Background
Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose‐dependent cardiotoxicity. In an ...effort to prevent this cardiotoxicity, different cardioprotective agents have been studied.
Objectives
The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010) and EMBASE (1980 to November 2010) databases. In addition, we handsearched reference lists, conference proceedings of the International Society of Paediatric Oncology (SIOP) and American Society of Clinical Oncology (ASCO) meetings (1998 to 2010) and ongoing trials registers.
Selection criteria
Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional therapy or placebo in cancer patients (children and adults) receiving anthracyclines.
Data collection and analysis
Two review authors independently performed the study selection, risk of bias assessment and data extraction including adverse effects.
Main results
We identified RCTs for the eight cardioprotective agents N‐acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N‐acetylcysteine, L‐carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta‐analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified.
Authors' conclusions
No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from ...serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms.
To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas.
The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.
To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs).
We determined CEs grade 3 or higher: congestive heart ...failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events CTCAE, version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models.
Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE.
CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.
Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants ...associated with ACT in patients treated for childhood cancer.
We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands.
We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT.
We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.
Cumulative anthracycline dose is one of the strongest predictors of heart failure (HF) after cancer treatment. However, the differential risk for cardiotoxicity between daunorubicin and doxorubicin ...has not been rigorously evaluated among survivors of childhood cancer. These risks, which are based on hematologic toxicity, are currently assumed to be approximately equivalent.
Data from 15,815 survivors of childhood cancer who survived at least 5 years were used. Survivors were from the Emma Children's Hospital/Academic Medical Center (n = 1,349), the National Wilms Tumor Study (n = 364), the St Jude Lifetime Cohort Study (n = 1,695), and the Childhood Cancer Survivor Study (n = 12,407). The hazard ratio (HR) for clinical HF through age 40 years for doses of daunorubicin and doxorubicin (per 100-mg/m(2) increments) was estimated by using Cox regression adjusted for sex, age at diagnosis, treatment with other anthracycline agents and chest radiation, and cohort membership.
In total, 5,144 (32.5%) patients received doxorubicin as part of their cancer treatment, whereas 2,243 (14.7%) received daunorubicin. On the basis of 271 occurrences of HF during a median follow-up time after cohort entry of 17.3 years (range, 0.0 to 35.0 years), the cumulative incidence of HF at age 40 years was 3.2% (95% CI, 2.8% to 3.7%). The average ratio of HRs for daunorubicin to doxorubicin was 0.45 (95% CI, 0.23 to 0.73). A similar ratio was obtained by using a linear dose-response model, which yielded an HR of 0.49 (95% CI, 0.28 to 0.70).
Compared with doxorubicin, daunorubicin was less cardiotoxic among survivors of childhood cancer than most current guidelines suggest. This may have implications for follow-up guidelines. The feasibility of substitution of doxorubicin with daunorubicin in childhood cancer treatment protocols to reduce cardiotoxicity should be additionally investigated.
Background
Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood.
Neuroblastoma cells ...have the unique capacity to accumulate Iodine‐123‐metaiodobenzylguanidine (¹²³I‐MIBG), which can be used for imaging the tumour. Moreover, ¹²³I‐MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localization of skeletal lesions. If these are present, MIBG follow‐up scans are used to assess the patient's response to therapy. However, the sensitivity and specificity of ¹²³I‐MIBG scintigraphy to detect neuroblastoma varies according to the literature.
Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of ¹²³I‐MIBG scans. Due to its clinical use and importance, it is necessary to determine the exact diagnostic accuracy of ¹²³I‐MIBG scintigraphy. In case the tumour is not MIBG avid, fluorine‐18‐fluorodeoxy‐glucose (18F‐FDG) positron emission tomography (PET) is often used and the diagnostic accuracy of this test should also be assessed.
Objectives
Primary objectives:
1.1 To determine the diagnostic accuracy of ¹²³I‐MIBG (single photon emission computed tomography (SPECT), with or without computed tomography (CT)) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.
1.2 To determine the diagnostic accuracy of negative ¹²³I‐MIBG scintigraphy in combination with 18F‐FDG‐PET(‐CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old, i.e. an add‐on test.
