Maria Teresa Di Tullio

Disseminated neuroblastoma (stage IV and IV-S) in the first year of life. Outcome related to age and stage

Background. Infants (age 0–11 months) with disseminated neuroblastoma are known to have a better prognosis than older children with the disease, but there is little information regarding factors that influence the outcome of the disease in these patients.

Treatment of pediatric Hodgkin disease tailored to stage, mediastinal mass, and age. An Italian (AIEOP) multicenter study on 215 patients.

Background. Attempting to optimize treatment results in pediatric Hodgkin disease while minimizing major side effects, at least in early‐stage patients, in 1983 the Italian Association of Pediatric Hematology and Oncology (AIEOP) conceived a multicenter study tailored according to stage, bulky mediastinal mass, and age.

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 cardiotoxic 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 β-adrenoceptor antagonists (β-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.

Localized neuroblastoma. Surgical and pathologic staging

Sixty‐five children with neuroblastoma without evidence of distant metastases underwent initial tumor resection. Seventeen with no evidence of lymph node involvement in whom tumor resection was complete (Group 1) received no further antitumor therapy. One child died postoperatively; disease recurred in the bone marrow of one child at 52 months, the child subsequently died. Fifteen were alive without disease, giving an 82% actuarial five year survival. Forty‐eight children with minimal residual tumor and/or regional lymph node involvement (Group 2) received two 5‐day courses of Peptichemio (1.2 mg/kg/d) and the 29 children in this group who were older than 1 year of age at diagnosis were randomized to receive either radiotherapy to the tumor bed in addition or no radiotherapy. In Group 2, ten of the 48 have relapsed: six of 17 with initial lymph node involvement, three of four with tumor rupture at operation, and one of eight with tumor extension to the intervertebral foramen. No relapses were seen in the 19 children with minimal residual tumor confined to the tumor bed. Only one of the 18 Group 2 children who were younger than 1 year of age at diagnosis relapsed. Of the 29 Group 2 children who were older than 1 year of age at diagnosis, five relapses occurred in the 14 who received radiotherapy and four relapses in the 15 who did not receive radiotherapy. All six children with disseminated relapse died. Actuarial 5‐year survival in Group 2 is 87%, and actuarial relapse‐free survival, 76%.

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

The prevention of anthracycline cardiotoxicity is particularly important in children who can be expected to survive for decades after cancer chemotherapy with these agents. The rapid increase in clinical toxicity at doses greater than 550 mg/m(2) of doxorubicin (DOX) has made this dose the limiting one in order to avoid DOX-induced cardiac failure. However, arbitrary dose limitation is inadequate because of variability of individual tolerance. Decreasing myocardial concentrations of anthracyclines (ANT) and their metabolites and schedule modification of administration can reduce anthracycline cardiotoxicity. Anthracycline structural analogues such as epirubicin, idarubicin and mitoxantrone have been used in clinical practice. In addition, the liposomal ANT, which can be incorporated into a variety of liposomal preparations, are a new class of agents that may permit more specific organ targeting of ANT, thereby producing less cardiac toxicity. Much interest has focused on the administration of ANT in conjunction with another agent that will selectively attenuate the cardiotoxicity. As is known, the ANT chelate iron and the DOX-iron complex catalyzes the formation of extremely reactive hydroxyl radicals. Many agents, such as dexrazoxane (DEX), able to remove iron from DOX, have been investigated as anthracycline cardioprotectors. Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated. Whether long-term cardiac toxicity will also be avoided in surviving patients has not yet been determined.

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)

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.

FAT BODY MASS AND PHARMACOKINETICS OF ORAL 6-MERCAPTOPURINE IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

To evaluate the reasons for the wide variability in bioavailability of orally administered 6-mercaptopurine in children with acute lymphoblastic leukemia, we studied several pharmacokinetic parameters of the drug in 18 affected children receiving remission maintenance therapy, and compared them with their anthropometric data and with the results of intestinal function tests. No correlation was found between estimates of small intestinal absorption (the oral lactose tolerance test and 1 h blood xylose test) and 6-mercaptopurine serum levels. Of the anthropometric measurements considered, only the weight/height percentile (an index of the fat body mass) strongly and linearly correlated with the area under the curve of 6-mercaptopurine. The dose of 75 mg of 6-mercaptopurine/m2 of body surface resulted in higher serum concentrations in children below the 75th percentile than in those with a weight/height ratio exceeding the 75th percentile. In conclusion, these data caution about the risk of underdosing 6-mercaptopurine in overweight children when administering it on the basis of body surface area.

Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia

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-xL 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-xL and bax overexpression were frequent (about 70%). EFS was directly correlated to age < 6 years (p= 0.0178), non-T phenotype (p= 0.0470), WBC at diagnosis < 20000/µl (p= 0.0093), response to induction therapy with prednisone (p= 0.0211) and inversely correlated to mutated p53 or overexpression of p53 (p= 0.0039) and high intensity of BclxL expression (p= 0.0055). OS was directly correlated with age < 6 years (p= 0.0004), female gender (p= 0.0139), non-T phenotype (p= 0.0012), WBC at diagnosis < 20000/µl (p= 0.0187), response to induction therapy with prednisone (p= 0.0211), wild type p53 or low expression of p53 (p= 0.035). When all factors were considered in a stepwise Cox regression analysis, only the good response to PDN (p= 0.013) and the low intensity of Bcl-xL expression (p= 0.001) were independent significant prognostic factors with regard to EFS. Moreover, only age (p= 0.022), gender (p= 0.036) and WBC at the diagnosis (p= 0.050) were independent prognostic factors with regard to OS. Moreover, the mutated status of p53 was statistically correlated to the resistance to the induction therapy with PDN (correlation coefficient: - 0.349, p = 0.008). In conclusion, both bcl-xL and bax were frequently expressed at high intensity, but only bcl-xL was an independent predictor of EFS in our series. Moreover, p53 alterations were uncommon and alone not strong independent predictors of outcome, but they were correlated to poor response to therapy with PDN and inversely correlated to EFS and OS in univariate analysis.

Glucocordicoids 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 Go/G1 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.

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

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.