Early Detection of Anthracycline-Induced Cardiotoxicity in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Low Cumulative Dose.

We investigated the left ventricular (LV) function, using for the first time strain (S) and strain rate (SR) imaging, in long-term survivors affected by acute lymphoblastic leukemia treated with a low cumulative dose of anthracyclines, and in presence of a normal global LV systolic and diastolic function. A total of 21 were enrolled in the study. The mean cumulative dose of anthracylines was 180 mg/m2 (range: 120-210 mg/m2). As control group 21 age-sex matched healthy subjects were included. Radial S (17 ± 3% vs. 55 ± 6%, P < 0.0001) and SR (2.1 ± 0.3 vs. 3.0 ± 0.8 1\s, P < 0.0001), assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared with controls. Conversely, myocardial performance index was not able to discriminate between patients and controls. In this preliminary study, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical LV dysfunction than other echocardiographic measurements.

Bax mutation and overexpression inversely correlate with immature phenotype and prognosis of childhood germ cell tumors.

Primary childhood germ cell tumors (GCTs) represent a rare and heterogeneous group of tumors that varies in histologic differentiation, age of presentation and clinical outcome. In malignant neoplasms, apoptosis is a prognostic marker and a predictive factor of response to therapy. Therefore, the study of the expression and mutation of molecules involved in the regulation of apoptosis could be useful in order to both predict the clinical outcome and design self-tailored therapeutic approaches. We retrospectively analysed tissue samples of 54 childhood GCTs. The expression of p53 and BAX protein was assessed by immunohistochemistry (IHC). Moreover, we investigated the presence of mutations in the BAX and p53 genes SSCP-PCR and direct sequencing. IHC analysis of BAX protein expression showed that 14 out of 54 tumors (26%) had no BAX protein expression, in the remaining 40 patients (74%) the intensity of BAX was low in 20 patients (37%) and high/intermediate in 20 (37%). BAX was mutated in 6 patients. p53 was expressed in 43 patients (79.6%), was not detectable in the remaining 11 (20.4%) and mutated in only 3 patients. p53 mutational status and expression were not correlated to the overall survival (OS). On the other hand, both IHC score and mutations for BAX were correlated to sacrococcygeal primary localization. BAX mutations were inversely correlated with OS (p=0.0419) while BAX IHC intensity was directly correlated with OS (p=0.0376). The stratification for histotype showed a direct correlation between BAX IHC and OS in both immature teratoma (p=0.045) and mixed malignant GCT (p=0.010) while the correlation was lost in mature teratoma (p=0.300). These results indicate that both mutations and BAX protein levels are useful molecular biological markers for prognosis and clinical management of pediatric GCT.

Evaluation of left ventricular function in long-term survivors of childhood Hodgkin disease.

BACKGROUND: Data on the presence of myocardial abnormalities in long-term Hodgkin disease survivors are contradictory. The purpose of this study was to determine if myocardial performance index (MPI) was capable of discovering cardiac abnormalities. PROCEDURE: Echocardiographic evaluation was performed in 31 survivors of Hodgkin disease (mean age 17.0 years), who received doxorubicin as part of chemotherapeutic treatment (median dose 164.8 +/- 42.5 mg/m(2)). Control group comprised 22 healthy subjects (mean age 16.7 years). RESULTS: Peak A velocity was increased (P = 0.004) and peak E/A velocity ratio was lower (P = 0.002) in patients compared to controls. Mean isovolumetric contraction time was longer in patients than in controls (P = 0.0001). Ejection time was significantly shorter in patients than in the controls (P = 0.001). Consequently, the MPI was significantly greater in the patients than in the controls (P = 0.0001). Abnormal MPI was found in 25/31 patients (83%). CONCLUSIONS: The Doppler-derived index of combined systolic and diastolic myocardial performance demonstrates the presence of subtle cardiac abnormalities in the majority of Hodgkin disease survivors.

Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management.

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children. It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF. In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction. The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.

Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia (ALL).

Molecular parameters involved in the prediction of response of childhood acute lymphoblastic leukemia (ALL) are still unclear. We have evaluated the expression and mutational status of p53 and the expression of bcl-x(L) and bax in a series of 62 consecutive children (median age: 4 years; 38 males and 24 females) affected by de novo ALL. Alterations and overexpression of p53 were uncommon events (9/62, 14.5%) while bcl-x(L) and bax overexpression were frequent (about 70%). EFS was directly correlated to age<6 years (p=0.0178), nonT phenotype (p=0.0470), WBC at diagnosis

Long-term results of the first Italian Association of Pediatric Hematology and Oncology protocol for the treatment of pediatric B-cell non-Hodgkin lymphoma (AIEOP LNH92).

