Lesson learned from high-dose chemotherapy for high-risk breast cancer (What you see is what you mean).
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
R Gelber
Publications and source records attributed to R Gelber.
Interobserver agreement in the electrocardiographic diagnosis of acute myocardial infarction in patients with left bundle branch block.
STUDY OBJECTIVE: To determine the interobserver agreement between cardiologists and emergency physicians in the ECG diagnosis of acute myocardial infarction (AMI) in patients with left bundle branch block (LBBB) using the ECG algorithm previously described by Sgarbossa et al. METHODS: Using the Sgarbossa ECG algorithm, 4 cardiologists and 4 emergency physicians independently interpreted a test set of 224 ECGs with LBBB, of which 100 ECGs were from patients with an evolving AMI. A subset of 25 ECGs was reinterpreted by each reader to test intraobserver agreement for AMI as well as interobserver agreement for the degree of ST-segment deviation. Agreement rates for AMI were estimated using the kappa statistic. In addition, the sensitivity and specificity for diagnosing AMI were determined for each reader, using the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) enzyme criteria for AMI as the gold standard. The study was conducted at 3 university-affiliated medical centers. The test set contained ECGs from 100 patients enrolled in the GUSTO I trial with LBBB on their initial ECG and an evolving AMI confirmed by serum cardiac enzyme changes, and 124 control patients from the Duke Databank for Cardiovascular Disease who had stable, angiographically documented coronary artery disease and LBBB. RESULTS: There was excellent interobserver agreement (kappa=0.81, 95% confidence interval [CI] 0.80 to 0.83) between cardiologists and emergency physicians for diagnosing AMI. Intraobserver agreement kappa values for AMI diagnosis by cardiologists and emergency physicians were 0.81 (95% CI 0.67 to 0.94) and 0.71 (95% CI 0.54 to 0.89). The median sensitivity for diagnosing AMI by cardiologists and emergency physicians was 73% (range 66% to 80%) versus 67% (range 61% to 75%); median specificity was 98% (range 97% to 99%) versus 99% (range 98% to 99%). Spearman rank correlation coefficients for the degree of ST-segment deviation in all 12 leads was 0.86 (95% CI 0.85 to 0.87) among all readers. CONCLUSION: There is excellent interobserver agreement between cardiologists and emergency physicians for diagnosing AMI when applying the Sgarbossa ECG algorithm to patients with LBBB. Emergency physicians should be able to reliably use this algorithm when evaluating patients.
Adult↗
Methodological and statistical issues of quality of life (QoL) and economic evaluation in cancer clinical trials: report of a workshop.
In recent years, quality of life (QoL) and economic evaluations have become increasingly important as additional outcome measures in cancer clinical trials. However, both fields of research are relatively new and in need of finding solutions to a substantial number of specific methodological problems. This paper reports on the proceedings of a symposium aimed at summarising and discussing some of the most contentious methodological and statistical issues in QoL and economic evaluations. In addition, possible solutions are indicated and the most pertinent areas of research are identified. Issues specific to QoL evaluations that are addressed include clinically meaningful changes in QoL scores; how to analyse QoL data and to handle missing and censored data and integration of length of life and QoL outcomes. Issues specific to economic evaluations are the advantages and disadvantages of various outcome measures; statistical methods to analyse economic data and choice of decision criteria and analytical perspective. How to perform QoL and economic evaluations in large and simple trials and whether the gap between QoL and utility measures can be bridged are also discussed.
Clinical Trials as Topic↗
Randomized study of the tolerance and efficacy of high- versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128). Pediatric AIDS Clinical Trials Group.
The current dosage of zidovudine for children is 180 mg/m2 every 6 h. To investigate whether a lower dosage was equally effective, human immunodeficiency virus (HIV)-infected children (3 months to 12 years) with mild to moderate symptoms were randomly assigned to receive either high-dose (180 mg/m2/dose) or low-dose (90 mg/m2/dose) zidovudine (double-blind). Treatments were compared with respect to neuropsychologic function, survival, clinical and laboratory evidence of disease progression, and safety and tolerance. Four hundred twenty-six HIV-infected children were enrolled; median time for receipt of study drug was 35 months. Zidovudine in either dose was well tolerated, with no difference in efficacy or tolerance by treatment group using any clinical or laboratory parameter. In children with mild to moderate disease, a reduction of zidovudine to 90 mg/m2/dose will result in substantial cost savings and should be the recommended dose.
AIDS Dementia Complex↗
Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.
