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Clinical, biochemical, and sonographic evaluation of the remaining kidney function and size was performed in 34 patients, 12 males and 22 females, ages 2.1–19.6 years, nephrectomized for Wilms' tumor at least 2 years before (mean 8.6). All patients had normal blood pressure and serum bicarbonates. Two of them had microhematuria, four proteinuria 4 mg/m2/hr, and 11 microalbuminuria (MA) >20 mg/24 hr. Only one patient had reduced creatinine clearance and maximum bipolar length (MBL) as well as kidney volume (KV)

PURPOSE To define factors that influence outcome in children with localized but unresectable neuroblastoma by retrospective investigation of response to therapy and outcome in 21 Italian institutions. PATIENTS AND METHODS Of 145 assessable children diagnosed between 1979 and 1990, 77 were treated between 1979 and 1984 with three consecutive standard-dose (SD) protocols, and 68 between 1985 and 1990 with a high-dose (HD) protocol. All protocols included chemotherapy, followed by resection of primary tumor if feasible. If at least partial resection was achieved, consolidation therapy followed, except that from 1985 onward, patients considered disease-free following surgery received no further treatment. RESULTS Ninety-four of 145 patients (65%) achieved a complete response (CR) or partial response (PR) with chemotherapy and 75 (52%) subsequently underwent complete resection of the primary tumor. Eighty-one patients are alive (73 without disease, eight with disease), 63 have died, and one is lost to follow-up. The 5-year overall survival (OS) rate is 55% and progression-free survival (PFS) rate 50%. Both OS and PFS correlated with response to chemotherapy, removal of primary tumor, HD therapy, and serum lactate dehydrogenase (LDH) levels. Infants (< 1 year), independent of primary tumor site, and children aged 1 to 15 years with a nonabdominal primary tumor, did better compared with children aged 1 to 15 years with an abdominal primary tumor (PFS, 72% and 64% v 30%; P < .001 and < .01, respectively). Outcome of this last group improved with the HD protocol (PFS, 40% v 23%; P = .01). CONCLUSION In children with unresectable neuroblastoma, risk categories can be defined by age and primary tumor site. HD chemotherapy should be investigated for the poor-risk category age 1 to 15 years with an abdominal primary tumor.

Background and Objective. Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported. Design and Methods. From 1991 to 1995, 1194 children (1 year, non-T-ALL, BFM risk factor (RF)

Chemotherapy is a recognized cause of morphological alterations to the proximal intestine. Lactose malabsorption, the functional consequence of a small intestinal enzymatic derangement, has been shown to play an important role in causing gastrointestinal symptoms in subjects receiving chemotherapy. To establish a rational basis for the exclusion of lactose from the diet and to reduce the risk of developing gastrointestinal symptoms, we conducted a study of lactose absorption in 20 children during cancer chemotherapy. Because lactose is an important nutritional sugar, the tolerance of lactose provided by yogurt was examined. Lactose absorption was investigated by a hydrogen breath test (BT) after oral ingestion of milk (250 ml) containing physiological doses of lactose (12 g). The effect of yogurt supplementation was also tested by BT after meals of yogurt (450 g) also containing physiological doses of lactose (12.1 g). In 11 children, lactose malabsorption was detected by BT during the study before any gastrointestinal symptom revealed this status. Of these 11 children, no gastrointestinal discomfort developed in five receiving a lactose-excluded diet. In contrast, in the six children not restricted in lactose intake, gastrointestinal symptoms were observed 4 to 13 weeks after lactose malabsorption was detected by BT. The findings of our study suggested the usefulness of dietary supplementation with yogurt, a lactose-containing food, in children who developed lactose malabsorption. In fact, all lactose-malabsorbent children showed good lactose absorption and tolerance when tested by yogurt BT.(ABSTRACT TRUNCATED AT 250 WORDS)

Publisher Summary This chapter discusses the results of a study examining germ cell tumors (GCTs) in children. In January 1991, a protocol for the diagnosis and treatment of GCTs in children was activated in 15 Italian pediatric centers. The diagnosis was made by the histological examination of a specimen obtained by surgical resection or biopsy and serum tumor marker positivity. Treatment was based on tumor site, histology, and stage. In the study, eighty-four patients were entered (40 males, 44 females), age range 0 to 14 years (median 5.1 years). The histological features were the following: (1) mature teratoma, 45 patients, (2) immature teratoma, 12 patients (eight grade II, four grade III), (3) MNSGCT 24 patients, including 2 cases of malignant relapse of one mature and one immature teratoma, and (4) seminomatous tumor, 5 patients. One patient with a SC tumor had a local malignant recurrence six months after surgical resection: the patient was disease-free 14 months after a second resection and 2 courses of chemotherapy (JE/IVA).

