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At least 991 records · Page 55Linked to original sources
PubMed2004

Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors.

PURPOSE: To determine the safety and toxicity of carmustine (BCNU) and temozolomide (TMZ) with radiotherapy (RT) in newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Patients >18 years old with anaplastic astrocytoma, a Karnofsky performance status score of > or =60, and adequate pulmonary function were eligible. All patients provided informed consent. Standard RT started within 5 weeks of diagnosis. In both arms, 150 mg/m(2) of TMZ was given on Days 1-5 of RT. In Arm 1, 200 mg/m(2) of carmustine was given on Day 1 of RT. In Arm 2, 150 mg/m(2) of carmustine was given on Day 5 of RT. After RT, TMZ and carmustine were repeated for a total of six cycles. RESULTS: A total of 15 and 14 patients were enrolled in the two pilot arms. Because of hematologic and pulmonary toxicities, dose reductions by the second cycle of therapy occurred in >70% of the patients in Arm 1 and >50% in Arm 2 despite a reduction in the carmustine dose. CONCLUSION: The results of these pilot studies have implications for the design of studies testing the initial treatment of brain tumors. Because of the poor tolerance of the combination, the multicooperative group Phase III study consists of two randomized arms of single-agent carmustine vs. single-agent TMZ.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

The mu-opioid receptor gene-dose dependent reductions in G-protein activation in the pons/medulla and antinociception induced by endomorphins in mu-opioid receptor knockout mice.

There appear to be different relationships between mu-opioid receptor densities and the acute and neuroadaptive mu-opioid agonist-induced responses of the multiple opioid neuronal systems, including important pons/medulla circuits. The recent success in creating mu-opioid receptor knockout mice allows studies of mu-opioid agonist-induced pharmacological and physiological effects in animals that express no, one or two copies of the mu-opioid receptor gene. We now report that the binding of mu-opioid receptor ligand, [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin to membrane preparations of the pons/medulla was reduced by half in heterozygous mu-opioid receptor knockout mice and eliminated in homozygous mu-opioid receptor knockout mice. The endogenous mu-opioid agonist peptides endomorphin-1 and -2 activate G-proteins in the pons/medulla from wild-type mice in a concentration-dependent fashion, as assessed using [35S]guanosine-5'-o-(3-thio)triphosphate binding. This stimulation was reduced to half of the wild-type levels in heterozygous mice and eliminated in homozygous knockout mice. The intracerebroventricular injection of either endomorphin-1 or endomorphin-2 produced marked antinociception in the hot-plate and tail-flick tests in wild-type mice. These antinociceptive actions were significantly reduced in heterozygous mu-opioid receptor knockout mice, and virtually abolished in homozygous knockout mice. The mu-opioid receptors are the principal molecular targets for endomorphin-induced G-protein activation in the pons/medulla and the antinociception caused by the intracerebroventricular administration of mu-opioid agonists. These data support the notion that there are limited physiological mu-opioid receptor reserves for inducing G-protein activation in the pons/medulla and for the nociceptive modulation induced by the central administration of endomorphin-1 and -2.

Analgesics, Opioid↗
PubMed2003

Reduction of dose delivered to the rectum and bulb of the penis using MRI delineation for radiotherapy of the prostate.