PURPOSE: To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored a workshop in September 1993. Participants included representatives from the Childrens Cancer Group (CCG), Pediatric Oncology Group (POG), Dana-Farber Cancer Institute (DFCI), St Jude Children's Research Hospital (SJCRH), and the CTEP. METHODS: Workshop participants presented and reviewed data from ALL clinical trials, using weighted averages to combine outcome data from different groups. RESULTS: For patients with B-precursor (ie, non-T, non-B) ALL, the standard-risk category (4-year event-free survival [EFS] rate, approximately 80%) will include patients 1 to 9 years of age with a WBC count at diagnosis less than 50,000/microL. The remaining patients will be classified as having high-risk ALL (4-year EFS rate, approximately 65%). For patients with T-cell ALL, different treatment strategies have yielded different conclusions concerning the prognostic significance of T-cell immunophenotype. Therefore, some groups/institutions will classify patients with T-cell ALL as high risk, while others will assign risk for patients with T-cell ALL based on the uniform age/WBC count criteria. Workshop participants agreed that the risk category of a patient may be modified by prognostic factors in addition to age and WBC count criteria, and that a common set of prognostic factors should be uniformly obtained, including DNA index (DI), cytogenetics, early response to treatment (eg, day-14 bone marrow), immunophenotype, and CNS status. CONCLUSIONS: The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.
Adolescent↗
AZT trial in Thailand.
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Antiviral Agents↗
Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.
BACKGROUND AND METHODS: Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over one hour, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. RESULTS: From April 1991 through December 20, 1993, the cutoff date for the first interim analysis of efficacy, 477 pregnant women were enrolled; during the study period, 409 gave birth to 415 live-born infants. HIV-infection status was known for 363 births (180 in the zidovudine group and 183 in the placebo group). Thirteen infants in the zidovudine group and 40 in the placebo group were HIV-infected. The proportions infected at 18 months, as estimated by the Kaplan-Meier method, were 8.3 percent (95 percent confidence interval, 3.9 to 12.8 percent) in the zidovudine group and 25.5 percent (95 percent confidence interval, 18.4 to 32.5 percent) in the placebo group. This corresponds to a 67.5 percent (95 percent confidence interval, 40.7 to 82.1 percent) relative reduction in the risk of HIV transmission (Z = 4.03, P = 0.00006). Minimal short-term toxic effects were observed. The level of hemoglobin at birth in the infants in the zidovudine group was significantly lower than that in the infants in the placebo group. By 12 weeks of age, hemoglobin values in the two groups were similar. CONCLUSIONS: In pregnant women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, a regimen consisting of zidovudine given ante partum and intra partum to the mother and to the newborn for six weeks reduced the risk of maternal-infant HIV transmission by approximately two thirds.
Adult↗
Expression of BCL-2 in primary breast cancer and its correlation with tumour phenotype. For the International (Ludwig) Breast Cancer Study Group.
BACKGROUND: The role of apoptosis (programmed cell death) in the development and progression of breast cancer is unknown. Recently the bcl-2 gene has been shown to block apoptosis and thus may promote tumour development. BCL-2 is localized to the luminal cells of the normal breast, which are considered to be the origin of malignant breast disease. PATIENTS AND METHODS: Immunocytochemistry using anti bcl-2- antibody was performed on 107 breast cancer specimens belonging to node-positive patients from the Ludwig Breast Cancer Studies I-IV and the results were correlated with survival, tumour grade, S-phase, oestrogen and progesterone receptor status and c-erb B-2 expression. Western and Southern blotting together with immunofluorescence were performed on the breast cancer cell lines BT-20, BT-474, MDA-MB-361, T47-D and MCF-7. RESULTS: In the breast cancer derived cell line MCF-7 BCL-2 is expressed to a level similar to that of the B-lymphoma cell line Karpas 231 with t(14;18)(q32.3;q21.3), but no evidence of a rearrangement or gene amplification was identified. In a study of 107 breast cancers from the International Breast Cancer Study Group Trials I-IV we have demonstrated a very significant inverse correlation of BCL-2 with c-erbB-2 expression (p = 0.002), and a positive correlation with oestrogen receptors (p = 0.001) and progesterone receptors (p = 0.05). In this study there was no correlation of expression with S-phase fraction in the tumours or with any stage in the cell cycle as assessed in MCF-7 cells. CONCLUSION: We conclude that BCL-2 might contribute to the malignant phenotype of breast cancer by modulation of biological behaviour of cancer cells.
Adult↗
Roles of soluble fibronectin and beta 1 integrin receptors in the binding of Mycobacterium leprae to nasal epithelial cells.
