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Biomedical subjects

R Kaplan

Publications and source records attributed to R Kaplan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

Adult↗
PubMed2000

Combined defect in membrane expression and activation of platelet GPIIb--IIIa complex without primary sequence abnormalities in myeloproliferative disease.

Defects in glycoprotein (GP)IIb-IIIa or in its activation may cause abnormal platelet aggregation and a bleeding diathesis. We report studies in a 67-year-old man with a myeloproliferative disease and markedly abnormal platelet responses. By flow cytometry, platelet binding of two complex-specific anti-GPIIb-IIIa monoclonal antibodies (mAbs), A2A9 and 10E5, was approximately 50% of normal. An enzyme-linked immunosorbent assay (ELISA) using immobilized kistrin showed 18% of normal membrane GPIIb-IIIa complex. By immunoblot analysis, GPIIb and GPIIIa levels in platelet lysates and membranes were near normal. Activation of GPIIb-IIIa, monitored with mAb PAC-1, was markedly decreased (< 20% of normal) in response to ADP, thrombin and platelet-activating factor (PAF); expression of ligand-induced binding sites (LIBS) was < or = 30% of normal. Signal transduction-independent LIBS expression, induced by echistatin, was approximately 60% of normal, suggesting that the integrin present had intact ligand-binding capability. Sequence analysis of GPIIb and GPIIIa cDNA, and platelet mRNA levels for both subunits, were normal. These findings document an acquired combined defect in membrane expression (secondary to a defect in post-translational processing of the complex) and inside-out signalling-dependent activation of the GPIIb-IIIa complex.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

[Epidemiology of delirium in elderly inpatients].

Our objective was to determine delirium incidence and risk factors in a cohort of elderly inpatients. We randomly selected 149 patients, aged 65 years or older, from admission to general wards, without evidence of delirium. They were evaluated daily with the Confusion Assessment Method, an instrument validated for the diagnosis of delirium. We obtained relative risks for delirium and those independently associated were included in a logistic regression model. We used the chi-square test with Yate's corrections for univariate analysis, and t-test for comparisons of means. We observed that 51 patients (20.5%) developed delirium during their hospital stay. Severity of disease (RR 1.28, 1.14-1.43), having chronic diseases (RR 3.45, 2.4-4.96), and having fever at admission (RR 1.84, 1.33-2.56) were found independently associated with delirium. Patients who developed delirium had longer hospital stay (9.87 days +/- 3.48 vs 6.95 days +/- 2.45, p < 0.05) and higher mortality (RR 2.19, CI 1.26-3.79). We conclude that delirium in our setting is very frequent and has negative effects on resource utilization and mortality in elderly inpatients. Its association with the severity of the disease seems interesting. Appropriate prospective identification of patients at risk for delirium may allow the implementation of preventive strategies in order to minimize the impact of this complication.

Aged↗
PubMed1999

Selective deletion of antigen-specific, activated T cells by a humanized MAB to CD2 (MEDI-507) is mediated by NK cells.

CD2 is a 50-kDa transmembrane glycoprotein that plays an important role in T and natural killer (NT) lymphocyte functions. CD2 serves as both an adhesion molecule and as a costimulatory molecule through interactions with its ligand, CD58, on antigen presenting or target cells. Consistent with earlier studies using a rat anti-CD2 mAb, we have shown that treatment of alloantigen stimulated T lymphocytes with a humanized mAb, MEDI-507 (IgG1, kappa), induced hyporesponsiveness to subsequent stimulation with alloantigen but not to mitogen (phytohemagglutinin). Fluorescence-activated cell sorting analysis of cells from mixed lymphocyte reaction (MLR) treated with MEDI-507 revealed pronounced deletion of T and NK cells, consistent with lack of proliferation in the MLR. MEDI-507 F(ab')2 fragments did not have inhibitory activity or induce deletion of lymphocytes in the MLR. Removal of the NK cell subset by magnetic bead depletion using anti-CD16 and anti-CD56 mAbs eliminated both the T cell deletion and the inhibitory effect. Reconstitution of NK depleted responder populations using autologous NK cells restored the MEDI-507-mediated deletion activity to levels measured in the original MLR. Formaldehyde-fixed NK cells failed to mediate the MEDI-507-induced deletion effect. Altogether, our studies indicate that activated T cells with MEDI-507 bound to CD2 are preferential targets for autologous NK cells through a nonapoptotic cytotoxic mechanism.

Adult↗
PubMed1999

Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Androgens↗
PubMed1998

Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain.

PURPOSE: This study compared the clinical efficacy of oxycodone hydrochloride controlled-release (CR) tablets administered every 12 hours with immediate-release (IR) oxycodone tablets administered four times daily in patients with cancer-related pain. PATIENTS AND METHODS: Cancer patients who required therapy for moderate to severe pain were randomized to CR oxycodone every 12 hours (n=81) or IR oxycodone four times daily (n=83) for 5 days in a multicenter, double-blind study. Pain intensity was assessed four times daily (categorical scale of none, slight, moderate, and severe); acceptability of therapy was assessed twice daily (categorical scale of very poor, poor, fair, good, and excellent). RESULTS: Pain intensity remained slight during the study, with mean oxycodone doses of 114 mg/d (range, 20 to 400 mg/d) for CR and 127 mg/d (range, 40 to 640 mg/d) for IR. Acceptability of therapy was fair to good with both treatments. While standard conversion ratios provided an acceptable dose for many patients, a protocol amendment that allowed initial titration and use of rescue medication reduced the discontinuation rate for lack of acceptable pain control (from 34% to 4% with CR and from 31% to 19% with IR before and after amendment, respectively) without increasing the discontinuation rate for adverse events (from 8% to 7% with CR and from 13% to 11% with IR). Fewer adverse events were reported with CR (109) than with IR (186) oxycodone (P=.006). CONCLUSION: CR oxycodone every 12 hours was as effective as IR oxycodone four times daily in managing moderate to severe cancer-related pain and was associated with fewer reports of adverse events.

Analgesics, Opioid↗
PubMed1998

Long-term administration of controlled-release oxycodone tablets for the treatment of cancer pain.

We conducted a study of the safety of controlled-release (CR) oxycodone tablets (OxyContin Tablets) administered chronically to patients with cancer-related pain in a usual clinical setting. These patients had participated in 1 of 2 double-blind, active-control studies. Our study was an open, 3-month treatment study that included 87 patients. Patients received CR oxycodone tablets every 12 hr in a manner that reflected typical clinical practice. Supplemental immediate-release (IR) oxycodone was available PRN for breakthrough pain. Patients recorded medication use, adverse events, and evaluations of pain intensity and acceptability of therapy in a daily diary. Forty-four patients (51%) completed all 12 weeks of study; 43 patients (49%) discontinued participation. At baseline and throughout the study period, the overall mean pain-intensity score was slight to moderate. A comparison of initial and final doses showed a significant but modest increase in total daily CR oxycodone dose. An increase or decrease in titration of the oxycodone dose occurred for 66 patients (84%) at least once during the 12-week study period, primarily for increased pain. Forty-four patients (56%) did not undergo dose titration when the latter was indicated. Half of the patients used IR oxycodone rescue almost daily; the mean number of rescue doses per day was 1.5. Despite stable pain control and an increasing total daily CR oxycodone dose, the percentage of patients reporting common opioid-related adverse events decreased over the course of the study. CR oxycodone tablets administered every 12 hr were successfully used to manage cancer pain over a 12-week period. Importantly, side effects diminished over time without a concomitant change in efficacy.

Administration, Oral↗
PubMed1998

Thyroxine abuse.

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Adult↗