PURPOSE: The prostate volume delineated on MRI is smaller than on CT. The purpose of this study was to determine the influence of MRI- vs. CT-based prostate delineation using multiple observers on the dose to the target and organs at risk during external beam radiotherapy. MATERIALS AND METHODS: CT and MRI scans of the pelvic region were made of 18 patients and matched three-dimensionally on the bony anatomy. Three observers delineated the prostate using both modalities. A fourth observer delineated the rectal wall and the bulb of the penis. The planning treatment volume (PTV) was generated from the delineated prostates with a margin of 10 mm in three-dimensions. A three-field treatment plan with a prescribed dose of 78 Gy to the International Commission on Radiation Units and Measurements point was automatically generated from each PTV. Dose-volume histograms were calculated of all PTVs, rectal walls, and penile bulbs. The equivalent uniform dose was calculated for the rectal wall using a volume exponent (n = 0.12). RESULTS: The equivalent uniform dose of the CT rectal wall in plans based on the CT-delineated prostate was, on average, 5.1 Gy (SEM 0.5) greater than in the plans based on the MRI-delineated prostate. For the MRI rectal wall, this difference was 3.6 Gy (SEM 0.4). Allowing for the same equivalent uniform dose to the CT rectal wall, the prescribed dose to the PTV could be raised from 78 to 85 Gy when using the MRI-delineated prostate for treatment planning. The mean dose to the bulb of the penis was 11.6 Gy (SEM 1.8) lower for plans based on the MRI-delineated prostate. The mean coverage (volume of the PTV receiving > or =95% of the prescribed dose) was 99.9% for both modalities. The interobserver coverage (coverage of the PTV by a treatment plan designed for the PTV delineated by another observer in the same modality) was 97% for both modalities. The MRI rectum was significantly more ventrally localized than the CT rectum, probably because of the rounded tabletop and no knee support on the MRI scanner. CONCLUSIONS: The dose delivered to the rectal wall and bulb of the penis is significantly reduced with treatment plans based on the MRI-delineated prostate compared with the CT-delineated prostate, allowing a dose escalation of 2.0-7.0 Gy for the same rectal wall dose. The interobserver coverage was the same for CT and MRI delineation of the prostate. A statistically significant difference in position between the CT- and MRI-delineated rectum was observed, probably owing to a different tabletop and use of knee support.

Aged↗
PubMed2002

Intensity-modulated radiotherapy of the female breast.

Current methods for intensity-modulated radiotherapy (IMRT) in breast cancer use forward planning based on equivalent radiological path length to design intensity modulated tangential beams. Compared to conventional tangential techniques, dose reduction of organs at risk is limited using these techniques. We developed a method for intensity modulation of multiple beams for adjuvant radiotherapy of breast cancer by application of a virtual bolus defined on CT for inverse optimization. This method enables multibeam IMRT, which provides improved sparing of lung and heart tissue. In this paper, we present the general aspects of this approach and an evaluation of the optimum beam configuration for IMRT based on inverse treatment planning. We compared this method to conventional techniques. Different clinical examples illustrate the possible indications and feasibility of this new approach. This method is superior to conventional techniques because of the reduction of high-dose area of a substantial cardiac volume in those cases where the parasternal lymph nodes are part of the target volume.

Adult↗
PubMed1999

Raltitrexed (Tomudex) concomitant with radiotherapy as adjuvant treatment for patients with rectal cancer: preliminary results of phase I studies.

Radiotherapy, either alone or in combination with chemotherapy, may reduce local recurrence of rectal cancer following surgery and improve survival of patients with operable and advanced/recurrent/inoperable disease. Chemotherapy with 5-fluorouracil in combination with radiotherapy has been used both before and after surgery; however, the optimum schedule is unclear. In addition, alternative chemotherapy with raltitrexed (Tomudex) may be more convenient and better tolerated. The preliminary results of three phase I dose-finding studies are described, combining escalating doses of raltitrexed with radiotherapy as pre- or postoperative treatment for operable rectal cancer or as treatment for advanced/inoperable/recurrent rectal cancer. The recommended dose of raltitrexed when combined with adjuvant radiotherapy is likely to be 2.6 mg/m2. This is a small dose reduction compared with the dose of raltitrexed for the treatment of advanced colorectal cancer (3.0 mg/m2); however, toxicity appears to be lower using the pre-operative approach. Neo-adjuvant therapy with raltitrexed plus radiotherapy also demonstrated clinical activity in the pre-operative study, which showed that 22% of patients achieved a complete response and 56% a partial response. Once the recommended dose has been defined in each setting, large-scale studies will be undertaken as appropriate.

Aged↗
PubMed2003

A phase II study of rebeccamycin analog NSC 655649 in patients with metastatic colorectal cancer.

