Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside,tetrahydrouridine, and carboplatin

Summary Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m² in three patients, 1,200 mg/m² in five patients), tetrahydrouridine (THU: 2,800 mg/m² in two patients, 2,646 mg/m² in one patient, 2,100 mg/m² in five patients), and carboplatin (900 mg/m² in four patients, 720 mg/m² in one patient, 450 mg/m² in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630±1170 ng/ml).Supported by the Don Monti Memorial Research Foundation     

Utility of voice therapy in the management of vocal fold polyps and cysts.

OBJECTIVE: To evaluate the efficacy of voice therapy in the management of vocal fold polyps and cysts. STUDY DESIGN AND SETTING: Retrospective review of vocal fold cysts and polyps undergoing voice therapy in a tertiary care center. Symptom resolution or persistence resulting in surgical intervention was the main outcome measure. RESULTS: Fifty-seven patients were identified, of which 49.1% achieved symptom resolution with voice therapy alone. Patients with complete glottal closure and muscle tension dysphonia did not have a better response than those with incomplete glottal closure and without muscle tension dysphonia (P = 0.1, chi(2), respectively). Patients with translucent polyps more commonly responded to voice therapy than fibrotic, hyaline, or hemorrhagic polyps, 81.8% versus 15.4% and 25.0% response rate, respectively (P = 0.002, chi(2)). CONCLUSIONS: Voice therapy is an effective treatment modality for vocal fold polyps and cysts. SIGNIFICANCE: A multidisciplinary approach including a trial of voice therapy is warranted.     

Prevention of sexually transmitted HIV infection: A meta-analytic review of teh behavioral outcome literature

Social learning theory-based models have recently provided the foundation for a series of twelve controlled human immunodeficiency virus (HIV) risk reduction intervention studies that have examined sexual behavior change. These interventions have been tested with adolescents, gay and bisexual men, inner-city women, college students, and seriously mentally ill adults. We report the first meta-analysis of these intervention studies. We found that, as expected, the mean weighted effect of HIV-risk reduction interventions on behavioral outcomes was positive and strongly significant (d₊=0.25). Moreover, the studies’ effect sizes were consistently positive, ranging from 0.11 to 0.53, and were largest when the outcomes were measured close in time to the intervention. We discuss other methodological challenges that, if solved, should enhance the success of future HIV-risk reduction interventions.     

Medication Outcome in ECT-Resistant Depression

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.     

Distinct autophosphorylation sites sequentially produce autonomy and inhibition of the multifunctional Ca2+/calmodulin-dependent protein kinase

The multifunctional Ca2+/calmodulin-dependent protein kinase (multifunctional CaM kinase) may be an important mediator for neurotransmitters and hormones that utilize Ca2+ as a "second messenger." We examined the ability of autophosphorylation to convert the multifunctional CaM kinase to a Ca2+/calmodulin-independent (autonomous) form to determine whether autophosphorylation is a mechanism for short- or long-term enhancement of Ca2+ action. As the kinase incorporates phosphate during continuous stimulation by Ca2+/calmodulin, its ability to phosphorylate exogenous substrates becomes increasingly autonomous. Withdrawal of Ca2+ after a critical level of phosphate incorporation is reached leads to a "burst" or rapid increase in Ca2+-independent autophosphorylation. The "burst" of autophosphorylation is distinct from the initial Ca2+-dependent autophosphorylation, however, since it inhibits substrate phosphorylation. Both Ca2+-dependent and Ca2+-independent substrate phosphorylation are inhibited by this autonomous autophosphorylation. Thus, autophosphorylation has a dual role in modulating the activity of multifunctional CaM kinase. It initially enables the kinase to continue phosphorylating substrates after Ca2+ levels decline, but it eventually suppresses this autonomous activity. Tryptic phosphopeptide mapping demonstrates that appearance of phosphothreonine-containing peptides is common to several conditions used to generate an autonomous enzyme. Sequencing reveals the critical "autonomy" site to be threonine286. The inhibitory mode of autophosphorylation involves 3 additional phosphopeptides containing a serine and a threonine residue.     

