Guidelines for the use of long-term central venous catheter in children with hemato-oncological disorders. On behalf of supportive therapy working group of Italian Association of Pediatric Hematology and Oncology (AIEOP).

In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other "highly needed CVC patients"; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.

Treatment of advanced neuroblastoma: feasibility and therapeutic potential of a novel approach combining 131-I-MIBG and multiple drug chemotherapy.

Biological and clinical observations suggest that initial marked reduction of resistant clones may be critical in any attempt to improve long-term results in advanced neuroblastoma (NB). The aim of this pilot study is to determine short-term toxicity and efficacy of a new therapeutic model based on the simultaneous use of multiple drug chemotherapy and specific irradiation using 131-I-MIBG. The study population consisted of 21 patients, from 1 to 8 years of age with good 131-I-MIBG uptake. 16 extensively pre-treated patients with refractory or relapsed disease were divided into 2 groups. In Group 1 (9 patients) the basic chemotherapy regimen consisted in cisplatin at the dose of 20 mg/m(2) i.v. per day infused over 2 h, for 4 consecutive days; on day 4 Cy 2 g/m(2) i.v. was administered over 2 h followed by Mesna. Group 2 (7 patients) was treated with basic chemotherapeutic regimen plus VP16 and Vincristine. VP16 at the dose of 50 mg/m(2) i.v. per day was administered as a 24 h infusion on days 1-3; Vincristine 1.5 mg/m(2) i.v. was administered on days 1 and 6. On day 10 a single dose of 131-I-MIBG (200 mCi) with a high specific activity (>1.1 GBq/mg) was administered to both Groups by i.v. infusion over 4-6 hours. A further 5 patients were treated at diagnosis: 2 with the same regimen as Group 1 and 3 with the same as Group 2. The severity of toxicity was graded according to World Health Organization (WHO) criteria. Assessment of tumour response was monitored 4-6 weeks after the beginning of combined therapy (CO-TH). Response was defined according to INSS (International Neuroblastoma Staging System) criteria. No extra-medullary toxicity was observed in any patient. Haematological toxicity was the only toxicity observed and seemed mainly related to chemotherapy. Myelosuppression was mild in the 5 patients treated at diagnosis. No serious infections or significant bleeding problems were observed. In the 16 resistant patients, 12 PR, 1 mixed response and 3 SD were obtained. In the 5 patients treated at diagnosis 2 PR, 1 CR and 2 VGPR were observed. No alteration in 131-I-MIBG uptake was observed after the chemotherapy preceding radio-metabolic treatment. The therapeutic results of this pilot regimen of CO-TH resulted in a high percentage of major response after only a single course in both resistant patients and patients treated at diagnosis. Because of the minimal toxicity observed in patients studied at diagnosis so far, there is room for gradual intensification of the treatment. It is to be hoped that this suggested novel approach may represent an important route of investigation to improve final outcome in patients with advanced NB.

Progressive disease in children with medulloblastoma/PNET during preradiation chemotherapy.

The overall prognosis in children with medulloblastoma/PNET has not significantly improved over the past decade. Intensive neoadjuvant chemotherapy has not yet adequately explored. We evaluated the short-term clinical results of an intensive chemotherapy regimen in high risk children with newly diagnosed MB/PNET, after surgery and before radiation. Twelve previously untreated patients with high-risk medulloblastoma/PNET, according to Chang's classification, were treated with the following chemotherapy regimen: high dose carboplatin 600 mg/m2/day on days 1 and 2; the same course was administered 4 weeks later. One month later, high dose cyclophosphamide 2 g/m2/day on days 1 and 2, followed by an identical course 4 weeks later. Vincristine 1, 5 mg/m2 i.v. was given on the first day of each course. Systemic evaluation of the disease included imaging of the entire neuraxis, including MRI of the entire spine. Out of 12 enrolled, 7 patients were able to be evaluated for a residual disease after surgery. After two cycles of high dose carboplatin, we noted 1 CR, 4 PR and 2 MR. After the subsequent two cycles of high dose cyclophosphamide we observed an additional response in 4 cases. On the other hand, 4 patients clearly showed evidence of PD immediately after the first course of cyclophosphamide (2 cases) or following the second course. Three of the 4 patients had shown respectively 1 CR and 2 PR after the second course of carboplatin. Whereas it was confirmed that 2 courses of high dose carboplatin is effective in high risk MB/PNET children, we observed an unacceptable number of PD during the subsequent high dose cyclophosphamide therapy. A review from the literature also suggests that, in general, the longer radiotherapy is delayed, the higher the incidence of PD. In the search for the optimal drug combination in "sandwich chemotherapy" for children with high risk MB/PNET, PD must be reduced to an acceptable incidence, since a high number of PD may significantly lower the probability of long-term survival.