The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated antitumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status > or = 70%, age > or = 18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500 mg/m2 by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1-6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/microl (116-16,374/microl) and 276 x 10(3)/ microl (5-769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.

Adult↗
PubMed2005

[Comparison of conventional full spine radiographs and fluoroscopic scanning method in young patients with idiopathic scoliosis].

PURPOSE: Evaluation of low-dose full spine radiographs using fluoroscopic images for the assessment of the Cobb angle measurement in patients with scoliosis. MATERIAL AND METHODS: Twenty-one consecutive patients (aged 10 - 27 years, mean age 14 years) with a conventional full spine examination (film speed class 800) underwent a follow-up exam using digital pulsed fluoroscopy (Multi Diagnost 4, Philips Medical Systems, Eindhoven, The Netherlands). The mean follow-up was 9 months. During a synchronized scan with a C-arm speed of 4 cm/sec fluoroscopic images were stored with a pulsed frequency of 3 images per second. The single images were merged and reconstructed to one image with the software Easy Spine (Philips medical Systems, Eindhoven, The Netherlands). The corresponding dose-area product values (DAP) of both methods were compared. Three independent observers assessed Cobb angles and image quality for each technique. RESULTS: The mean DAP values for conventional imaging was 94.9 cGy x cm (2) and for fluoroscopy 7.8 cGy x cm (2), respectively. A significant dose reduction of 91.8 % (CI 91 % to 95 %) was calculated. The average absolute angle difference between the observers was found to be 2.7 degrees for conventional imaging and 2.4 degrees for the fluoroscopic method. Interobserver standard deviation of 2.9 degrees was lower than the 5.3 degrees for conventional images. Image quality was better in the conventional images. CONCLUSION: Using the scanning method, we could achieve a mean reduction of the radiation dose of 92 %, while the accuracy of the Cobb angle measurements was comparable for both techniques despite of reduced image quality of digital fluoroscopy.

Adolescent↗
PubMed1991

[Severe late-onset dystonia while on fluspirilene].

Shooting, tonic cramps of the neck muscles with jolt-like contractions in the mouth and jaw regions and propulsive movements of both arms developed in a 25-year-old woman who, over a period of six months, had been given nine intramuscular injections of the depot neuroleptic fluspirilene, 1.5 mg each, because of apathy and depression. Treatment with biperiden (up to 20 mg daily) and benzodiazepines was unsuccessful, while tiapride (up to 1000 mg daily) brought about slight improvement and 15 mg haloperidol achieved complete remission. However, distinct parkinsonian features developed. Slow gradual reduction of the haloperidol dose again led to extrapyramidal motor symptoms, even when tiapride or bromocriptine was given as well. After six months' administration of clozapine, up to 500 mg daily, and gradual dose reduction all symptoms fully regressed. This case demonstrates that the risk of extrapyramidal motor abnormalities from "neuroleptic anxiolysis" should not be underestimated.

Acute Disease↗
PubMed1998

Coadministration of zidovudine and interleukin-2 increases absolute CD4 cells in subjects with Walter Reed stage 2 human immunodeficiency virus infection: results of ACTG protocol 042.

Interleukin-2 (IL-2) can increase numbers of absolute CD4 cells in persons infected with the human immunodeficiency virus who are receiving antiretroviral therapy. Twenty-five subjects with > 400/mm3 absolute CD4 cells received zidovudine and low-dose intravenous or subcutaneous IL-2 (< or = 10(6) U/m2). Absolute CD4 cells increased significantly during IL-2 treatment, and 56% of the subjects achieved a maximal increase of > or = 500 cells/mm3. A dose-response relationship favored increasing IL-2 doses, and subcutaneous delivery offered greater increases than intravenous administration. Fifteen subjects had persistent increases of > or = 100 cells/mm3 6 weeks after IL-2 was discontinued. No changes occurred in delayed-type hypersensitivity or helper T cell responses to recall antigens. Cell-mediated cytotoxicities increased against Daudi cells. IL-2 was well tolerated and only 1 subject required dose reduction. Relatively low-dose IL-2 delivered by subcutaneous or intravenous routes may provide an important complement to antiretroviral therapy to increase absolute CD4 cells with the potential for less toxicity than with higher IL-2 doses.