Secondary objectives:
2.1 To determine the diagnostic accuracy of 18F‐FDG‐PET(‐CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.
2.2 To compare the diagnostic accuracy of ¹²³I‐MIBG (SPECT‐CT) and 18F‐FDG‐PET(‐CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. This was performed within and between included studies. ¹²³I‐MIBG (SPECT‐CT) scintigraphy was the comparator test in this case.
Search methods
We searched the databases of MEDLINE/PubMed (1945 to 11 September 2012) and EMBASE/Ovid (1980 to 11 September 2012) for potentially relevant articles. Also we checked the reference lists of relevant articles and review articles, scanned conference proceedings and searched for unpublished studies by contacting researchers involved in this area.
Selection criteria
We included studies of a cross‐sectional design or cases series of proven neuroblastoma, either retrospective or prospective, if they compared the results of ¹²³I‐MIBG (SPECT‐CT) scintigraphy or 18F‐FDG‐PET(‐CT) imaging, or both, with the reference standards or with each other. Studies had to be primary diagnostic and report on children aged between 0 to 18 years old with a neuroblastoma of any stage at first diagnosis or at recurrence.
Data collection and analysis
One review author performed the initial screening of identified references. Two review authors independently performed the study selection, extracted data and assessed the methodological quality.
We used data from two‐by‐two tables, describing at least the number of patients with a true positive test and the number of patients with a false negative test, to calculate the sensitivity, and if possible, the specificity for each included study.
If possible, we generated forest plots showing estimates of sensitivity and specificity together with 95% confidence intervals.
Main results
Eleven studies met the inclusion criteria. Ten studies reported data on patient level: the scan was positive or negative. One study reported on all single lesions (lesion level). The sensitivity of ¹²³I‐MIBG (SPECT‐CT) scintigraphy (objective 1.1), determined in 608 of 621 eligible patients included in the 11 studies, varied from 67% to 100%. One study, that reported on a lesion level, provided data to calculate the specificity: 68% in 115 lesions in 22 patients. The sensitivity of ¹²³I‐MIBG scintigraphy for detecting metastases separately from the primary tumour in patients with all neuroblastoma stages ranged from 79% to 100% in three studies and the specificity ranged from 33% to 89% for two of these studies.
One study reported on the diagnostic accuracy of 18F‐FDG‐PET(‐CT) imaging (add‐on test) in patients with negative ¹²³I‐MIBG scintigraphy (objective 1.2). Two of the 24 eligible patients with proven neuroblastoma had a negative ¹²³I‐MIBG scan and a positive 18F‐FDG‐PET(‐CT) scan.
The sensitivity of 18F‐FDG‐PET(‐CT) imaging as a single diagnostic test (objective 2.1) and compared to ¹²³I‐MIBG (SPECT‐CT) (objective 2.2) was only reported in one study. The sensitivity of 18F‐FDG‐PET(‐CT) imaging was 100% versus 92% of ¹²³I‐MIBG (SPECT‐CT) scintigraphy. We could not calculate the specificity for both modalities.
Authors' conclusions
The reported sensitivities of ¹²³‐I MIBG scintigraphy for the detection of neuroblastoma and its metastases ranged from 67 to 100% in patients with histologically proven neuroblastoma.
Only one study in this review reported on false positive findings. It is important to keep in mind that false positive findings can occur. For example, physiological uptake should be ruled out, by using SPECT‐CT scans, although more research is needed before definitive conclusions can be made.
As described both in the literature and in this review, in about 10% of the patients with histologically proven neuroblastoma the tumour does not accumulate ¹²³I‐MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging and assess response to therapy. Additional tests might for example be 18F‐FDG‐PET(‐CT), but to be certain of its clinical value, more evidence is needed.
The diagnostic accuracy of 18F‐FDG‐PET(‐CT) imaging in case of a negative ¹²³I‐MIBG scintigraphy could not be calculated, because only very limited data were available. Also the detection of the diagnostic accuracy of index test 18F‐FDG‐PET(‐CT) imaging for detecting a neuroblastoma tumour and its metastases, and to compare this to comparator test ¹²³I‐MIBG (SPECT‐CT) scintigraphy, could not be calculated because of the limited available data at time of this search.
At the start of this project, we did not expect to find only very limited data on specificity. We now consider it would have been more appropriate to use the term "the sensitivity to assess the presence of neuroblastoma" instead of "diagnostic accuracy" for the objectives.
Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this ...often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as ...methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.
The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this ...aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
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