BACKGROUND: Childhood B-cell lymphomas (B-NHLs) represent a group of aggressive malignancies that are amenable to high-intensity chemotherapy regimens. In 1992, the Italian Association of Pediatric Hematology and Oncology (AIEOP) initiated a prospective clinical trial involving the diagnosis and treatment of childhood B-NHL based on a well established strategy developed by the Berlin-Frankfurt-Munster Group. METHODS: Between November 1992 and October 1997, 163 children who had B-NHL were treated prospectively in the first national AIEOP trial. Disease staging was performed according to the St. Jude staging system, and treatment was assigned on the basis of risk group (R1, R2, or R3), which took into account disease stage and resectability and serum lactate dehydrogenase (LDH) levels. RESULTS: Of the 144 evaluable patients, 11 had Stage I disease, 35 had Stage II disease, 76 had Stage III disease, and 22 had Stage IV disease. Thirteen, 54, and 77 patients were included in risk groups R1, R2, and R3, respectively. The 10-year overall survival (OS) and event-free survival (EFS) rates for the overall population were 89.4% and 81.8%, respectively; the EFS rates for patients in risk groups R1, R2, and R3 were 100%, 86.9%, and 75.1%, respectively. Multivariate analysis indicated that age > or = 10 years, disease histology other than Burkitt or Burkitt-like lymphoma, and LDH levels > or = 1000 international units per liter had negative prognostic value. Analysis of the toxicity (according to the World Health Organization grading system) associated with 710 of the 748 chemotherapy cycles administered revealed 855 cases of Grade 3 or 4 toxicity, with 73% being cases of hematologic toxicity. Toxic episodes were most common after the first chemotherapy cycle and were equally common in the R2 and R3 risk groups. To date, the development of a second malignancy has not been observed in any patient in the study cohort. CONCLUSIONS: Long-term follow-up of the current study (AIEOP LNH92) confirms the observation of a favorable outcome for patients with B-NHL treated with short, intensive chemotherapy regimens and raises the possibility that non-Burkitt or non-Burkitt-like histology and age > or = 10 years may have negative prognostic value for patients with childhood B-NHL.

Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo.

Childhood Acute Lymphoblastic Leukemia (ALL) represents approximately 40% of pediatric cancers, but molecular mechanisms involved in the therapeutic resistance of ALL are still unclear. The disregulation of cell cycle could be a mechanism of progression of leukemic blasts and glucocorticoids (GCs), the main pharmacological agent in the treatment of ALL, could affect cell cycle distribution. In our study we have evaluated cell cycle distribution and the expression of several molecules involved in cell cycle regulation in blasts collected from 32 patients with ALL before and 48 h after treatment with GCs. A significant increase of the percentage of ALL blasts in G(0)/G(1) phase was recorded after treatment with GCs in 22 (69%) out of 32 patients and 18 of these patients were also good responders to GC therapy. In these patients an increase of the expression of at least one of the 4 evaluated CDKIs (p15, p16, p21 and p27) was found in 29 out of 32 patients (90.6%) without any change in CDK2 and 4 expression. All patients expressed detectable levels of Rb-1 phosphorylation at the diagnosis. Twenty (63%) patients showed a decrease, while two patients showed an increase of p110 Rb-1 phosphorylation and no changes were detected in the remaining 10 patients after GC therapy. The univariate analysis showed that the reduction of pRb-1 phosphorylation was significantly higher in B-cell lineage patients and in good responders. In conclusion, this is the first report that evaluate the Rb-1 function as predictor of response in childhood ALL and our data suggest that its hypophosphorylation and, consequently, reduced activity correlates with a statistical significance with the responsiveness to GC therapy. These results suggest that Rb-1 can be a useful molecular target for the therapy of this subset of patients.

Comparison of left ventricular function by echocardiogram in patients with Wilms' tumor treated with anthracyclines versus those not so treated.

The aim of this report was to evaluate late left ventricular function in survivors of Wilms' tumor and to compare patients treated with anthracyclines with those treated without anthracycline and with normal subjects. Wilms' tumor survivors treated without anthracycline had no myocardial abnormalities. A large percentage of patients treated with anthracycline presented with increased end-systolic wall stress. Results indicate that there is a high incidence of subclinical cardiovascular abnormalities in such patients.