F. Casale

Deferoxamine followed by cyclophosphamide, etoposide, carboplatin, thiotepa, induction regimen in advanced neuroblastoma: Preliminary results

Based upon phase I and II studies of deferoxamine alone and in combination with cytotoxic agents cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT), we initiated a single arm multicentre trial in 1992 for advanced neuroblastoma. 57 of 65 patients who entered the trial were evaluable. Following 4 courses of the D-CECaT, almost all the patients underwent surgery. Toxicity was moderate and mainly reversible myelosuppression. The post-surgically defined responses in stage 3 high risk, stage 4 moderate risk and stage 4 high risk patients included 24 complete responses, 26 partial responses, and 3 minor responses, and 4 patients had progressive disease. These patients are being followed to determine the impact of this programme on their overall survival.

Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry

Background The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. Design and Methods We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. Results During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51–0.61) and 0.70 (95% CI: 0.65–0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53–0.62) overall, and 1.08 (95% CI: 0.99–1.17) when analyses were restricted to married/cohabiting women Conclusions Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

Effect of Protracted High-Dose l-Asparaginase Given as a Second Exposure in a Berlin-Frankfurt-Münster–Based Treatment: Results of the Randomized 9102 Intermediate-Risk Childhood Acute Lymphoblastic Leukemia Study—A Report From the Associazione Italiana Ematologia Oncologia Pediatrica

PURPOSE To assess in a randomized study the therapeutic effect of the addition of high-dose L-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)-based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m(2) repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi L-asparaginase product. RESULTS Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P =.64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively. CONCLUSION No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.

Iodine-131 metaiodobenzylguanidine scintigraphy for localization of lesions in children with neuroblastoma: comparison with computed tomography and ultrasonography.

Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy, computed tomography (CT) and ultrasonography (US) were used to localize tumour lesions in 28 children with histologically proven neuroblastoma. Overall, a total of 73 lesions were detected on imaging studies. MIBG scintigraphy, CT and US localized 63 (86%), 49 (67%) and 36 (49%) of these lesions, respectively. The findings of the three imaging techniques were concordant in respect of only 31 (42%) of the lesions. The best agreement among MIBG scintigraphy, CT and US was observed for abdominal lesions (the techniques were concordant for 22 of 23 lesions, i.e. 96%). MIBG scintigraphy detected nine out of ten (90%) liver metastases, but agreement with CT and US was observed in only six instances (60%). The imaging findings were concordant in respect of only two (33%) out of six lymph node metastases; the MIBG scan was normal in the other four cases. Imaging agreement was observed for a lesion located in the pelvis. MIBG and CT findings were concordant in four lesions located in the chest, but US was not performed. MIBG scintigraphy depicted the majority (96%) of the skeletal lesions (23/24); CT showed five of these, but, again, US was not performed. The imaging findings were not concordant as regards the remaining five lesions located in different anatomical sites. The results indicated that MIBG imaging is more sensitive that CT and US in localizing the majority of neuroblastoma lesions. Since the metastatic spread of neuroblastoma is unpredictable, we recommend MIBG scintigraphy as the initial imaging modality for staging of these patients. US and, particularly, CT should be performed thereafter to clarify the anatomical detail of the lesions detected on MIBG scans, or when MIBG findings are normal or equivocal.

Standard-dose and high-dose peptichemio and cisplatin in children with disseminated poor-risk neuroblastoma: two studies by the Italian Cooperative Group for Neuroblastoma.

