Using health-related quality of life measures to predict cardiac function in survivors exposed to anthracyclines.

PURPOSE: As the number of pediatric cancer survivors increases, so does the number of survivors previously exposed to anthracyclines as part of their cancer therapy. Because screening is costly, some have suggested that health-related quality of life (HRQL) measures might be useful in focusing screening tests on those patients with cases most likely to display positive findings. This study reports on the predictive ability of HRQL measures to detect patients with abnormalities on serial cardiac testing. METHODS: Using 127 patients from the ACE-Inhibitor after Anthracycline (AAA) Trial, this study compared serial measures of the Short Form-36 (SF-36; for ages > 13 years) and Child Health Questionnaire-Child Form 87 (CHQ-CF87; for ages < or = 13 years) to serial cardiac performance tests including echocardiographic shortening fraction, left ventricular end systolic wall stress (LVESWS), LVESWS-index, and maximal cardiac index (MCI; a measure of cardiac output at peak exercise). RESULTS: Generally, there was no clinically or statistically significant correlation between any HRQL measure and any cardiac function measure except between MCI and vitality and physical functioning. For each of these measures, the correlation between MCI was statistically significant (P < .006), but each HRQL subscale could explain no more than 7% of the variation in MCI. HRQL measures were not predictive of any other cardiac function measure. CONCLUSION: HRQL measures should not be used in isolation as a screen for cardiac function abnormalities in patients exposed to anthracylines who already have a mild degree of ventricular dysfunction. Patient history appears to be no substitute for cardiac testing in this cohort.     

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.     

The validity of bioelectrical impedance models in clinical populations.

Bioelectrical impedance analysis (BIA) is the most commonly used body composition technique in published studies. Herein we review the theory and assumptions underlying the various BIA and bioelectrical impedance spectroscopy (BIS) models, because these assumptions may be invalidated in clinical populations. Single-frequency serial BIA and discrete multifrequency BIA may be of limited validity in populations other than healthy, young, euvolemic adults. Both models inaccurately predict total body water (TBW) and extracellular water (ECW) in populations with changes in trunk geometry or fluid compartmentalization, especially at the level of the individual. Single-frequency parallel BIA may predict body composition with greater accuracy than the serial model. Hand-to-hand and leg-to-leg BIA models do not accurately predict percent fat mass. BIS may predict ECW, but not TBW, more accurately than single-frequency BIA. Segmental BIS appears to be sensitive to fluid accumulation in the trunk. In general, bioelectrical impedance technology may be acceptable for determining body composition of groups and for monitoring changes in body composition within individuals over time. Use of the technology to make single measurements in individual patients, however, is not recommended. This has implications in clinical settings, in which measurement of individual patients is important.     

Educating early childhood teachers for the global world

Teachers for the twenty-first century for the global world need to be proficient in technology and skilled as reflective practitioners. They need to be able to reflect on diversity in myriad ways: learning styles, special needs, cultural differences, racial differences, developmentally appropriate differences, teaching styles and personality differences of children, teachers, parents, community members and administrators. The paradigni shift of the twenty-first century is that teachers need to be team players who are skilled at operating in a variety of collaborative partnerships.

The Early Childhood Program Faculty, at NEIU, with the help of a Teacher Quality Education grant, developed with six universities in Illinois called Illinois Professionals Learning Partnerships (IPLP), set out to adapt the NEIU/ECED program for the twenty-first century in a global world by focusing on four goals: (1) increasing technology and writing skills across the curriculum, (2) developing reflective skills and understanding of diversity (special needs, multicultural/international cultures), (3) developing student experience working in collaborative partnerships and (4) increasing clinical experiences.

The IPLP grant enabled the ECED program to: (1) spend intensive time on changing the curriculum in two retreats a year, (2) develop a faculty cohort including tenure track faculty, visiting lecturers and adjuncts, (3) develop a combined program of research and program development, (4) recruit and hire three new tenure track international faculty, (5) develop professional development schools and intensive field experiences, (6) combine resources for many grants, (7) develop short-term international experiences and faculty exchange programs and (8) increase technology skills of students and faculty through action laboratories on using video technology, digital cameras, reflective email discussions and videography.     

Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia.

