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  • 1
    ISSN: 1573-904X
    Keywords: temozolomide ; cancer ; population pharmacokinetics ; nonlinear mixed-effects models ; pharmacokinetics-toxicity relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate covariate effects on the pharmacokinetics of temozolomide in cancer patients, and to explore the dose-pharmacokinetics-toxicity relationship of temozolomide. Methods. Non-linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical trials. All patients in the phase I trials had advanced cancer. Patients in the phase II trials had anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectively developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease, smoking status, and selected concomitant medications. Descriptive statistics were used to summarize the toxicity and temozolomide dose and exposure relationship. Results. The pharmacokinetics of temozolomide follows a one-compartment model with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GBM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m2, and 8.8 L/hr for female with BSA equal to 1.7 m2. The mean clearance for MM patients was slightly higher. The inter-subject variability in clearance was 15%, and the residual variability was 26%. Other factors investigated in this analysis had little effect on clearance. The overall incidence of neutropenia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predict nadir neutrophil and platelet counts due to large variability in counts. Conclusions. The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1615-6706
    Keywords: Schlüsselwörter: Paraneoplastisches Syndrom ; Myelitis ; Funikuläre Spinalerkrankung ; Key Words: Paraneoplastic syndrome ; Myelitis ; Subacute combined degeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract: Paraneoplastic syndroms of the central nervous system may precede the clinical presentation of a tumor by years. An early diagnosis may improve the prognosis of the underlying disease. We report clinical and imaging sings of a patient presenting with paraneoplastic polyneuropathy and myelitis, 18 months before the diagnosis of a small anaplastic breast carcinoma could be made. Spinal MRI showed primarily involvement of the dorsal columns, thought to be suggestive of a subacute combined degeneration due to vitamin B12 deficiency.
    Notes: Zusammenfassung: Paraneoplastische Erkrankungen des Zentralnervensystems sind seltene Frühsymptome einer Tumorerkrankung. Ihre Erkennung kann eine schnelle Behandlung der Grunderkrankung bewirken und ist zudem von großer differenzialdiagnostischer Bedeutung. Das diagnostische Verfahren zur Beurteilung einer medullären Schädigung ist heute die MRT. Wir berichten über den Fall einer Patientin mit paraneoplastischer sensorischer Neuropathie und Myelitis, die der klinischen Diagnose eines Mammakarzinoms um 18 Monate vorausging. Bemerkenswert war der bevorzugte Befall der Hinterstränge des Rückenmarks, der differenzialdiagnostisch an eine funikuläre Spinalerkrankung denken ließ.
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  • 3
    ISSN: 1432-0851
    Keywords: Key words Monoclonal antibodies ; Single-chain antibodies ; Antibody engineering ; Recombinant antibody ; Human colon cancer xenografts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti-TAG-72 mAb B72.3 and CC49) are among the most extensively studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb can be minimized by genetic humanization of these antibodies, where non-human regions are replaced by the corresponding human sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup IV germline variable light chain (Hum4 VL). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K a) for hu/muCC49 and muCC49 constructs were 1.1 × 106 M−1 and 1.4 × 106 M−1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive tumors.
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  • 4
    ISSN: 1573-7217
    Keywords: breast cancer ; catalase ; glutathione peroxidase ; malondialdehyde ; reactive oxygen metabolites ; superoxide dismutase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Reactive oxygen metabolites (ROMs), including superoxide anion (O2 ·−), hydrogen peroxide (H2O2) and hydroxyl radical (·OH), play an important role in carcinogenesis. There are some primary antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which protect against cellular and molecular damage caused by the ROMs. We conducted the present study to determine the rate of O2 ·− and H2O2 production, and concentration of malondialdehyde (MDA), as an index of lipid peroxidation, along with the SOD, GPx and CAT activities in 54 breast cancer (BC) patients. Forty-two age- and sex-matched patients with minor surgical problems, who had no history of any neoplastic or breast disorders, were taken as controls. The rate of O2 ·− production was significantly higher (p〈0.001) in BC patients than controls, irrespective of clinical stages and menopausal status. Similarly, H2O2 production was significantly higher in BC patients, especially in stage III and postmenopausal groups, as compared to the respective controls. MDA concentration was also observed significantly elevated in stage II (p〈0.001), stage III (p〈0.01), postmenopausal (p〈0.005), and premenopausal (p〈0.02) group as compared to their corresponding controls. SOD and GPx activities were found significantly raised in all the groups (p〈0.001), except the GPx activity was found a smaller alteration in stage IV (p〈0.02). On the contrary, CAT activity was found significantly depressed in all the study groups. The maximum depression was observed in stage II (−61.8%). Lower CAT activity in our study may be the effect of higher production of ROMs, particularly O2 ·− and ·OH. SOD and GPx, however, were less effected by these higher ROMs production. The results of our study have shown a higher ROMs production and decreased CAT activity, which support the oxidative stress hypothesis in carcinogenesis. The relatively higher SOD and GPx may be due to the response of increased ROMs production in the blood. However, the higher SOD and GPx activities may be inadequate to detoxify high levels of H2O2 into H2O leading to the formation of the most dangerous ·OH radical followed by MDA. Therefore, administration of CAT may be helpful in the management of BC patients. However, further elaborate clinical studies are required to evaluate the role of such antioxidant enzymes in BC management.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-2681
    Keywords: electroelasticity ; approximate theories ; anisotropic bodies ; double forces
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract We use a mixed 3-dimensional variational principle to derive 2-dimensional equations for an anisotropic plate-like piezoelectric body and one-dimensional equations for an anisotropic beam-like piezoelectric body. The formulation accounts for double forces without moments which may change the thickness of the plate and deform the cross-section of the rod. The dependence of the bending rigidities of a transversely isotropic plate upon the angle between the normal to the midsurface and the direction of transverse isotropy is exhibited. The plate equations are used to study the cylindrical deformations of a transversely isotropic plate due to equal and opposite charges applied to its top and bottom surfaces. It is also found that a piezoelectric circular rod with axis of transverse isotropy not coincident with its centroidal axis and subjected to electric charges at the end faces is deformed into a non-prismatic body.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1438-1435
    Keywords: Key words Home teleradiology – Resident supervision – Subspecialist teleconsultations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Study objective: To determine whether teleconsultations by first-year radiology residents with faculty thoracic radiologists, using diagnostic-quality teleradiology workstations in the radiologists' homes, would add clinical value for the acute management of intensive care unit patients after regular working hours. Design and setting: First-year radiology residents recorded key findings on new computed chest radiographs from 173 cardiothoracic intensive care unit patients. After consulting with home-based thoracic radiologists on the same images via teleradiology, they recorded any revisions to their original interpretations. An interdisciplinary evaluation panel determined whether the revisions of the residents' initial readings after the teleradiology consultations would have influenced the acute clinical care of these patients. Measurements and results: In 119 of the 173 cases (69 %), differences in key findings on the chest images were observed between the first-year residents' preliminary readings and their revised readings after teleconsultation with a thoracic radiologist. The evaluation panel determined that the changes in key findings after the teleconsultations could have influenced acute patient care in 86 of the 173 cases (50 %). Conclusions: Through rapid teleradiology consultations with residents, focusing on the key findings on newly-obtained computed chest images, home-based thoracic radiologists provided information of added clinical value for the acute management of cardiothoracic intensive care unit patients in one-half of the cases studied. Diagnostic workstations in the homes of faculty subspecialists may enable first-year radiology residents on night or weekend duty to obtain clinical supervision from faculty subspecialists that approximates more closely the level of supervision that they receive during regular working hours.
    Type of Medium: Electronic Resource
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