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.

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.The authors report a series of 110 infants with disseminated neuroblastoma with disease diagnosed between March 1976 and February 1991 in 21 institutions participating in the Italian Cooperative Group on Neuroblastoma (ICGNB). Of the 110 infants, 34 had Stage IV disease, and 76 had Stage IV-S disease.The 5-year survival probability was 77% for all patients, 71% for those with Stage IV disease, and 81% for those with Stage IV-S disease. Of the 34 infants with Stage IV disease, the 9 who were 5 months or younger at the time of disease diagnosis are all alive (1 with active disease) at 7-143 months after diagnosis, whereas of the 25 infants who were 6-11 months of age at the time of disease diagnosis, 10 have died. Of the 76 infants with Stage IV-S disease, 12/64 who were 5 months of age or younger at the time of disease diagnosis died (mostly of massive hepatomegaly); 9 of these deaths occurred in infants with disease diagnosed before they were 2 months old, whereas 1 death occurred in the 12 infants with disease diagnosed when they were 6-11 months old. Four infants with Stage IV-S disease achieved complete disease remission and subsequently had relapse of disease. High levels of serum LDH and low urinary excretion of vanillylmandelic acid were associated with worse prognosis.The authors suggest that infants older than 6 months of age who have Stage IV disease require aggressive therapy. For infants with disease diagnosed before they are 2 months old, Stage IV-S disease may have a worse prognosis than Stage IV disease.

Advanced neuroblastoma is one of the most lethal pediatric malignancies. Several antitumor compounds are able to induce tumor regression, and a dose-response relationship has been demonstrated for some of them. A significant improvement in both response rate and duration of survival has thus been obtained by treatment intensification [1–4]. In the Italian experience, the median survival time of children treated with aggressive chemotherapy has been doubled compared with historical controls [5]. However, the higher initial response rate and the prolonged remission time has resulted in only a marginal improvement in cure rate, presently not exceeding 25% [6, 7]. Hematopoietic growth factors (colony-stimulating factors, CSFs), by mitigating the myelotoxic effect of chemotherapy, may reduce the treatment-related morbidity and thus permit the delivery of higher dosages and the shortening of intervals between chemotherapy courses [8, 9].

Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARA-C), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Patients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR.

ZusammenfassungInnerhalb der Italienischen Neuroblastom-Kooperativgruppe wurden 671 Patienten in der Zeit von 1979 bis 1988 registriert, wovon 183 Sauglinge waren. Hinsichtlich Stadieneinteilung und U

Zusammenfassung18 Sauglinge wurde in der Italienischen Kooperativstudie RMS-79 registriert und behandelt. 10 Patienten hatten ein Rhabdomyosarkom (7 ein «embryonales», 3 ein «alveo-lares», 8 andere We

8503 Background: Little is known about the prognostic role of multidrug resistance (MDR) in newly diagnosed childhood with acute lymphoblastic leukemia (ALL). The aim of this retrospective study was to evaluate in 85 children with ALL the impact of P-glycoprotein 170 (p-gp) product of the mdr-1 gene on achievement of complete remission (CR), and clinical outcome. Methods: MDR-1 protein expression was performed by immunocytochemistry (ICC), and flow cytometry (FC). MDR-1 functional activity was performed by rhodamine (Rhd)-123 efflux test with or without verapamil. All patients enrolled in our study were treated with AIEOP 91–95 protocols. Results: Forty patients (47%) expressed MDR1 protein at significant levels, and 45 (53%) were MDR1 negative. Forty-three of the last patients were also negative for MDR1 function, while 34 out of 40 (85%) patients MDR-1 positive preserved the function. Rhd-123 efflux was inhibited by the MDR modulator verapamil in 12 of 40 (30%) patients. After induction treatment, CR wa...

A multicentric retrospective study on leukemic ophthalmopathy (LO) is reported, including 38 patients (21 males, 17 females) with acute leukemia (AL) observed from 1976 to 1985. LO developed in four patients at the time of diagnosis of AL; ten were in first complete remission (eight off therapy), 12 in second remission, and 12 in combined relapse. The children were treated according to different schedules of systemic and intrathecal chemotherapy with or without radiotherapy (RT) of the affected eye. Ocular remission occurred in 32 of 38 patients, but with subsequent ocular relapse in six of the 32. Complete remission after LO treatment lasting for more than 24, 30, 40, and 78 months was observed in four of the ten children with isolated LO in first AL marrow remission. The authors concluded that systemic and intrathecal chemotherapy probably is associated with RT (at least 30 Gy to the affected eye). Aggressive treatment is justified because children with isolated ocular relapse can still be cured.

