Longevity, stress response, and cancer in aging telomerase-deficient mice.
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Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established. The telomerase null mouse provides an opportunity to understand the effects associated with critical telomere shortening at the organismal level. We studied a variety of physiological processes in an aging cohort of mTR-/- mice. Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging. However, age-dependent telomere shortening and accompanying genetic instability were associated with shortened life span as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, we found an increased incidence of spontaneous malignancies. These findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism. (+info)
Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity.
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The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a murine monoclonal recognizing the surface domain of the TAG-72 antigen and has been widely used in human clinical trials. After our initial encouraging studies (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer, we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p. administration. In the first arm of the study, patients (3 pts/dose level) received an i.p. infusion of either 2 or 10 mg of B72.3 labeled with either 1, 10, 15, or 25 mCi of 90Y. Pharmacokinetic studies demonstrated that concentrations of 90Y-labeled B72.3 persist in peritoneal fluid with half-lives >24 h after i.p. administration. In addition, 90Y-labeled B72.3 was absorbed rapidly into the plasma with peak levels achieved within 48 h, and levels declined slowly thereafter. Cumulative urinary excretion of the 90Y label was 10-20% of the administered dose which suggests significant whole-body retention of the radiolabel. Biopsy specimens of bone and marrow obtained at 72 h after administration demonstrated significant content of the label in bone (0.015% of the dose/g) with relatively little in marrow (0.005% of the dose/g). The maximal tolerated dose was determined to be 10 mCi because of hematological toxicity and platelet suppression. This typically occurred on the 29th day after administration and was thought to be a consequence of the irradiation of the marrow from the bony deposition of the radiolabel. In an effort to suppress the bone uptake of 90Y, patients were treated with a continuous i.v. infusion of EDTA (25 mg/kg/12 h x 6) infused immediately before i.p. administration of the radiolabeled antibody. Patients (3 pts/dose level) were treated with doses of 10, 15, 20, 25, 30, 35, 40, or 45 mCi of 90Y-labeled B72.3 for a total of 38 patients. EDTA administration resulted in significant myeloprotection, which allowed escalation to the maximal tolerated dose of 40 mCi. Dose-limiting toxicity was thrombocytopenia and neutropenia. Studies of plasma and peritoneal fluid pharmacokinetics demonstrate no changes compared with patients without EDTA pretreatment. Cumulative urinary excretion of the radiolabel was not increased in patients pretreated with EDTA compared with the untreated group. However, analysis of biopsy specimens of bone and marrow demonstrated that bone and marrow content of the 90Y label was 15-fold lower (<0.001% injected dose/g) than a companion group without EDTA. Four responses were noted in patients who received 15-30 mCi of 90Y-labeled B72.3 with response durations of 1-12 months. These results demonstrate the myeloprotective ability of EDTA, which allows safe i.p. administration of higher doses of 90Y-labeled B72.3 and, therefore, clearly warrant an expanded Phase II trial in patients with minimal residual disease after standard chemotherapy or for the palliation of refractory ascites. (+info)
Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer.
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A significant myeloprotective effect of melatonin in mice treated with etoposide, cyclophosphamide or carboplatin has been reported. The present study was designed to evaluate if the same effect could be observed in patients receiving chemotherapy. Twenty previously untreated patients with inoperable lung cancer received two cycles of carboplatin (given at area under the curve 5 by the Calvert formula) on day 1 and etoposide (150 mg m(-2) i.v.) on days 1-3 every 4 weeks. Melatonin 40 mg or placebo (double-blind) was given orally in the evening for 21 consecutive days, starting 2 days before chemotherapy. Patients were randomized to receive melatonin either with the first or the second cycle. Complete blood cell count with differential was done three times per week for 3 weeks. The median age of the cohort was 60 years (range 42-69), 16 patients had non-small cell and four patients small-cell lung cancer, 12 stage III and eight stage IV disease. In a multivariate analysis including age, sex, diagnosis, stage, performance status, doses of carboplatin and etoposide, and concomitant treatment with melatonin or placebo, the haematological parameters--depth and duration of toxicity for haemoglobin, platelets and neutrophils (ANC)--were not significantly different between cycles with/without melatonin. The mean ANC nadir and the mean number of days with ANC < 0.5 x 10(9) l(-1) were 0.5 x 10(9) l(-1) and 2.5 days, respectively, with/without melatonin. We concluded that, in patients with lung cancer, melatonin given orally at a dose of 40 mg per day for 21 days in the evening, does not protect against the myelotoxic effect of carboplatin and etoposide. (+info)
Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement.