The mechanisms by which Mycobacterium leprae invades the human host are presently unknown. We investigated the ability of M. leprae to bind to human RPMI 2650 cells, a human nasal septal epithelial cell line, using both microscopic observation and an ELISA technique. The results demonstrated that M. leprae adheres to nasal cells after binding to soluble fibronectin. Furthermore, it was observed that M. leprae could bind to the beta 1 chain of the integrins in the absence of serum or mucus. These results demonstrated that M. leprae uses fibronectin and fibronectin receptors on the surface of epithelial cells to bind and possibly invade the nasal epithelial cells.
Amino Acid Sequence↗
Chronic anterior uveitis in leprosy: an insidious cause of blindness.
Chronic low grade anterior uveitis is the commonest cause of blindness in leprosy. It is usually asymptomatic until the late stages, and often patients seek help only after irreversible visual impairment has occurred. We present herewith several cases of this entity to emphasise the insidious nature of the disease, the extent of ocular damage it can cause, and the importance of early detection and treatment.
Adult↗
Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities.
Ninety-seven children who were diagnosed with acute lymphoblastic leukemia before 10 years of age and treated with chemotherapy alone, chemotherapy plus 1800-cGy cranial irradiation (RT), or chemotherapy plus 2400-cGy RT were evaluated for effects of therapy on dentofacial development. All patients were seen at least 5 years postdiagnosis. Dental abnormalities were determined from panoramic radiographs, and craniofacial evaluations were made from lateral cephalometric radiographs. Ninety-one (94%) of all patients and 41 (100%) of patients younger than 5 years of age at diagnosis had abnormal dental development. The severity of these abnormalities was greater in children who received treatment before 5 years of age and in those who received RT. Observed dental abnormalities included tooth agenesis, arrested root development, microdontia, and enamel dysplasias. Craniofacial abnormalities occurred in 18 of 20 (90%) of those patients who received chemotherapy plus 2400-cGy RT before 5 years of age. Mean cephalometric values of this group showed significant deficient mandibular development. The results of this study suggest that the severity of dentofacial-developmental abnormalities secondary to antileukemia therapy are related to the age of the patient at the initiation of treatment and the use of cranial RT.
Adolescent↗
Late effects of central nervous system treatment of acute lymphoblastic leukemia in childhood are sex-dependent.
The authors measured the cognitive function and physical growth of 51 children who had been treated for acute lymphoblastic leukemia with chemotherapy, cranial irradiation and intrathecal methotrexate, and who had remained disease-free for five to 12 years. A comparison group of 15 children treated for Wilms' tumor was also studied. Cognitive impairment and growth retardation were greater among the leukemia group. Of potentially greater significance, however, was the finding that female sex was the pre-eminent risk factor for central nervous system toxicity resulting from treatment. Cognitive impairment, short stature and excessive weight were all more prevalent among females than males. Approximately half the children were microcephalic, but there was no sex difference. Age at evaluation and diagnosis, as well as socio-economic status, were differentially related to outcomes for the two sexes. The authors believe the sex differences were indicative of a fundamental interaction between postnatal neural development and other biological processes.
Body Height↗
Improved methodology for analyzing local and distant recurrence.
Studies of radiation therapy and/or surgery in the treatment of cancer frequently use actuarial methods to estimate curves of time to local failure and compare two such curves with statistical methods originally developed for survival data. In such analyses, patients who fail first in distant sites or die before local failure are considered censored for time to local failure. While the arithmetic of these calculations is usually correct, the interpretation of the results is almost universally incorrect. For example, an actuarial Kaplan-Meier curve of time to breast recurrence after breast conserving treatment consistently overestimates the percentage of patients who would benefit from a subsequent mastectomy. Actuarial methods require the assumption that time to local failure and time to distant failure are statistically independent. For most human malignancies this is not a reasonable assumption, since there are always some patient subgroups at high risk of both local and distant failure and some patient subgroups at low risk for either type of failure. Without the assumption of independence, the time to local failure distribution is not well defined. The basic problem is that estimating time to local failure falls into the category of analyzing "competing risks," since the various causes of failure are competing for the same patient. For this reason, the effects of a particular treatment on local failure cannot be assessed separately from its effects on distant failure. This report explains the concepts of statistical independence, nonidentifiability, and competing risks and illustrates the pitfalls of using actuarial methods to assess local tumor control.(ABSTRACT TRUNCATED AT 250 WORDS)
Actuarial Analysis↗
Postremission induction intensive sequential chemotherapy for children with AML--treatment results and prognostic factors.
