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The mechanisms underlying exercise-induced asthma are not well understood buy cialis professional in united states online erectile dysfunction doctor london. The hyperosmolarity hypothesis proposes that water loss from the airway causes hypertonicity of 4 airway cells purchase cialis professional without a prescription impotence 36, leading to release of inflammatory mediators and subsequent bronchoconstriction. Another hypothesis suggests that hyperventilation leads to cooling of airway cells, and after Quick-relief medications for asthma Page 6 of 113 Final Report Update 1 Drug Effectiveness Review Project exercise the rewarming process leads to dilatation of bronchiolar vessels accompanied by fluid exudation, mediator release, and bronchoconstriction. Exercise-induced asthma can affect elite and recreational athletes. Prevalence is reported 4 as 17% in athletes participating in winter Olympics, 35% among athletes competitive in cold 4 4 weather sports, and 9% among school children. Treatment focuses on avoidance of the particular activities that precipitate bronchospasm, adequate warm-up periods, and pharmacologic therapy. The last of these usually consists of an 4 inhaled short-acting beta -agonist 15 minutes prior to exercise. Additional, daily therapy may be2 required for management of underlying chronic asthma. Inhaled beta2-agonists Beta -agonists act mainly to relax airway smooth muscle by stimulating beta -receptors, which in2 2 2 turn increase cyclic AMP and produce functional antagonism to bronchoconstriction. Beta -2 5 agonists may also have anti-inflammatory properties, as suggested by in vitro experiments. The short-acting beta -agonists2 relax airway smooth muscle and increase airflow within 1 30 minutes and last 4 to 5 hours. They are the drug of choice for treating acute asthma symptoms and exacerbations and are used for preventing exercise-induced bronchospasm. The 1 short-acting beta -agonists are not recommended for regularly scheduled, daily use. Numerous clinical studies have demonstrated that albuterol hydrofluoroalkane 134a formulations have safety and efficacy comparable to albuterol 6-8 chlorofluorocarbon formulations. Inhaled anticholinergic agents Anticholinergic (antimuscarinic) agents such as ipratropium bromide have been used in the treatment of acute and chronic asthma. These drugs act on muscarinic receptors to inhibit the effects of acetylcholine, thus causing smooth muscle relaxation. In asthma, ipratropium bromide 9 is less potent and its bronchodilation slower than beta -agonists, but its effects last up to 6 hours. They noted, however, that addition of multiple doses of anticholinergic agents to beta -agonists improves lung function and avoids hospital admission in2 some patients. Quick-relief medications for asthma Page 7 of 113 Final Report Update 1 Drug Effectiveness Review Project 11 Table 1. Pharmacokinetics, indications and dosing of included drugs Half-life and other Dose relevant adjustments for Drug How pharmacokinetic FDA labeled Dosing (inhaled special Trade name(s) supplied features indications doses) populations Short-acting beta-agonists Albuterol Inhalation Absorption: Time to Asthma, treatment Asthma, Pediatric patients: (salbutamol in HFA aerosol peak and prophylaxis treatment and Asthma, Canada) powder: 0. Scope and Key Questions The purpose of this review is to compare the benefits and harms of short-acting beta -agonists2 and ipratropium bromide used for quick relief of asthma symptoms. For the original report we included long- and short-acting beta -agonists for the treatment of asthma (including exercise-2 induced asthma) and chronic obstructive pulmonary disease. For Update 1 we were asked to focus only on short-acting drugs for quick relief of asthma symptoms (quick-relief medications for asthma). Therefore, for this report we included from the original report only sections that relate to short-acting beta -agonists. We included short-acting beta -agonists used on a regular2 2 basis in the original report, and we also updated that information in Update 1. We added ipratropium bromide to the review, and we did not include studies of chronic obstructive pulmonary disease. We also did not update metaproterenol for Update 1, per the request of our participating organizations. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and, based on these, the eligibility criteria for studies. These preliminary questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the Quick-relief medications for asthma Page 9 of 113 Final Report Update 1 Drug Effectiveness Review Project scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. The participating organizations approved the following key questions to guide this review: Key Questions 1. What are the comparative efficacy and effectiveness of quick-relief medications used to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm? What are the comparative incidence and severity of adverse events reported from using quick-relief medications to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm? Are there subgroups of patients for which quick-relief medications used to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm differ in efficacy, effectiveness, or frequency and severity of adverse events? METHODS Literature Search To identify relevant citations, 2 independent reviewers identified potentially relevant titles and abstracts from the Cochrane Central Register of Controlled Trials (Issue 1, 2006), Cochrane Database of Systematic Reviews, DARE, and MEDLINE (1966 to February, week 4, 2006). For Update 