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OBJECTIVES: To investigate the progression of joint damage in early rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of the wrist and determine whether this technique can be used to predict prognosis. METHODS: An inception cohort of 42 early patients has been followed up prospectively for one year. Gadolinium enhanced MRI scans of the dominant wrist were obtained at baseline and one year and scored for synovitis, tendonitis, bone marrow oedema, and erosions. Plain radiographs were performed concurrently and scored for erosions. Patients were assessed clinically for disease activity and HLA-DRB1 genotyping was performed. RESULTS: At one year, MRI erosions were found in 74% of patients (31 of 42) compared with 45% at baseline. Twelve patients (28.6%) had radiographic erosions at one year. The total MRI score and MRI erosion score increased significantly from baseline to one year despite falls in clinical measures of inflammation including erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and swollen joint count (p < 0.01 for all). Baseline findings that predicted carpal MRI erosions at one year included a total MRI score of 6 or greater (sensitivity: 93.3%, specificity 81.8%, positive predictive value 93.3%, p = 0.000007), MRI bone oedema (OR = 6.47, p < 0.001), MRI synovitis (OR = 2.14, p = 0.003), and pain score (p = 0.01). Radiological erosions at one year were predicted by a total MRI score at baseline of greater than 13 (OR = 12.4, p = 0.002), the presence of MRI erosions (OR = 11.6, p = 0.005), and the ESR (p = 0.02). If MRI erosions were absent at baseline and the total MRI score was low, radiological erosions were highly unlikely to develop by one year (negative predictive value 0.91 and 0.92 respectively). No association was found between the shared epitope and erosions on MRI (p = 0.4) or radiography (p = 1.0) at one year. CONCLUSIONS: MRI scans of the dominant wrist are useful in predicting MRI and radiological erosions in early RA and may indicate the patients that should be managed aggressively. Discordance has been demonstrated between clinical improvement and progression of MRI erosion scores. (+info)
Hematopoietic damage prior to PBSCT and its influence on hematopoietic recovery.
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BACKGROUND AND OBJECTIVE: Patients with malignancies receive chemotherapy to induce tumor remission which could damage hematopoiesis and adversely influence hematopoietic reconstitution after transplantation. In the present study we used a long-term culture (LTBMC) system and clonogenic assays to evaluate the marrow damage in patients selected to receive peripheral blood stem cell transplantation (PBSCT). DESIGN AND METHODS: Thirty-five patients - 20 with breast cancer (BC), 9 with non-Hodgkin's lymphoma (NHL) and 6 with Hodgkin's disease (HD) - were included. Bone marrow aspiration was performed one day prior to the initiation of the conditioning therapy. CFU-GM were cultured in methylcellulose with PHA-LCM. Delta assays of plastic adherent progenitor cells (PD) were performed according to Gordon's method. LTBMC were established for 5 weeks. RESULTS: There were fewer CFU-GM from all patient groups than from normal BM (p<0.05). In contrast, the number of immature progenitor cells (PD) was not decreased. The total number of CFU-GM produced by LTBMC patients was significantly reduced (p<0.05). The adherent layer from patients was often qualitatively different. In order to know whether the hematopoietic damage could affect hematopoietic reconstitution, we correlated culture data with time taken to reach peripheral cell counts. A negative correlation (r= - 0.71) was found between percentage of stromal layer and time taken to reach 20x10(9) platelets/L (tplat= 20x3-0.08% stromal layer). INTERPRETATION AND CONCLUSIONS: We can conclude that prior to PBSCT, hematopoietic function is impaired at both the level of committed progenitor cells and that of BM stroma. This damage could influence platelet recovery. (+info)
First-line high-dose sequential chemotherapy with rG-CSF and repeated blood stem cell transplantation in untreated inflammatory breast cancer: toxicity and response (PEGASE 02 trial).