Anti-HIV Agents↗
PubMed1992

Clustering of adverse drug events: analysis of risk factors for cerebellar toxicity with high-dose cytarabine.

BACKGROUND: Cerebellar toxicity is a severe, therapy-limiting adverse reaction of cytarabine given in high doses. The Food and Drug Administration received a report of an increased frequency of cerebellar toxicity at the University of Wisconsin Hospital and Clinics after a switch from the product (Cytosar-U) manufactured by The Upjohn Co., Kalamazoo, Mich., to the generic form made by Quad Pharmaceuticals, Inc., Indianapolis, Ind. PURPOSE: To compare the incidence of cerebellar toxicity in Quad-treated patients with Upjohn-treated patients, a record-based cohort study was conducted at the University of Wisconsin Hospital and Clinics between January 1986 and August 1989. METHODS: The incidence of cerebellar toxicity was studied in 63 leukemia patients according to the manufacturer of the product received (34 Upjohn only, 25 Quad only, and four both manufacturers). The relative risk of cerebellar toxicity was adjusted for other known risk factors. RESULTS: Patients in the manufacturer-defined treatment groups did not differ significantly with respect to age, sex, type of leukemia, disease stage, calculated creatinine clearance, presence of abnormal liver function tests, or total dose received. The crude relative risk of cerebellar toxicity comparing the Quad product with the Upjohn product was 5.0 (95% confidence interval = 1.8-13.7). Adjustment for potential confounders did not alter the association. Other risk factors for cerebellar toxicity, independent of manufacturer, were age greater than 50 years, type of leukemia, disease stage, total dose greater than or equal to 20 g/m2, abnormal pretreatment liver function, and reduced creatinine clearance. CONCLUSION: This study found a significantly higher incidence of cerebellar toxicity with high-dose cytarabine manufactured by Quad Pharmaceuticals when compared with the incidence of cerebellar toxicity with the Upjohn product. Further research at independent institutions would be necessary to allow generalization of this finding. In addition, our findings suggest that a dose reduction in high-dose cytarabine therapy may be indicated for patients with reduced glomerular filtration rates.

Adolescent↗
PubMed2003

Doxil-induced regression of pleuro-pulmonary metastases in a patient with malignant meningioma.

Metastatic meningioma is a rare disease, which has no effective chemotherapy. We report on a treatment of this condition with Doxil, a liposomal doxorubicin formulation. A 60-year-old woman with massive pleuro-pulmonary metastases from recurrent cranial meningioma was treated with Doxil (50-37.5 mg/m2) for 18 months with near-complete resolution of metastases and disappearance of pleural fluid. The only significant toxicities observed were stomatitis and hand-foot syndrome, which resolved with dose reduction and increase of dosing intervals. Doxil was cleared very slowly in this patient with a monoexponential half-life of 108 h. The patient remains in near-complete response for 6 months after treatment discontinuation. This is the first report on an effective chemotherapy in a patient with typical metastatic meningioma. The exact mechanism accounting for such an effective drug action is not clear, but may be related to a particularly high microvascular permeability to the liposome carriers in these metastatic lesions.

Antineoplastic Agents↗
PubMed2001

Follow-up of a patient with chronic hepatitis C-associated cryoglobulinemia during four and a half years of maintenance interferon treatment.

In this report, we present a patient with chronic hepatitis C-associated cryoglobulinemia who was kept on maintenance interferon treatment because of flare-ups in cryoglobulinemia-associated signs and hepatitis after withdrawal, dose reduction, and increase in dose intervals of interferon. This type of interferon use for treatment of cryoglobulinemia gave us a chance to observe the long-term effects of interferon on cryoglobulinemia and chronic hepatitis C remission for biochemical, virologic, and histologic aspects.