Veno-occlusive disease of the liver in right-sided Wilms' tumours.

Veno-occlusive disease of the liver (VOD) is an important complication in children with Wilms' tumour. Although in most patients this complication resolves uneventfully, fatal cases have been reported. Several observations strongly suggest that actinomycin-D is the likeliest cause of VOD in Wilms' tumour, but VOD seems to be rather uncommon in other malignancies treated with chemotherapy including actinomycin-D. The present case of VOD and the review of the literature stress the pathogenetic and clinical implications of VOD in the presence of a Wilms' tumour treated with actinomycin-D, originating in the right kidney. Greater awareness of this 'predisposing factor' may alert paediatricians to the presence of minimal signs of the syndrome.

[Evaluation of late cardiac toxicity of anthracycline in childhood]. / Valutazione della cardiotossicità tardiva da antracicline in età pediatrica.

OBJECTIVES: To examine left ventricular function in patients previously treated with anthracycline for childhood malignancies. To evaluate the importance of age at the beginning of therapy, of total cumulative dose and of length of follow-up on late cardiac effects of anthracyclines. DESIGN: Cross sectional echocardiography study of left ventricular function. PATIENTS: Eighteen patients surviving between 1 and 9 years (median 2 years) from end of chemotherapy. Cumulative doses were between 120 and 550 mg/mq (median 275 mg/mq). Age at the beginning of chemotherapy was between 1.8 and 12.25 years (median 5.17 years). Nineteen healthy subjects were also studied as control group. METHODS: Assessment of transmitral diastolic pulsed wave Doppler flow patterns and of transaortic pulsed wave Doppler flow patterns. Evaluation of systolic function measured by M-mode echocardiography. RESULTS: Patients compared to controls showed a significative reduction of Ejection Fraction, of Shortening Fraction, of peak early phase to peak atrial phase filling velocity ratio and an increase of peak atrial phase filling velocity and of time-velocity integral of peak filling atrial phase. These alterations were more evident at doses higher than 250 mg/m2, in patients whose therapy started before 5 years of age and in patients whose follow-up was longer than 5 years. CONCLUSIONS: Significant abnormalities of systolic and diastolic function may appear some years after the end of anthracycline therapy for childhood malignancies. Therefore patient's continued follow-up is necessary in order to guide patient care and to better chemotherapeutic protocols.

Role of 131I-metaiodobenzylguanidine in the treatment of neuroblastoma.

BACKGROUND: Standard chemo-radiotherapy methods for the treatment of children with advanced neuroblastoma (NBL) including bone marrow transplant approaches have been disappointing. These poor results can be ascribed to the evolution of residual drug-resistant cell populations. Curative attempts should therefore be directed to their elimination during induction treatment. This can best be accomplished through the use of multiple, non-cross-resistant agents early in therapy. 131I-Metaiodobenzylguanidine (131I-MIBG) provides a mechanism for the delivery of high doses of radiation to NBL lesions. Experience reported from several institutions indicates an approximate 50% response rate in previously treated children with advanced NBL. CONCLUSIONS: A better strategy is to employ 131I-MIBG together with intensive chemotherapy at the time of diagnosis. A pilot study adopting these principles and supported by laboratory data has been designed and is underway.

Cytogenetic evidence for a less malignant leukemic cell population in the central nervous system in a critical case of acute myeloblastic leukemia.