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Despite the generalization of induction chemotherapy and a better outcome for chemosensitive diseases, the prognosis of inflammatory breast cancer (IBC) is still poor. In this work, we evaluate response and toxicity of high-dose sequential chemotherapy with repeated blood stem cell (BSC) transplantation administered as initial treatment in 100 women with non-metastatic IBC. Ninety-five patients (five patients were evaluated as non-eligible) of median age 46 years (range 26-56) received four cycles of chemotherapy associating: cyclophosphamide (C) 6 g m(-2) - doxorubicin (D) 75 mg m(-2) cycle 1, C: 3 g m(-2) - D: 75 mg m(-2) cycle 2, C: 3 g m(-2) - D: 75 mg m(-2) - 5 FU 2500 mg m(-2) cycle 3 and 4. BSC were collected after cycle 1 or 2 and reinfused after cycle 3 and 4. rG-CSF was administered after the four cycles. Mastectomy and radiotherapy were planned after chemotherapy completion. Pathological response was considered as the first end point of this trial. A total of 366 cycles of chemotherapy were administered. Eighty-seven patients completed the four cycles and relative dose intensity was respectively 0.97 (range 0.4-1.04) and 0.96 (range 0.25-1.05) for C and D. Main toxicity was haematological with febrile neutropenia ranging from 26% to 51% of cycles; one death occurred during aplasia. Clinical response rate was 90% +/- 6%. Eighty-six patients underwent mastectomy in a median of 3.5 months (range 3-9) after the first cycle of chemotherapy; pathological complete response rate in breast was 32% +/- 10%. All patients were eligible to receive additional radiotherapy. High-dose chemotherapy with repeated BSC transplantation is feasible with acceptable toxicity in IBC. Pathological response rate is encouraging but has to be confirmed by final outcome. (+info)
Ticlopidine and clopidogrel.
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The thienopyridines ticlopidine and clopidogrel are inhibitors of platelet function in vivo. Their mode of action has not been defined, but it appears that they require conversion to as yet unidentified metabolites that are noncompetitive antagonists of the platelet ADP receptor. Inhibition of platelet aggregation with these compounds is delayed until 24 to 48 hours after administration. Maximum inhibition occurs after 3 to 5 days, and recovery is slow after drug withdrawal. Ticlopidine is effective in preventing cardiovascular events in cerebrovascular, cardiovascular, and peripheral vascular disease, with an efficacy that is similar to aspirin. However, its use is associated with significant and sometimes fatal adverse reactions, specifically neutropenia and bone marrow aplasia. Gastrointestinal side effects and skin rashes are common and result in discontinuation of therapy in up to 10% of patients. Clopidogrel is at least as effective as aspirin in preventing cardiovascular events in patients with a history of vascular disease. It appears to be safer than ticlopidine, although its efficacy in acute coronary syndromes or post-coronary-stent insertion has not been reported. Important outstanding issues are whether clopidogrel adds to the benefit of aspirin and whether the combination of these agents is safe. If so, this combination may become the standard for antithrombotic therapy in cardiovascular disease. (+info)
Measurement of vitamin B12-binding proteins of plasma. II. Interpretation of patterns in disease.
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The technique described in the preceding paper was applied to 12 abnormal sera selected for their increase in one or more B12-binding proteins. Even in the presence of large amounts of R-type binder, the ammonium sulfate technique gave a reliable separation of R binding proteins from TC II. Measurement of the TC II in abnormal sera gave results identical to those obtained by the more standard gel filtration. The R binders of four subjects with myeloproliferative disease were further separated into alpha2-R and alpha1-R. The pattern of B12 binding of polycythemia vera (PV) was an exaggeration of the normal pattern. Binding to alpha2-R was three to four times that to alpha1-R, although the total amounts bound to both were increased. In chronic myelogenous leukemia (CML), both alpha2-R and alpha1-R were also increased, but in contrast to binding in normal sera, alpha1-R predominated. In order to interpret the findings, either whole serum R or alpha1-R and alpha2-R from patients with myeloproliferative disease were subject to isoelectric focusing. Alpha2-R consisted pricipally of components isoelectric at pH 2.9, 3.0, and 3.1. These components were present in only minor amounts in normal serum and were somewhat increased in the serum of PV. These components were very much increased in the serum of CML and predominated. Alpha2-R consisted of those components isoelectric at pH 3.4,3.6, and 4.0. These components predominated in the unsaturated binding capacity of normal sera and that of PV. It was concluded that the division of plasma R binders into alpha1-R and alpha1-R by the technique described provided information useful in the study of myeloproliferative diseases. (+info)