PURPOSE The objective of the present study was to determine whether an increase in the intensity of therapy improves outcome for children with disseminated poor-risk neuroblastoma. PATIENTS AND METHODS From January 1982 through November 1989, 181 children 1 year or older with newly diagnosed disseminated neuroblastoma were entered onto two consecutive studies of the Italian Cooperative Group for Neuroblastoma (ICGNB): 75 (study NB82) were enrolled from 1982 to 1984 and were treated with standard-dose (SD) chemotherapy, and 106 (study NB85) were enrolled from 1985 to 1989 and received high-dose (HD) chemotherapy. In both treatment protocols, induction therapy included peptichemio and cisplatin (at SD or HD, respectively) and removal of the primary tumor. In study NB82, children who achieved complete or partial tumor regression received SD consolidation therapy, and in study NB85 they received three cycles of HD chemotherapy (3cCT) or one cycle of myeloablative therapy (MAT) followed by autologous bone marrow transplantation (ABMT). RESULTS Compared with group NB82, the NB85 group had significantly fewer failures (no tumor response or disease progression) after administration of peptichemio (9% v 31%; P < .01), had more complete responses (CRs) and partial responses (PRs) both after treatment with cisplatin (60% v 43%; P = .01) and after surgery (76% v 57%; P < .01), and was more likely to have achieved complete excision of the primary tumor (70% v 46%; P < .01). Overall survival (OS) and progression-free survival (PFS) at 5 years were 11% and 9% in NB82, and 27% and 18% in NB85 (P < .01 for both); however, in NB85, relapses occurred even after 5 years of CR, so that PFS curves converge approximately 7 years after diagnosis. Median survival time was 14 months in NB82 and 24 months in NB85. Children in the NB85 group who after achievement of CR were consolidated with 3cCT had a 5-year PFS of 24% compared with 32% of those treated with MAT followed by ABMT (P = .5). CONCLUSION Intensified therapy improves response rate and prolongs survival of children with disseminated neuroblastoma, although its impact on the eventual cure rate remains to be established.

The Bcl-2/Bax and Ras/Raf/MEK/ERK signaling pathways: implications in pediatric leukemia pathogenesis and new prospects for therapeutic approaches.

The Bcl-2/Bcl-xL/Bax and the Ras/Raf/MEK/ERK (MAPK) pathways are often deregulated in many human cancers and especially in acute lymphoblastic leukemia and acute myeloid leukemia. A result of molecular alterations of these pathways is uncontrolled cell growth and survival, ultimately resulting in oncogenic transformation and progression. Aberrant expression of Bcl-2/Bax and MAPK can lead to therapeutic resistance. In this review, the Bcl-2 and MAPK pathways are analyzed, focusing the attention on their molecular alterations, and the complex interactions between these signaling cascades are also analyzed. The observation that both MAPK and Bcl-2/Bax signaling play a central role in the pathogenesis of human cancer suggests that this kinase cascade represents a novel opportunity for the development of new anticancer targeted therapies designed to be less toxic than conventional chemotherapy. The evidence that they are often implicated in sensitivity and resistance to leukemia therapy suggests that characterization of the cancer genome may offer personalized cancer genomic information that can lead to the formulation of much more effective personalized therapy.

High Erk-1 activation and Gadd45a expression as prognostic markers in high risk pediatric haemolymphoproliferative diseases.

Studies on activated cell-signaling pathways responsible for neoplastic transformation are numerous in solid tumors and in adult leukemias. Despite of positive results in the evolution of pediatric hematopoietic neoplasias, there are some high-risk subtypes at worse prognosis. The aim of this study was to asses the expression and activation status of crucial proteins involved in cell-signaling pathways in order to identify molecular alterations responsible for the proliferation and/or escape from apoptosis of leukemic blasts. The quantitative and qualitative expression and activation of Erk-1, c-Jun, Caspase8, and Gadd45a was analyzed, by immunocytochemical (ICC) and western blotting methods, in bone marrow blasts of 72 patients affected by acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (ALL) and stage IV non-Hodgkin Lymphoma (NHL). We found an upregulation of Erk-1, Caspase8, c-Jun, and Gadd45a proteins with a constitutive activation in 95.8%, 91.7%, 86.2%, 83.4% of analyzed specimens, respectively. It is worth noting that all AML patients showed an upregulation of all proteins studied and the high expression of GADD45a was associated to the lowest DFS median (p = 0.04). On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04). Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells. These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.