The use of anencephalic infants as organ sources. A critique

The recent abandonment of the only active US protocol for harvesting organs from anencephalic "donors" indicates both the practical and the ethical problems inherent in such an effort. Various data suggest that surprisingly few such organs would actually end up benefiting other children. Attempts to revise either the Uniform Anatomical Gift Act or the Uniform Determination of Death Act to allow organ removal from spontaneously breathing anencephalic infants face major ethical objections. Even if this posed no ethical problem in theory, the ultimate harm to society would not be offset by the good of the few surviving recipients of these organs. Furthermore, providing anencephalic infants with intensive care would tend to preserve the brain stem as effectively as the other organs, predictably rendering the occurrence of brain death unlikely. Thus, despite the great need for newborn organs, anencephalic infants are not as attractive a source as some had hoped.     

Policies of academic medical centers for disclosing financial conflicts of interest to potential research participants.

PURPOSE: To document the current state of institutional review board (IRB) and conflict of interest committee policies regarding disclosures of financial conflicts of interest to potential research participants, and to use this information to identify and share models for effectively achieving disclosure. METHOD: The authors identified the 123 U.S. academic medical centers that have IRBs and sought their IRB and institutional policies regarding financial conflicts of interest. In February and March 2004, using manual and key word searches, each institution's Web site was searched to identify documents containing information regarding the disclosure of financial conflicts of interest. Letters were sent to 24 institutions that had either no information or incomplete information posted on their Web sites. To assess institutions' guidelines for disclosure, the authors extracted and content coded each institution's information on disclosure. RESULTS: Relevant information was obtained from 120 (98%) academic medical centers (AMCs), of which 57 (48%) mentioned disclosing financial conflicts to potential research participants. Of these 57, 33 (58%) included verbatim language that could be used in informed consent documents. AMCs' recommendations and requirements for disclosure included details of the financial arrangement, administrative management of conflicts of interest, and encouragement of dialogue between the investigator and the potential research participant. CONCLUSIONS: Considerable variability exists concerning the specific information that should be disclosed. Most of the AMCs' policies were consistent with the goal of protection from legal liability. Significant questions remain, however, concerning the goals of disclosure and the most effective methods for achieving those goals.     

Monoclonal anti-(T,G)-A—L antibodies: Characterization of fine specificity and idiotype expression

The technique of polyethylene glycol mediated cell fusion was used to establish 22 monoclonal cell lines secreting anti-(T,G)-A—L antibody. Cell lines were derived from C3H.SW and B10 mice and produced antibody with light chains and predominantly γ₁, heavy chains. Fine-specificity analysis demonstrated that 15 cell lines made antibodies that also recognize a determinant present on GAT, GT (9:1) and GT (1:1), whereas little, if any, serum antibody demonstrates this cross-reaction. Fourteen antibodies, derived from both B10 and C3H.SW mice, bear idiotypic determinants defined by Lewis anti-[B10 anti-(T,G)-A—L], but only two, both from C3H.SW mice, react with Lewis anti-[C3H.SW anti-(T,G)-A—L]. Adsorption studies indicate that no hybridoma tested bore the complete set of idiotypic determinants defined by either serum.     

Raised carcinoembryonic antigen level as an indicator of recurrent disease in follow up of patients with colorectal cancer.

BACKGROUND. Serum carcinoembryonic antigen level is raised in 80% of patients undergoing colonic resection for cancer. Subsequent elevation in the follow-up period may precede signs and symptoms as an indicator of recurrent disease. there is little evidence that "classical" follow up of patients in the general surgical outpatient clinic improves either survival or quality of life. Regular carcinoembryonic antigen level estimation requested by the general practitioner, allied to day-case colonoscopic surveillance may be a more rational approach. AIM. A study was undertaken to investigate the relationship between raised carcinoembryonic antigen level and the recurrence of colorectal cancer in patients following a curative primary resection. METHOD. Retrospective analysis was carried out on the notes of 125 patients who had attended a dedicated hospital colorectal follow-up clinic between 1988 and 1992. Carcinoembryonic antigen level data were obtained by subsequent examination of the University of Edinburgh Department of Clinical Chemistry (immunoassay section) carcinoembryonic antigen database. RESULTS. A single carcinoembryonic level result of more than 100 ul-1 (normal range less than 60 ul-1) was found to be a highly sensitive (87%), specific (89%), and accurate (88%) indicator of recurrent disease. Raised carcinoembryonic antigen level preceded symptoms in 72% of patients with recurrence of colorectal cancer. CONCLUSION. Sequential laboratory estimation of carcinoembryonic antigen level organized by the general practitioner may represent an accurate method of detecting recurrent colorectal disease. Hospital review could be limited to colonoscopic surveillance and restaging of patients referred with evidence of recurrent disease.