infection of all CNS cell-types. Analysis of the infected brain tissue by the polymerase chain reaction (PCR) confirmed the presence of a dense HHV-6 infection in the tissue, and demonstrated that the virus present in the CNS tissue was predominantly the A variant of HHV-6. This is the first demonstration of invasive tissue disease caused by HHV-6 in an HIV-infected infant.
AIDS-Related Opportunistic Infections↗
Defining, identifying, and studying high-risk families: developing cohorts for epidemiologic study.
Many issues arise in planning epidemiologic studies of individuals at high risk for developing hereditary cancers. The most important are (a) determination of the information that can best be studied in epidemiologic settings; (b) selection of proper study designs; (c) acknowledgment of the ethical, psychosocial, and legal issues that will arise in these studies; and (d) anticipation of the logistical issues involved in large, multicenter studies. The breakout session "Developing Cohorts for Epidemiologic Study: Defining and Identifying High-Risk Families" examined these issues, and the results of that session are summarized here. There was general consensus that little information exists regarding the prevalence of genetic mutations that predispose individuals to increased cancer risk, the risks conferred by specific mutations and by gene-environment interactions, and the efficacy of potential interventions. Adequately controlled observational and randomized studies provide the best mechanism for obtaining this information, despite the considerable ethical and strategic difficulties that will arise in the planning and conduct of such studies.
Breast Neoplasms↗
Weighted least squares analysis of repeated categorical measurements with outcomes subject to nonresponse.
In this paper, we describe a two-step weighted least squares method for analyzing repeated categorical outcomes when some individuals are not observed at all times of follow-up. Other weighted least squares methods for analyzing repeated measures data with missing responses have previously been proposed by Koch, Imrey, and Reinfurt (1972, Biometrics 28, 663-692) and Woolson and Clarke (1984, Journal of the Royal Statistical Society, Series A 147, 87-99). These methods give consistent estimators if the responses are missing completely at random, as discussed in Rubin (1976, Biometrika 63, 581-592). We propose a two-step method that will give consistent results under the weaker condition of missing at random, and compare it with the other two methods.
Adolescent↗
Risks and benefits of femoropopliteal percutaneous balloon angioplasty.
PURPOSE: The purpose of this study was to evaluate the efficacy of angioplasty in the treatment of femoropopliteal arterial disease. METHODS: From 1980 to 1991, 126 angioplasty procedures were performed in 131 limbs of 106 patients with 175 femoropopliteal lesions (26 common femoral, 118 superficial femoral, and 31 popliteal). Critical ischemia was present in 55 limbs (42%), and claudication was present in 76 (58%). Angioplasty was performed for a single lesion in 87 limbs (66%) and for multiple lesions in 44 (34%). In 13 limbs (10%) the most severe lesion was an occlusion; in 118 (90%) all lesions were stenoses. Distal runoff was good (2 or 3 vessels patent) in 72 limbs (55%) and poor (0 or 1 vessel patent) in 59 (45%). RESULTS: Death within 30 days occurred in 0.8%, nonfatal systemic morbidity in 7.1%, and local morbidity in 1.6% of procedures. Multivariate analysis revealed that indication and age were predictive of increased morbidity and mortality rates. Immediate success was achieved in 95% of limbs treated. Mean follow-up time was 2.0 years. The overall 5-year cumulative primary patency rate was 45% (+/- 5%). In a proportional hazards model indication and lesion type were predictive (p < 0.01) of long-term failure, with relative risks of 2.0 (1.2 to 3.3) and 2.7 (1.3 to 5.6), respectively. The 5-year primary patency rate after angioplasty for stenoses and claudication was 55% (+/- 7%), for stenoses and critical ischemia it was 29% (+/- 11%), and for occlusions it was 36% (+/- 14%). CONCLUSION: These results suggest that femoropopliteal angioplasty is a low-risk procedure with acceptable long-term results in patients with claudication and stenoses.
Angioplasty, Balloon↗
Varying intensity of postremission therapy in acute myeloid leukemia.
The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6-thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four-year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.
Acute Disease↗
Sertraline-augmented lithium therapy of organic mood syndrome.
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1-Naphthylamine↗
Prospective double-blinded comparison of MR imaging and aortography in the preoperative evaluation of abdominal aortic aneurysms.
The authors conducted a prospective double-blind study comparing spin-echo axial and coronal magnetic resonance (MR) imaging with aortography in the preoperative evaluation of 20 patients with abdominal aortic aneurysms. Receiver-operating-characteristic (ROC) analysis was used to evaluate the performance of MR imaging versus aortography in assessing arterial stenotic disease. Both modalities were equivalent in demonstrating the upper extent of the abdominal aortic aneurysms with respect to the renal and visceral arteries. MR imaging was superior in demonstrating aneurysmal iliac arteries and intraluminal thrombus. Although aberrant venous anatomy, associated pathologic changes, and other concomitant lesions were demonstrated with MR imaging, it performed poorly in assessing arterial stenoses and occlusions. Thus, the authors caution against the routine substitution of spin-echo MR imaging for aortography in the evaluation of abdominal aortic aneurysms. Conventional angiography should continue to be performed in patients with suspected mesenteric ischemia, significant hypertension, and symptomatic iliofemoral atherosclerosis, at least until robust MR angiographic techniques have proved themselves under similar rigorous clinical evaluation.
Aged↗
Arterial response to ketanserin and aspirin in patients with advanced peripheral atherosclerosis.
