Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Clinical and angiographic variables affecting the progression of coronary artery disease as determined by quantitative angiography

To assess by serial quantitative angiography, the significance of clinical and angiographic variables that affect the progression of coronary artery disease (CAD). Progression of disease by sequential angiography is unpredictable and the role of clinical risk factors controversial. Various intervention trials have demonstrated less progression and even regression in hyperlipidemic patients. Correlates of progression have included a younger age, unstable angina, and greater involvement of the coronary arteries, with few studies looking at angiographic features of individual lesions. Serial angiograms on 74 patients were analyzed by computer assisted quantitative angiography using absolute measurements. A total of 99 diseased segments were analyzed for progression defined as an absolute reduction of 20% in luminal cross-sectional area. A preliminary correlation coefficient was calculated for each of the clinical and angiographic variables to detect any association with progression, and the odds ratio determined.The presence of any of the clinical risk factors-diabetes, hypertension, serum cholesterol, smoking, and a family history of coronary disease could not predict progression. The use of beta blockers was three times less likely to be associated with progression (odds ratio 0.33). While the presence of distal disease was associated with progression of a more proximal lesion (odds ratio 2.4), eccentricity, branch point location, lesion length, calcification, thrombus, or the presence of collaterals did not influence progression of disease in an individual segment. In conclusion, the presence of any of the clinical risk factors could not predict progression of disease in an individual coronary segment as determined by serial quantitative angiography, and the use of beta blockers and the absence of coexistent distal disease was associated with less progression of disease in an individual coronary segment. This may be related to changes in wall stress, reduced platelet interactions, and the integrity and permeability of the vascular endothelium to lipids.     

Chemotherapy for non-small cell lung cancer in elderly patients

STUDY OBJECTIVE: To determine the appropriate chemotherapy regimen for inoperable, chemotherapy-na?ve non-small cell lung cancer (NSCLC) in elderly patients. SETTING: National teaching hospital in Taiwan. DESIGN: We retrospectively analyzed data from our clinical trials for a total of 270 patients and compared them with the data from other studies, addressing the elderly in particular or providing subgroup information on age, to analyze the feasibility of current chemotherapy options for elderly patients and possible alternative approaches. RESULTS: The response rates and median survival times of fit elderly patients with NSCLC who were receiving appropriate new anticancer drugs for chemotherapy, including single-agent or combination treatment, were no worse than those of younger patients, and the response rates may have been even higher in the elderly patients, while survival time was slightly poorer in this group. The risk of adverse side effects, such as myelosuppression and peripheral neuropathy, may be higher in elderly patients, who also visit the hospital more frequently. Some items on the lung cancer symptom scale for elderly patients were rated as being slightly worse than those for younger patients after chemotherapy. CONCLUSION: Advanced age alone should not preclude chemotherapy. New single-agent drugs, and non-platinum-based or platinum-based doublets, can all be considered as appropriate treatment for selected fit elderly patients with advanced NSCLC.     

Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations

OBJECTIVE: The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, 2 single-nucleotide polymorphisms (SNP) in the CRP gene (+838, +2043) have been shown to be associated with CRP concentrations and/or SLE risk in a British family-based cohort. Our study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the influence of 3 additional CRP tagSNP (-861, -390, +90) on SLE risk and serum CRP concentrations. METHODS: DNA from 337 Caucasian women who met the American College of Rheumatology criteria for definite (n = 324) or probable (n = 13) SLE and 448 Caucasian healthy female controls was genotyped for 5 CRP tagSNP (-861, -390, +90, +838, +2043). Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction, pyrosequencing, or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the chi-squared distribution, Z-test, Fisher's exact test, and analysis of variance. Haplotype analysis was performed using EH software and the haplo.stats package in R 2.1.2. RESULTS: While none of the SNP were found to be associated with SLE risk individually, there was an association with the 5 SNP haplotypes (p < 0.001). Three SNP (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes. CONCLUSION: Our data suggest that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.     