1 we searched these databases until June 2, 2008. Search terms included drug names and indications (see Appendix A for complete search strategies). To identify additional studies, we also searched reference lists of included studies and reviews and we reviewed dossiers submitted by pharmaceutical companies. All citations were imported into an electronic database (EndNote 9. Articles deemed potentially relevant after review of titles and abstracts were retrieved in full-text form. Two independent reviewers achieved consensus on all included and excluded articles. Excluded articles were coded in the EndNote database with the reason for exclusion. Study Selection We reviewed a selection of drugs currently available in the United States and of interest to the organizations participating in the Drug Effectiveness Review Project (Table 1). In addition, we were asked to review 2 drugs available only in Canada: terbutaline (Bricanyl™) and fenoterol (Berotec™). Weexcludedstudiesthatexaminedmixed populations where outcomes were not presented for subgroups of interest to us. We examined studies that present 1 or more of the primary outcomes of interest to this review, effectiveness outcomes and outcomes related to safety and harms. For effectiveness and safety, published and as well as unpublished English-language reports in any geographic setting were included if they had a total sample size • 10. We included letters if primary data were presented and there was sufficient detail to evaluate quality. We excluded abstracts and conference proceedings, as these publications generally do not have sufficient detail to assess Quick-relief medications for asthma Page 10 of 113 Final Report Update 1 Drug Effectiveness Review Project internal or external validity.

Some genes order cialis professional with mastercard medication that causes erectile dysfunction, such as TET2 and TP53 purchase discount cialis professional on line weak erectile dysfunction treatment, can have one or both alleles affected. Certain lesions could be more clinically important than others and it will Disclosures require very large studies to capture these nuances. The same is true Conflict-of-interest disclosure: The author is on the board of for different activating lesions in oncogenes. At the moment, we directors or an advisory committee for Genoptix and Celgene, has largely ignore these differences when interpreting mutations in consulted for Genoptix and Celgene, and has received honoraria hematologic malignancies. Ac- MDS, but can also complicate the interpretation of mutational data. For example, gene mutations associated with a favorable prognosis 2. The 2008 revision of may be “trumped” by less favorable coexisting mutations. Con- the World Health Organization (WHO) classification of my- versely, a prognostically adverse mutation may become irrelevant if eloid neoplasms and acute leukemia: rationale and important it occurs alongside a mutation that predicts a high likelihood of changes. International scoring system for evaluating prognosis in myelodysplastic syndromes. Problem 4: the relative importance of molecular versus Blood. NCCN Clinical An argument can be made for considering only clinical findings Practice Guidelines in Oncology: myelodysplastic syndromes. The incidence and impact of otherwise complex and diverse set of molecular abnormalities. The lower dysfunction that cell-intrinsic mutation patterns do not capture. However, we know that certain molecular abnormalities, such as 2010;34(12):1551-1555. TP53 mutations, are strongly associated with outcomes even after 7. Impact of the taking clinical features into account. Getting that weighting right will require the analysis of 8. A prognostic score for very large cohorts of patients and may need to be repeated regularly patients with lower risk myelodysplastic syndrome. How we treat lower risk myelodysplastic Summary syndromes. The widespread adoption of the IPSS helped to improve the clinical 10. A decision analysis of care of patients with MDS and spurred the development of newer allogeneic bone marrow transplantation for the myelodysplastic prognostic models to refine risk stratification. Each has slight syndromes: delayed transplantation for low-risk myelodyspla- differences that may favor their use in certain situations, but none sia is associated with improved outcome. Proposal for a new more about the molecular mechanisms that give rise to MDS. These risk model in myelodysplastic syndrome that accounts for Hematology 2013 509 events not considered in the original International Prognostic 25. Molecular genetics of myelodysplastic Scoring System. Molecular pathophysiology of myelo- the MD Anderson Prognostic Risk Model for patients with dysplastic syndromes. Hematology Am Soc Hematol Educ tional prognostic scoring system for myelodysplastic syn- Program. Validation of the point mutations in myelodysplastic syndromes. The revised IPSS is lower-risk myelodysplastic syndromes. SF3B1 mutation in myelodysplasia with ring sideroblasts. Pfeilstocker M, Tuchler H, Schonmetzler A, Nosslinger T, N Engl J Med. Frequent pathway and recently proposed clinical, cytogenetical and comorbidity mutations of splicing machinery in myelodysplasia. P-104 Outcomes by in patients with myelodysplastic syndromes. IPSS-R in lenalidomide-treated patients with IPSS low-/Int-1- 2012;91(8):1221-1233. SNP array karyotyping in myelodysplastic syndromes and 18. Microarray-based MDS derived from an international database merge. J Clin classifiers and prognosis models identify subgroups with dis- Oncol. Komrokji RS, Corrales-Yepez M, Kharfan-Dabaja MA, et al. Hypoalbuminemia is an independent prognostic factor for 35. Mutation in TET2 overall survival in myelodysplastic syndromes. Rationale for ity in 7q myeloid disorders: clinical associations and genomic the clinical application of flow cytometry in patients with pathogenesis. Gain-of-function of Consortium and the European LeukemiaNet Working Group. Clonal diversity of recurrently cytometry in myelodysplastic syndromes: a report from an mutated genes in myelodysplastic syndromes. Molecular analysis ties in patients with myelodysplastic syndrome. Haemato- of different FLT3-ITD mutations in acute myeloid leukemia. TP53 mutations comorbidities with overall survival in myelodysplastic syn- in myelodysplastic syndrome are strongly correlated with drome: development of a prognostic model. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. Recent data show that multiple myeloma is consistently preceded by a precursor state (monoclonal gammopathy of undetermined significance [MGUS]/smoldering multiple myeloma [SMM]). This observation provides a framework for prospective studies focusing on transformation from precursor disease to multiple myeloma and for the development of treatment strategies targeting “early myeloma. Introduction related end-organ impairment in the presence of an M-protein and/or Although monoclonal gammopathy of undetermined significance monoclonal plasma cells. In the 2003 IMWG criteria, end-organ (MGUS) is commonly referred to as single entity in the literature, damage was defined using both the classic “CRAB” criteria of there are actually 2 kinds of MGUS: lymphoid (or lymphoplasmacy- hypercalcemia (serum calcium 11.

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Expanded clinical evaluation of lovastatin (EXCEL) study design and patient characteristics of a double blind generic cialis professional 20 mg otc erectile dysfunction caused by lisinopril, placebo controlled study in patients with moderate hypercholesterolemia cheap cialis professional 40mg amex erectile dysfunction organic. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Expanded clinical evaluation of lovastatin (EXCEL) study results III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia. Efficacy and tolerability of lovastatin in 3390 women with moderate hypercholesterolemia. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results two year efficacy and safety follow up. Hey-Hadavi JH, Kuntze E, Luo D, Silverman P, Pittman D, Lepetri B. Tolerability of atorvastatin in a population aged > or =65 years: a retrospective pooled analysis of results from fifty randomized clinical trials. Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Statins Page 98 of 128 Final Report Update 5 Drug Effectiveness Review Project 213. Garcia-Rodriguez LA, Gonzalez-Perez A, Stang MR, Wallander M-A, Johansson S. The safety of rosuvastatin in comparison with other statins in over 25,000 statin users in the Saskatchewan Health Databases. Garcia-Rodriguez LA, Masso-Gonzalez EL, Wallander M-A, Johansson S. The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care. The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy. Impact of statin dosing intensity on transaminase and creatine kinase. FDA adverse effects reports on statin-associated rhabdomyolysis. Statin safety: an assessment using an administrative claims database. Gaist D, Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. Comparison of the frequency of adverse events in patients treated with atorvastatin or simvastatin. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. Shepherd J, Vidt DG, Miller E, Harris S, Blasetto J. Safety of rosuvastatin: update on 16,876 rosuvastatin-treated patients in a multinational clinical trial program. Consistency of lipid-altering effects of ezetimibe/simvastatin across gender, race, age, baseline low density lipoprotein Statins Page 99 of 128 Final Report Update 5 Drug Effectiveness Review Project cholesterol levels, and coronary heart disease status: results of a pooled retrospective analysis. Effects of rosuvastatin on lipids, lipoproteins and apolipoproteins in the dyslipidaemia of diabetes. Bevilacqua M, Guazzini B, Righini V, Barrella M, Toscano R, Chebat E. Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: A 4-month, prospective, open-label, randomized, blinded - End point (probe) trial. Safety and efficacy of fluvastatin in hyperlipidemic patients with chronic renal disease. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety profiles. Colesevelam hydrochloride: a non- absorbed, polymeric cholesterol-lowering agent. An evaluation of CYP3A4 drug interactions with HMG-CoA reductase inhibitors. The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statins. Blagojevic A, Delaney JAC, Levesque LE, Dendukuri N, Boivin J-F, Brophy JM. Investigation of an interaction between statins and clopidogrel after percutaneous coronary intervention: a cohort study. A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. Impact of combined pharmacologic treatment with clopidogrel and a statin on outcomes of patients with non-ST-segment elevation acute coronary syndromes: perspectives from a large multinational registry. Lotfi A, Schweiger MJ, Giugliano GR, Murphy SA, Cannon CP, Investigators T. High- dose atorvastatin does not negatively influence clinical outcomes among clopidogrel treated acute coronary syndrome patients--a Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) analysis. Mukherjee D, Kline-Rogers E, Fang J, Munir K, Eagle K. Lack of clopidogrel-CYP3A4 statin interaction in patients with acute coronary syndrome. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial.