Endocrine Function in Subjects Treated for Childhood Hodgkins' Disease

Six prepubertal children (2 F and 4 M, aged 3-11.5 years, Group I) and six adults (3 F and 3 M, aged 15-21.5 years, Group II), were treated during childhood for Hodgkins Disease (HD). They received contemporary chemotherapy with either ABVD, MOPP or both and mantle or laterocervical irradiation. Three patients also received abdominal irradiation. All subjects were studied off therapy for 0.2—2 years (Group I) and 3—9 years (Group II). Pituitary function was investigated by evaluation of basal plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), Cortisol (F), estradiol (E2), and testosterone (T). In males, Τ was also measured 72h after 100 U/Kg i.m. of human chorionic gonadotropin. Semen analysis in males and pelvic ultrasound in females of Group II were also performed. Our patients showed significantly (P < 0.05-0.001) increased levels of: FSH in females of both groups and in males of Group II, LH in girls of Group I, PRL in girls of Group I and in males of both groups, TSH in females of both groups. Hodgkins patients showed significantly decreased levels of basal (p <0 .005) and stimulated (p < ±0.05) Τ in males of Group II. Moreover, all males of Group II showed oligo-azoospermia. Our results seem to indicate that combined theapy for childhood HD often results in abnormal endocrine function; in particular, increased PRL, FSH and TSH secretion. Reprint Address: Dr. Laura Perrone Via Belisar Corenzio 33 80127 Napoli, Italy INTRODUCTION Abnormal endocrine funct ion is a known complication of combined chemoand radiation-therapy for Hodgkins Disease (HD) /1 /. Most reports have focused on adult subjects and studied with the pituitary-thyroid or pituitary-gonadal axes separately. After therapy for childhood HD data on thyroid /2/ or gonadal /3,4/ function are conflicting, while data on Cortisol and prolactin secretion are scarce. The present study was aimed at evaluating the effects on the endocrine secretion of combined therapy for HD during childhood. PATIENTS AND METHODS We studied 12 subjects treated for HD during childhood with chemotherapy (ABVD: cases 1-3; MOPP: cases 9,12; ABVD plus MOPP: cases 4-8, 10, 11) and mantle (2500-5000 rad, cases 2, 5-9, 11), or laterocervical irradiation (1750-4500 rad, cases 1,3,4,10,12) associated with abdominal irradiation (2500 rad) in 3 cases (4,6,8). In all patients except case 12, lymphoangiography was performed. The age when studied was prepubertal in 6 cases (2 F and 4 M, aged 3-11.5 years, off-therapy since 0.2-2 years Group I) and adult in the other 6 (3 F and 3 M, aged 15-21.5 years, off-therapy since 3-9 years, Group II). Control groups consisted of 63 age and sex-matched subjects, 20 prepubertal (10 F and 10 M) and 43 adult (23 F and 20 M). Clinical data of patients are reported in Table 1. Informed consent of patients or of their parents was obtained. Fasting blood samples were taken after nocturnal rest and plasma stored at -25°C in several tubes to facilitate multiple determinations. Each sample VOL. 3, No. 3,1989 175 176 LPERRONE et al. TABLE 1: Clinical Data of Hodgkins Disease Cases Age at Age at Years therapy Radiation study off No. Sex (yr) Chemotherapy dose field (yr) therapy Group I 1 F 3.0 ABVD 2000 LC 4.7 1.0 2 Ε 9.0 ABVD 2 5 0 0 Μ 11.5 2.0 3 Μ 2.4 ABVD 2000 LC 3.0 0.3 4 Μ 6.7 ABVD+MOPP 2500 LC 9.4 1.2 2 5 0 0 A 5 Μ 10.0 ABVD+MOPP 2500 Μ 10.8 0.2 6 Μ 7.7 ABVD+MOPP 2500 Μ 8.6 0.2 2500 A Group II 7 F 12.2 ABVD+MOPP 4 0 0 0 Μ 15.0 3.0 8 Ε 15.0 ABVD+MOPP 4 0 0 0 Μ 18.2 3.