Adult↗
PubMed2005

Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy.

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Benzodiazepines↗
PubMed2004

Dose perturbation induced by radiographic contrast inside brachytherapy balloon applicators.

Phantom measurements and Monte Carlo calculations have been performed for the purpose of characterizing the dose perturbation caused by radiographic contrast inside the MammoSite breast brachytherapy applicator. Specifically, the dose perturbation is quantified as a heterogeneity correction factor (HCF) for various balloon radii and contrast concentration levels. The dose perturbation is larger for larger balloon radii and higher contrast concentrations. Based on a validated Monte Carlo simulation, the calculated HCF values are 0.99 for a 2 cm radius balloon and 0.98 for a 3 cm radius balloon at 6% contrast concentration levels, and 0.89 and 0.87 for 2 and 3 cm radius balloons, respectively, at 100% contrast concentrations. For a typical implanted balloon radius of 2.4 cm, the HCF values decrease from 0.99 at 6% contrast concentration to 0.90 at 100% contrast concentration. For balloons implanted in patients at our institution, the mean HCF is 0.99, corresponding to a dose reduction of approximately 1%. The contrast effect results in a systematic reduction in the delivered dose, therefore the minimal amount of radiographic contrast necessary should be used.

Angiography↗
PubMed1990

Failure to maintain high-dose treatment regimens during long-term use of zidovudine in patients with symptomatic human immunodeficiency virus type 1 infection.

Long-term tolerance of zidovudine treatment was retrospectively analysed in 97 patients with AIDS or AIDS-related complex. After one year of treatment 68% and after two years 87% of the patients had had at least one dose adjustment during their course of therapy. Myelotoxicity was the most common cause (58% of all cases) of dose reductions and therapy interruptions (dose adjustments). At the time of the first dose adjustment 33 patients (34%) were suffering from anaemia (Hb less than 6.0 g/dl), 20 patients (21%) from leukopenia (leukocytes less than 1.5 x 10(9], and 10 patients (10%) from thrombocytopenia (thrombocytes less than 75 x 10(9]. Fifty-six patients (57%) needed one or more blood transfusions during therapy. The median time from the start of therapy to the time of the first dose adjustment was 14 (range: 2-64) weeks in patients who had a first dose adjustment because of anaemia without co-existing leukopenia or thrombocytopenia, and 37 (range: 6-85) weeks in patients who had a first dose adjustment because of leukopenia without co-existing anaemia or thrombocytopenia (p = 0.01). Peripheral blood CD4 positive lymphocyte counts less than or equal to 100/mm3, anaemia, and CDC classification IV-C1 at the start of treatment were associated with a need for an early dose modification or blood transfusion rather than the need for dose modification per se.

AIDS-Related Complex↗
PubMed1997

Dose-dependent reduction of cardiac transmembrane potential by high-intensity electrical shocks.

Cardiac tissue dysfunction can result from high-intensity electrical shocks and is manifested as changes in transmembrane potential (Vm). Ten-millisecond shock pulses (SPs) of varying intensity and polarity were applied to frog ventricle in diastole, and Vm was quantified directly under the stimulating electrode by an optical method using voltage-sensitive dye. As SP intensities were increased, the shock-induced action potential (AP) plateau and AP amplitude (APAs) decreased sigmoidally toward 75-85% of the control AP amplitude (APAc) and zero, respectively. APAs was shifted toward lower current densities for anodal compared with cathodal SPs (half-maximal values 185 and 238 mA/cm2, respectively; P = 0.02). Recovery of APAs was marginally significant 1 s after SP delivery (P = 0.063). The peak change in Vm during SP (across all intensity levels) was -200% APAc for anodal and +125% APAc for cathodal pulses. In conclusion, we show that SP reduces APA in a sigmoidal fashion at strengths > 10-20 x diastolic threshold and is more deleterious for anodal polarities.

Action Potentials↗