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In another randomized study of children with high-risk ALL conducted by the DFCI ALL consortium (1996-2000) cheap 20 mg cialis professional amex erectile dysfunction caused by surgery, doxorubicin was administered to a total cumulative dose of 300 mg/m2 by bolus with or without the use of dexrazoxane before each dose purchase cialis professional no prescription erectile dysfunction pills non prescription, starting with the first dose of doxorubicin. Dexrazoxane reduced the incidence of doxorubi- cin-associated myocardial injury as measured by cardiac tro- ponin-T during treatment. Impor- tantly, the cardioprotection associated with dexrazoxane did not come with any increase in relapse risk: with a median follow-up of 8. Results of a single trial in pediatric Hodgkin patients raised concern that dexrazoxane might be associated with an increased risk of secondary acute myelogenous leukemia (AML)/myelodysplastic syndrome. However, it may not be sufficient to fully eliminate cardiac late effects. Additional or alternative therapeutic interventions need to be identified. Lipo- somal anthracyclines appear to be less cardiotoxic in adults than standard formulations of doxorubicin and daunorubicin, but the long-term cardiac consequences of these formulations, and whether they are as effective in treating leukemia as standard formulations, remains to be tested in the pediatric population. Mean echocardiographic left ventricular Z-score measurements 5 years after completing treatment in HR ALL patients randomized to receive doxorubicin alone or with dexrazoxane (DFCI Consortium Protocol 95–001) Doxorubicin alone Doxorubicin dexrazoxane P-value Fractional shortening 0. A Z-score of zero indicates that the mean of the observed values is at the expected meanforanormalpopulation. Symptomatic osteonecrosis has been observed in reported risk factors for the development of osteonecrosis include 2%–9% of children treated for ALL and can lead to significant pain female sex and high body mass index. In a series from risk for this complication for whom preventative strategies may be the Dutch Childhood Oncology Group (DCOG), 35 ALL patients targeted. Rates of osteonecrosis are significantly higher in sone is the principal corticosteroid that is used, especially during adolescents than in younger children. The challenge for clinical treated for ALL do not seem to have as high an incidence of investigators is to find a way to preserve the beneficial aspects of symptomatic osteonecrosis as teenagers, suggesting that the hor- dexamethasone treatment while preventing its bone complications. EFS of 205 high-risk patients treated on DFCI ALL Consortium Protocol 95-01 (1996-2000) by randomized treatment group (doxorubicin given alone or with dexrazoxane). In the patients with high-risk ALL suggest that altering the dosing SJCRH Total XV trial (2000-2007), all patients were treated schedule of dexamethasone may reduce the risk of osteonecrosis without cranial radiation; those considered at higher risk of relapse without adversely affecting antileukemic outcome. In that study, received more doses of intrathecal chemotherapy and more inten- high-risk patients were randomized to receive either 1 or 2 delayed sive systemic chemotherapy than lower-risk patients. Patients who received only 1 DI phase EFS of that trial was relatively favorable (5-year EFS of 86%), received dexamethasone continuously for 21 days (days 0-20) although some patients did significantly worse, including those with during that phase; patients receiving 2 DI phases received dexameth- CNS-3 disease at diagnosis. Comprehensive neurocognitive testing asone discontinuously during each of the phases (days 0-7 and then of patients treated on that protocol performed 2 years after the again days 14-20). For patients aged 10-21 years, alternate-week completion of consolidation therapy revealed that most survivors dosing of dexamethasone (ie, 2 DI phases) was associated with a performed well on global measures of cognitive ability; however, significantly lower cumulative incidence of osteonecrosis compared 40% of the tested cohort performed below average on a measure of with continuous dosing/1 DI phase (8. There was no significant 25 on measures of process speed and academic abilities, as well as difference in EFS in patients randomized to 1 versus 2 DI phases, greater parent report of learning problems, outcomes that are not indicating that the reduced frequency of osteonecrosis associated dissimilar to those reported for survivors who had received 18 Gy with alternate-week dosing of dexamethasone did not come at the cranial radiation in other clinical trials. Results of trials that randomized patients to receive cranial radiation Neurocognitive sequelae or not during upfront therapy