BACKGROUND: With the exception of a single study the cytogenetic aspects of leukemic cells in the central nervous system (CNS) have not been investigated. PATIENTS AND RESULTS: During the course of a work-in-progress on the chromosomal constitution both of the spinal fluid and of bone marrow (BM) in children with acute myeloblastic leukemia (AML), we have observed a unique case of AML and CNS leukemia (CNSL) at diagnosis. The patient showed the simultaneous presence at diagnosis of a 46 cytogenetic line in the spinal fluid and a 47 (+8) cell line in the BM, present in the great majority of the metaphases examined. DISCUSSION: This observation allows hypotheses on the relationship between BM and CNS disease in AML. Regardless of the pathogenetic mechanism, the cytogenetic findings of the present case clearly suggest that the leukemic population in the CNS compartment represents a less malignant cell process compared to the BM leukemic population. This easily fits in with the usually less malignant course of CNSL in AML. CONCLUSION: The foregoing findings may have critical pathogenetic and therapeutic implications.

Optimal use of the 131-I-metaiodobenzylguanidine and cisplatin combination in advanced neuroblastoma.

Neuroblastoma (NB), a childhood radiosensitive tumor, is very aggressive and malignant, in its disseminated form, despite very intensive chemotherapy, prognosis continues to be dismal. Owing to its capacity to concentrate in NB lesions, large doses of 131-I-MIBG, have given very encouraging therapeutic results in patients resistant to conventional therapy as well as at diagnosis. We recently reported the first attempt in combination therapy (CO-TH) using 131-I-MIBG and cisplatin. This new form of CO-TH appears very effective in obtaining a rapid and excellent response in relapsed patients. In this report, we describe the results of further experience with CO-TH in disseminated NB. We have attempted to verify to what extent interaction between the effects of the two agents may produce therapeutic benefit, and we have sought the optimization of CO-TH use. Three stage IV NB patients were treated with CO-TH. The following treatment schedule, was planned: day 1, cisplatin 50 mg/m3 i.v. over 6 h; day 2, 131-I-MIBG 100-130 mCi at high specific activity (-1.1 Gbq/mg) i.v. over 6 h followed, a week later, by the same treatment combination. The therapeutic results were encouraging. However, hematological toxicity continued to represent a major limiting factor. In view of the overall effectiveness of CO-TH, at the price of lasting hematological toxicity, it may be indicated as a consolidation regimen some time before conditioning chemotherapy for autologous bone marrow transplantation.

A human neuroblastoma xenograft model for 125-I-metaiodobenzylguanidine biodistribution studies.

We developed an animal model to evaluate the 125-I-metaiodobenzylguanidine (125-I-mIBG) biodistribution in tumor bearing mice. Six weeks old nude-atimic mice were subcutaneously injected with 30 x 10(6) cells of the human neuroblastoma (NB) cell line SH-SY5Y. TE-671, a rhabdomyosarcoma cell line, was used as a control tumor without a specific mIBG uptake mechanism. In order to prevent possible tumor rejection mediated by NK activity the anti asialo GM1 antiserum was administered intraperitoneally once a week for 4 weeks. The maximum anti asialo mediated effect was obtained by administering the first dose the same day as the cell implant. In this group of animals by 9 weeks 98% of mice had a measurable tumor. We have utilized this model to evaluate the biodistribution of 125-I-mIBG given as two different formulations: standard preparation with a specific activity of 84 mCi/mg and the no carrier added (n.c.a) formulation with a specific activity of approximately 8,000 mCi/mg. Our preliminary results indicate that the biodistribution of the two different formulations in the various organs are similar. Therefore it appears that n.c.a. mIBG should not cause an increased toxicity in possible normal target organs such as heart or adrenals. Additional experiments will be performed in this model to ascertain if there is a potential advantage of the clinical use of n.c.a. mIBG over the standard preparation.

Treatment with meta-[131I]iodobenzylguanidine and cisplatin in stage IV neuroblastoma.

Metastatic neuroblastoma (NB) continues to have a dismal prognosis. NB is a radiosensitive tumor. Owing to its high concentration in the NB lesions, Metaiodobenzylguanidine (MIBG) has the potential for specifically delivering very large radiation doses to the malignant cells. Encouraging results have been reported with [131I]MIBG used alone in patients resistant to conventional therapy and at diagnosis. We report the first attempts to explore the integration of this new treatment modality with chemotherapy. Among the drugs effective in NB, cisplatin was chosen because of its high degree of activity against NB, its mild hematologic toxicity and the known synergism between cisplatin and radiation. Four patients, 3 with relapsed, heavily pre-treated, progressive stage IV NB, and 1 with stage IV NB at diagnosis, all with a good [131I]MIBG uptake, were investigated with the combined therapy. Two complete remissions and one partial remission were observed in the relapsed patients 4-6 weeks following only one single course of both cisplatin and [131I]MIBG at the "standard" dosage. The only toxicity was hematologic, which was significant and relatively long-lasting, but was not associated with any serious infections or bleeding tendency. The general condition of these patients during the entire study period was excellent. The 4th patient, investigated at diagnosis with a modified less intensive treatment, obtained a partial remission with a mild hematologic toxicity. The provisional conclusion of this preliminary study is that this new form of combined therapy appears very effective in heavily pretreated relapsed patients with progressive disease, and could also be investigated in refractory patients and in patients at diagnosis.