This report deals with a randomized prospective multicentric clinical trial in childhood rhabdomyosarcoma (RMS) conducted to evaluate the toxicity and the effectiveness of dactinomycin (ACT-D) administered as high, single doses v five-day, divided doses administered in combination with vincristine (VCR) and cyclophosphamide (CYC). Fifty-five group III evaluable patients (pts) less than 15 years of age with tumor size greater than 5 cm in diameter, without high-risk features of CNS involvement, and 15 group IV RMS pts were randomized to receive VAC as primary chemotherapy (CT): VCR, 1.5 mg/m2 intravenously (IV) days 1 and 8; CYC, 275 mg/m2 IV days 1 through 5; and ACT-D, 0.45 mg/m2 IV days 1 through 5 every 28 days for three cycles (33 pts), or VAC-M: CYC, 150 mg/m2 intramuscularly (IM) days 1 through 7; VCR, 2.0 mg/m2 IV day 8; and ACT-D, 1.7 mg/m2 IV day 8 every 21 days for four cycles (37 pts). Major responses (complete plus partial responses [PR]) were obtained in 67% of the VAC pts and in 70% of the VAC-M pts. Toxic effects were low, and no increased toxicity was observed in pts treated with high, single-dose ACT-D. These results confirm the effectiveness and feasibility of single, high doses of ACT-D with the advantage of requiring less pt hospitalization.

Little is known about the prognostic role of multidrug resistance (MDR) in newly diagnosed childhood acute lymphoblastic leukemia (ALL). P-glycoprotein 170 (MDR1), a cellular drug efflux pump, is thought to be one of the major causes of MDR. The aim of this retrospective study was to evaluate in 85 children with ALL the impact of the MDR1 product of the mdr-1 gene on the achievement of complete remission (CR) and outcome. MDR1 protein expression was performed by immunocytochemistry (ICC), and flow cytometry (FC). MDR1 functional activity was performed by a rhodamine (Rhd)-123 efflux test with or without verapamil. All patients enrolled in our study were treated with AIEOP ALL 91-95 protocols. At diagnosis, 40 patients (47%) expressed MDR1 protein at significant levels, and 45 (53%) were MDR1 negative. Forty-three of the latter patients were also negative for MDR1 function, while 34/40 (85%) patients MDR1 positive preserved the function. Rhd-123 efflux was inhibited by the MDR modulator verapamil in 12/40 (30%) patients. After induction treatment, CR was achieved in 77/85 children (90.6%). All patients who did not achieve CR were MDR1 positive. Twenty-nine patients relapsed, 17 (58.6%) of whom were MDR1 positive. The 10-year overall survival (OS) rate, and disease-free survival (DFS) for MDR1 negative patients compared to MDR1 positive patients were 75.7% versus 54.8%, and 67.5% versus 46%, respectively. The 10-year event-free survival (EFS) rate was significantly higher (67.5% versus 36.8%) in the MDR1 negative group compared with the MDR1 positive population (p=0.001). Multivariate analysis showed that only EFS was independent of age, WBC count, immunophenotype, FAB subtype and prednisone response (p=0.019). Our results, derived from a monocentric study, demonstrate that MDR1 expression in childhood ALL is an independent adverse prognostic factor on outcome, and could be a useful biological marker of response in these patients. Moreover, MDR1 function was also a predictor of response, but only in univariate analysis.

Glucocorticoid resistance is often associated with treatment failure in children with acute lymphoblastic leukaemia (ALL) but the underlying molecular mechanisms are still unclear. In 30 consecutive children with ALL treated with prednisone we determined changes in the expression of Bcl-2, Bax and Bcl-xl proteins in leukemic lymphoblasts and related these to clinical features and rate of prednisone- induced apoptosis. The apoptotic index increased after prednisone therapy in 24 of the 30 patients. At diagnosis, we detected expression of Bcl-2 and Bcl-xl protein in 28 samples, while Bax expression protein was detected in 21 of the 30 patients. Prednisone treatment induced a decrease in Bcl-2 and Bcl-xl levels in 17 and 16 of the 28 patients, respectively, while Bax protein increased in 14 of the 21 patients. Twenty of the 30 patients studied were considered to be good prednisone responders, whereas 10 were poor responders. We observed a statistically significant decrease only for Bcl-xl protein expression in T phenotype ALL, in the poor responder group and in patients with >20000/mm 3 white cell count (WBC) at diagnosis. These data suggest a role of Bcl-xl in the mechanisms of protection of leukemic cells from apoptosis induced by glucocorticoids (GCs).