indicate that neurocognitive function- The neurocognitive impact of ALL treatment has been a major focus ing appears similar in irradiated and nonirradiated survivors treated of late effects research. Low and low average IQs were frequent findings in survivors of ALL treated in the 1970s, most of whom on contemporary regimens. In a DFCI ALL Consortium trial received cranial radiation at higher doses (24-28 Gy) than are (1996-2000), standard-risk patients were randomized to receive 18 typically administered with current regimens. With 5-10 years of Gy cranial radiation or more frequent dosing of intrathecal chemo- follow-up, survivors from this era were found to have a high therapy without radiation. EFS was not significantly different between the arms. Investigators groups in cognitive skills or in the frequency of children receiving from SJCRH performed cognitive testing on long-term survivors special education. Similar results were reported from the UK Radiation-associated neurocognitive impairment appears to be dose ALL clinical trials group, which conducted a randomized trial related. Long-term survivors treated with 18 Gy radiation (espe- comparing high-dose methotrexate and 24 Gy cranial radiation in cially those who were 3 years of age or older at diagnosis) appear to high-risk patients (1990-1997); at 3 and 5 years after treatment, have less severe neurocognitive sequelae than those who received there were no significant differences in IQ scores in irradiated and higher doses of radiation. In some studies, the overall cognitive nonirradiated high-risk patients, nor was there any difference in the functioning (including global IQ scores) in survivors who received proportion of patients with IQ scores 80. Because it appears that neurocognitive function may of memory impairment compared with those who had received 18 35 28 decline over time in ALL survivors, longer follow-up is Gy radiation. It is possible that, with longer follow-up, those necessary before making definitive conclusions. In one study of treated with lower-dose radiation may also develop these problems, 567 survivors who were 10 more years from initial diagnosis, but at a median of 25. The lowest rates observed in nonirradiated patients. The nonirradiated and 18 Gy-treated survivors both dose-related findings observed thus far in irradiated survivors, it demonstrated high rates of impairment in all neurocognitive would not be expected to be worse than that associated with 18 Gy domains, but there were few statistically significant differences noted between the 2 groups. However, the interventions that may prevent late neurocognitive sequelae in other CNS-directed therapies used to substitute for cranial radiation children with ALL (including those treated without cranial (such as extra doses of intrathecal chemotherapy and high-dose IV radiation) should remain a priority. It is likely that the 1% to 6%, depending on the treatment regimen and length of rate of SMNs in long-term ALL survivors will decrease as an follow-up. The use of dexrazox- overall cumulative incidence of SMN was 4% at 15 years and ane to prevent cardiotoxicty and alternate-week dosing of dexameth- 11% at 30 years. Testing strategies to these diagnoses were excluded, the cumulative incidence of SMNs further decrease late effects remains a priority, but should be done in at 30 years was 6%. In addition, an increased developing secondary solid tumors, including malignant gliomas understanding of host factors that predispose to toxicities (such as and meningiomas. Silverman, Department of Pediatric Oncology, Dana-Farber those patients still receiving radiation (Table 3), has not yet been Cancer Institute, 450 Brookline Avenue, Boston, MA 02215; Phone: elucidated. Cranial radiation has also been associated with the development of vascular malformations, which can lead to neurological symptoms and intracranial hemorrhage. Long-term results of radiation from upfront regimens is likely to substantially reduce the Dana-Farber Cancer Institute ALL Consortium protocols for children risk of CNS SMNs and secondary vasculopathies. To that end, on with newly diagnosed acute lymphoblastic leukemia (1985-2000). Improved survival for children and patients, including those with CNS-3 status at diagnosis and some adolescents with acute lymphoblastic leukemia between 1990 and 2005: T-ALL patients, determining whether the benefit of omitting cranial a report from the children’s oncology group. Nottage KA, Ness KK, Li C, Srivastava D, Robison LL, Hudson MM. Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia from the St. Secondary AML can also develop in long-term survivors, with Br J Haematol. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the higher (and/or more frequent) doses of epipodophyllotoxins and 41-43 Childhood Cancer Survivor Study.