OBJECTIVE: We tested the ability of magnesium sulfate to reduce hypertension and neonatal growth retardation in an animal model of preeclampsia. STUDY DESIGN: On day 17 of pregnancy, osmotic minipumps were inserted subcutaneously to continuously deliver either vehicle (saline control group), or N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day), or L-NAME (50 mg/kg/day) in combination with magnesium sulfate (60 mg/kg/day). Prior to insertion, blood pressure and heart rate were monitored with a pneumatic tail cuff device. Blood pressure measurements were repeated on days 18, 20, and 21 of pregnancy. Blood was obtained on days 17 and 21, along with urine, to assess magnesium levels and degree of proteinuria. Pups were weighed and measured at 48 hours postpartum. RESULTS: Rats receiving L-NAME developed hypertension within 24 hours of implantation (108 +/- 3.9 vs. 123 +/- 3.4 mmHg, p < 0.05). Magnesium sulfate, given along with L-NAME did not prevent mean blood pressure from increasing, but reduced it by day 21 compared to L-NAME given alone (107 +/- 3.4 vs. 122 +/- 8.7 mmHg, respectively, p < 0.05). Magnesium sulfate reduced neonatal growth retardation by improving the weight of the pups compared to pups from maternal rats given L-NAME alone (6.1 +/- 0.1 vs. 5.2 +/- 0.3 grams, respectively, p < 0.05). CONCLUSION: Maternal magnesium sulfate reduces blood pressure and increases neonatal size compared to L-NAME without magnesium. These findings support a beneficial effect of magnesium in preeclampsia.     

Cyclin d1 is a valuable prognostic marker in oropharyngeal squamous cell carcinoma.

BACKGROUND: The current tumor-node-metastasis system is inadequate to accurately classify patients in terms of prognosis. Thus, with the availability of recently developed molecular tools, considerable interest lies in discovering prognostic markers in order to guide treatment decisions. In this study, we sought to determine the prognostic significance of the cell cycle regulator cyclin D1 in oropharyngeal squamous cell carcinoma (OSCC). EXPERIMENTAL DESIGN: We studied the protein expression levels of cyclin D1 on a tissue microarray composed of 63 OSCCs with long-term follow-up data available. Protein expression was analyzed with an automated in situ quantitative (AQUA) method which allows preservation of tissue morphology while quantifying protein expression in paraffin-embedded tissue. RESULTS: The mean follow-up time was 35 months. High cyclin D1 nuclear expression was associated with increased 5-year local recurrence rate (48% versus 15%), inferior 5-year disease-free survival (16% versus 58%), and inferior 5-year overall survival (17% versus 53%). In multivariate Cox regression, high nuclear cyclin D1 expression was an independent predictor for local recurrence, disease-free survival, and overall survival at 5 years. CONCLUSIONS: Our results indicate that quantitative assessment of nuclear cyclin D1 expression level by automated in situ quantitative analysis is a strong predictor for outcome in OSCC. Thus, cyclin D1 may be a potential target for molecular intervention in patients with oropharyngeal squamous cell cancer.     

Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer.

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.     

High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation.

PURPOSE: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence. PATIENTS AND METHODS: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT. RESULTS: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04). CONCLUSION: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.     

Cytoskeletal genes regulation by chronic morphine treatment in rat striatum.

It has been previously suggested that morphine can regulate the expression and function of some proteins of the cytoskeleton. In the present study, we used real-time quantitative polymerase chain reaction to examine the effects of chronic morphine administration, in rat striatum, on 14 proteins involved in microtubule polymerization and stabilization, intracellular trafficking, and serving as markers of neuronal growth and degeneration. Chronic morphine treatment led to modulation of the mRNA level of seven of the 14 genes tested. Glial fibrillary acidic protein (Gfap) and activity-regulated cytoskeleton-associated protein (Arc) mRNA were upregulated, while growth associated protein (Gap43), clathrin heavy chain (Cltc), alpha-tubulin, Tau, and stathmin were downregulated. In order to determine if the regulation of an mRNA correlates with a modulation of the expression of the corresponding protein, immunoblot analyses were performed. With the exception of Gap43, the levels of Cltc, Gfap, Tau, stathmin, and alpha-tubulin proteins were found to be in good agreement with those from mRNA quantification. These results demonstrate that neuroadaptation to chronic morphine administration in rat striatum implies modifications of the expression pattern of several genes and proteins of the cytoskeleton and cytoskeleton-associated components.