BACKGROUND: In advanced atherosclerosis, endothelial lesions and turbulent flow in stenotic vessels result in platelet aggregation with the liberation of vasoactive factors, including thromboxane A2 and serotonin. This study was designed to assess the combined effect of these factors on arterial dimensions at the time of limb angiography in patients with advanced peripheral vascular disease. METHODS: Diameter changes of 53 segmental stenosis of large arteries were measured in digitized angiograms by a computerized objective method in response to either placebo (13 segments in 7 patients), ketanserin (23 segments in 23 patients), or ketanserin superimposed on aspirin (17 segments in 7 patients). Responses of arterial collaterals were evaluated by a coded assessment. Statistically significant vasodilatation was observed in both the stenotic and post-stenotic segments of the large arteries only when serotonin-2 receptor blockade with ketanserin and cyclo-oxygenase inhibition with aspirin were combined. RESULTS: In the area of the stenosis and in the post-stenotic segment diameter increased 8.2% +/- 2.3% (P = .032) and 7.3% +/- 1.3% (P less than .001), respectively, when aspirin was combined with ketanserin. Significant changes did not occur in either the placebo group or in the group receiving only ketanserin. In the area of stenosis, there was a good correlation between the relative baseline narrowing of the vessel and its vasodilatation after combined ketanserin and aspirin (r = .689; P = .002). Vasodilatation at the level of arterial collaterals also was significantly more pronounced when the combination was used (P less than .001). CONCLUSIONS: These findings suggest a component of vasoconstriction related to the deposition of activated platelets in stenotic segments of the large arteries in atherosclerosis.
Adult↗
Phase II clinical trial of carboplatin in relapsed and refractory leukemia.
Carboplatin is a second-generation platinum complex drug which has demonstrated activity against a variety of neoplasms including acute leukemia, particularly when given by continuous intravenous (i.v.) infusion. Adults with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), either refractory or in first or second relapse, were given a continuous i.v. infusion of carboplatin at a dose of 315 mg/m2 daily for 5 days. A second course was given if the bone marrow at day 14 showed persistent leukemia. If the marrow was hypoplastic, treatment was delayed until marrow recovery was documented. Those with residual leukemia were given a second course. Those achieving complete remission (CR) were given an additional course as consolidation. Of the 46 eligible patients entered (36 AML and 10 ALL) eight achieved CR (17%) of which 6 were AML and 2 ALL. Of nine primary refractory patients, two achieved CR, one AML and one ALL. Excluding the inevaluable patients (protocol violations, patient refused further therapy, early deaths prior to day 14, the CR rate was eight of 28 (29%). All except two CRs required two courses of induction. The non-hematologic toxicity was minimal except for renal and auditory toxicity. Renal toxicity greater than grade 2 was seen in 17 patients and was associated with concomitant use of nephrotoxic antibiotics. In two patients, renal failure was a major factor in the cause of death. Ototoxicity was observed in 11 patients, but was grade 3 in only three. There were 18 deaths during the study. Fourteen died of infection, two died of infection and hemorrhage, one died of hemorrhage while aplastic, and one died of other causes. This trial indicates that carboplatin is an active agent in acute leukemia and warrants further investigation.
Bone Marrow↗
Quality assurance in cardiovascular and interventional radiology.
In summary, quality assurance in medicine and in CVIR must be an important part of daily practice. The JCAHO is gradually moving toward quality improvement as a goal, rather than simply monitoring performance. Physicians must lead the way in dealing with the issues of monitoring performance, with the ultimate goal being the welfare of their patients. The model SCVIR QA program described above will help cardiovascular and interventional radiology sections of all sizes to meet these goals. Resources applied toward QA activities are investments for maximizing efficiency and productivity, while minimizing morbidity and mortality. These well-spent efforts will hopefully decrease the spiraling costs of medical care.
Cardiovascular System↗
Escalating the intensity of post-remission therapy improves the outcome in acute myeloid leukemia: the ECOG experience. The Eastern Cooperative Oncology Group.
These ECOG trials have demonstrated that progressive increments in the intensity of post-remission therapy result in improving long-term, disease-free survival in adults with AML. The median duration of disease-free survival and long-term outcome from different post-remission therapies are summarized in Table 4. [table: see text] Despite the suggestive evidence of the ordered increment in value of intensive consolidation therapy, allogeneic and autologous bone marrow transplantation, it remains to be proved that the differences observed in our preceding studies are statistically significant and clinically meaningful. These remaining questions led to the current ECOG study, EST 3489, a randomized intergroup study conducted with members of the Southwest Oncology Group. The study includes all patients with de novo AML up to age 55; the schema is shown in Figure 3. Induction therapy consists of idarubicin plus cytarabine instead of DAT. A modified short course of this induction therapy is repeated after CR. Patients who have a histocompatible sibling are offered allogeneic bone marrow transplantation. The remaining patients are randomized to receive either autologous bone marrow transplantation or a single course of high-dose cytarabine. Autologous bone marrow transplantation utilizes the previously described high-dose busulfan and cyclophosphamide regimen plus 4-HC purging of the bone marrow. The dosage of cytarabine in the intensive consolidation arm is 3 gm/M2/day IV on days 1-6. The results of this study should determine the relative merits of these different approaches to post-remission therapy. [table: see text] As mentioned earlier, demonstration of improved CR rates is limited by the morbidity and mortality from the myelosuppression that results from induction therapy. This is especially marked for older patients with AML. In patients, ages 55-70 years old, the ECOG is conducting a randomized trial (EST 1490) of conventional induction therapy +/- GM-CSF to determine if accelerated neutrophil recovery can reduce the mortality of induction therapy and thereby increase the remission rate. It may be that the application of GM-CSF and other colony-stimulating factors can increase the CR rate for all patients, increasing the number of patients potentially eligible for cure by post-remission therapy.
Acute Disease↗