Temperature prediction in high speed bone grinding using motor PWM signal

This research explores the feasibility of using motor electrical feedback to estimate temperature rise during a surgical bone grinding procedure. High-speed bone grinding is often used during skull base neurosurgery to remove cranial bone and approach skull base tumors through the nasal corridor. Grinding-induced heat could propagate and potentially injure surrounding nerves and arteries, and therefore, predicting the temperature in the grinding region would benefit neurosurgeons during the operation. High-speed electric motors are controlled by pulse-width-modulation (PWM) to alter the current input and thus maintain the rotational speed. Assuming full mechanical to thermal power conversion in the grinding process, PWM can be used as feedback for heat generation and temperature prediction. In this study, the conversion model was established from experiments under a variety of grinding conditions and an inverse heat transfer method to determine heat flux. Given a constant rotational speed, the heat conversion was represented by a linear function, and could predict temperature from the experimental data with less than 20% errors. Such results support the advance of this technology for practical application.     

A pulsatile blood vessel system for a femoral arterial access clinical simulation model

The model-based, rapid-prototyping-enabled design and manufacture of a pulsatile blood vessel (PBV) for high-fidelity mannequin-based clinical simulations is presented. The PBV presented here is a pressurized, flexible tube with alternating fluid pressure created by a pump to mimic the behavior of a human vessel in response to pulsatile pressure. The use of PBVs is important for the fidelity of a clinical simulator that requires residents to palpate and/or access the vessel. In this study, a PBV is presented which features the integration of 3D modeling using patient-specific computed tomography (CT) data, mold fabrication using rapid-prototyping, and finite element method for estimating the required pumping pressure to generate the same level of force (about 1.5 N) experienced by the user through palpation. The relationship between this palpation force and the vessel pressure is studied using two strategies: finite element analysis (FEA) and experiments in a femoral arterial access simulator with a pump, artificial vessel, and surrounding phantom tissue. The experimental results show a discrepancy of 8.7% from the FEA-predicted value. Qualitative validation is done by exposing and surveying 19 interventional cardiology residents at four major educational institutions to the simulator for accuracy of its feel. The overall survey results are positive.     

Immunologic profile of highly exposed yet HIV type 1-seronegative men

The host immune factors that determine susceptibility to HIV-1 infection are poorly understood. We compared multiple immunologic parameters in three groups of HIV-1-seronegative men: 14 highly exposed (HR10), 7 previously reported possibly to have sustained transient infection (PTI), and a control group of 14 low risk blood bank donors (BB). Virus-specific cellular immune assays were performed for CD4(+) T helper cell responses, CD8(+) cytotoxic T lymphocyte activity, CD8(+) cell chemokine release, and CD8(+) cell-derived antiviral soluble factor activity. General immune parameters evaluated included CCR5 genotype and phenotype, interferon alpha production by PBMCs, leukocyte subset analysis, and detailed T lymphocyte phenotyping. Comparisons revealed no detectable group-specific differences in measures of virus-specific immunity. However, the HR10 group differed from the BB group in several general immune parameters, having higher absolute monocyte counts, higher absolute CD8(+) T cell counts and percentages, lower naive and higher terminal effector CD8(+) cells, and lower levels of CD28(+)CD8(+) cells. These changes were not associated with seropositivity for other chronic viral infections. The PTI men appeared to have normal levels of monocytes and slightly elevated levels of CD8(+) T cells (also with increased effector and decreased naive cells). Although we cannot entirely exclude the contribution of other chronic viral infections, these findings suggest that long-lived systemic cellular antiviral immunity as detected by our assays is not a common mechanism for resistance to infection, and that resistance may be multifactorial. General immune parameters reflected by CD8(+) T cell levels and activation, and monocyte concentrations may affect the risk of infection with HIV-1, and/or serve as markers of exposure.