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Antineoplastic Combined Chemotherapy Protocols↗
The impact of induction anthracycline on long-term failure-free survival in childhood acute lymphoblastic leukemia.
Early intensive therapy might be critical in improving failure-free survival for children with acute lymphoblastic leukemia. Between 1973 and 1977, 107 children received vincristine and prednisone (VP) induction and 30 received the same two agents plus an anthracycline (VPA). Ninety-nine of the VP-treated group and all 30 of the VPA-treated patients achieved complete remission. At a median observation time of 10 years, 59 of 137 children remain in continuous complete remission. Failure-free survival was 37% for the VP group and 63% for the VPA group (p = 0.02). Failure-free survival for boys who received VP was 28%, compared with 68% for boys who received VPA (p = 0.007). All 11 extramedullary relapses and all seven relapses occurring beyond 3.8 years from diagnosis (three testicular and four bone marrow) were observed among the VP group. We conclude that use of an anthracycline during remission induction therapy influenced failure-free survival and that early results of successful antileukemic therapy in children must be confirmed by follow-up progress reports.
Antibiotics, Antineoplastic↗
Perioperative and conventionally timed chemotherapy in operable breast cancer: the Ludwig Breast Cancer Study V.
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Age Factors↗
Depletion of T cells from human bone marrow using monoclonal antibodies and rabbit complement. A quantitative and functional analysis.
Graft-versus-host-disease (GVHD) remains the principal complication of allogeneic bone marrow transplantation. In animal models mature T lymphocytes have been shown to be responsible for GVHD and, therefore, in vitro treatment of donor bone marrow using monoclonal T cell specific antibodies and complement is currently being investigated as a strategy for the prevention of GVHD. In the present studies anti-T12 and anti-T11 monoclonal antibodies and rabbit complement were used to remove T lymphocytes from normal bone marrow. The efficacy of depletion was investigated by immunofluorescence assays and by in vitro culture of the residual cells using nonspecific mitogens or allogeneic B cells as the proliferative stimulus in the presence of lymphocyte-conditioned medium containing interleukin 2 (IL-2). Immunofluorescence analysis showed complete depletion of T12+ and T11+ cells after treatment with the respective antibodies and with the combination. Nevertheless, culture of treated bone marrow with phytohemagglutinin (PHA) or concanavalin A (Con A) and conditioned media containing IL-2 resulted in the proliferation of mature T cells (T3+, T4+ or T8+, T11+). Stimulation of treated marrow with allogeneic cells (Laz 388) resulted in the growth of a population with natural killer (NK) cell phenotype (T3-, T11+, NKH1+). The latter population was found to be strongly cytotoxic against K562 cells, a standard NK target. As expected, NK cells that are T11+ and T12- appeared to be more effected by in vitro treatment with anti-T11 than with anti-T12. A clonogenic assay was then used to quantitate the efficacy of target cell depletion in vitro. Three sequential incubations of bone marrow with either anti-T12 or anti-T11 plus complement resulted in depletion of 1-2 logs of clonogenic cells. Treatment with both antibodies concurrently resulted in elimination of 2-3 logs of clonogenic target cells. Although multiple treatments with both anti-T12 and anti-T11 were more effective than similar treatment with only one antibody, it remains to be established whether such combinations will be necessary in the clinical setting or whether more selective depletion of T cells without removal of NK cells might be optimal.
Animals↗
First repeated bone scan in the observation of patients with operable breast cancer.
Data on 1,601 patients with node-positive operable breast cancer who were randomized in four different prospective adjuvant therapy trials were analyzed to evaluate the role of routine bone scans and the alkaline phosphatase value at regular intervals in screening for bone involvement. Bone scan was a prerequisite for randomization and was repeated within the first 12 months in 90% (1,441) of the patients. Abnormal or doubtful scan findings had to be verified by x-ray examination. The repeated scan results were normal in 1,263 (87.8%) patients, doubtful but with no radiologic evidence of bone metastasis in 161 (11%), and abnormal (radiologically confirmed) in 17 (1.2%). After a median observation of 4 years bone metastases as the first relapse developed in 136 (8.5%) patients. This occurred in 87 of 1,263 (6.9%) of the patients with normal repeated scan results and in 18 of 161 (11.2%) of those with doubtful repeated scan findings. Based on the results of the first repeated scan, early detection of a first recurrence in bone might have been possible for 2.4% of the population. Serum alkaline phosphatase levels were also without clinical use. Bone scan in the observation of patients with operable breast cancer should be performed only as dictated by the clinical situation.
Alkaline Phosphatase↗