Preoperative chemotherapy with carboplatin alone in high risk medulloblastoma.

Few studies have been carried out regarding preoperative chemotherapy utilized in the treatment of primitive neuroectodermal tumors/medulloblastomas (PNET/MB). In this paper, the authors report 3 cases of children under three years of age, with a presumed diagnosis of PNET/MB, who were preoperatively treated with chemotherapy consisting of high doses of carboplatin alone. The treatment improved the childrens' clinical condition prior to surgery and facilitated tumor removal, resulting in partial regression of the tumor. The preoperative single-drug therapy did not affect the histological diagnosis or prevent the presence of an effective degree of tumor sensitivity to the drug. All three children are still disease-free, after a mean follow-up period of 42 months.

Constitutional trisomy 8 and myelodysplasia: report of a case and review of the literature.

A diagnosis of myelodysplastic syndrome was made in an 18-year-old patient with Warkany syndrome due to constitutional trisomy 8 mosaicism. The possible causal role of this particular chromosome constitution with respect to myelodysplasia and embryonal childhood tumors is discussed.

Carboplatin in childhood medulloblastoma/PNET: feasibility of an in vivo sensitivity test in an "up-front" study.

Sixteen patients with high risk MB/PNET at diagnosis were included in a pilot study employing carboplatin (CBDCA) as a single drug prior to conventional therapy. The main goal of the study was to identify in a short-term trial a significant response that would predict further response to CBDCA in the single patient. Exploration of CBDCA activity was focused on response after the first course as compared to the response following the second course. A course consisted of CBDCA 600 mg/m2 on days 1 and 2 administered in a 1 h infusion to be repeated 3-4 weeks later. After two cycles we observed 1 CR and 9 PR, that is a 62% response rate. The first course resulted in 5 PR, 5 MR, 5 SD, and 1 PD; after the subsequent course in all responding patients, response persisted or improved whereas in no patient with SD any improvement was observed. The correlation of response to the first course with response to the second course was statistically significant (P = 0.0009). The main toxicity of the single course was hematologic and consisted of rapidly reversible grade 3-4 neutropenia and thrombocytopenia in 94% of patients. Pharmacokinetic studies showed a very limited interpatient variability of both Cmax 57.6 +/- 9.9 micrograms/ml) and AUC (15.3 +/- 1.5 mg/ml.min) of free CBDCA, which eliminates an important variable in the evaluation of response. In conclusion, this "in vivo test" appears effective, reasonably safe, and reproducible in identifying patients likely to benefit from CBCDA: after a period of time as short as 3-4 weeks following the first course, multidrug chemotherapy including CBDCA may be employed in the responding patients, whereas an alternative regimen would be indicated in the non-responding patients.

Failure of immunoglobulins to prevent neonatal thrombocytopenia in mothers with immunothrombocytopenic purpura.

We report the case of a full-term (gestational age: 39 weeks) female newborn of a mother affected by immunothrombocytopenic purpura, treated with a high total dose (2 g/kg) of intravenous IgG, administered over a 3-day period starting 3 days before delivery. Infant platelet count at birth was 20,000/mm3 and she showed a great number of petechiae on the first day of life. After a random donor platelet transfusion and treatment with intravenous high-dose IgG (400 mg/kg for 5 days), platelet count began to increase. We conclude that exogenous IgG, even at high concentrations, apparently does not significantly cross the placenta, despite adequate maternal blood levels.

Cytotoxicity of paclitaxel and docetaxel in human neuroblastoma cell lines.

Taxanes are an important new class of anticancer agents that inhibit cell division by the unique mechanism of increasing the rate of microtubule assembly and preventing microtubule depolymerisation. Using the colony inhibition assay, we compared the cytotoxicity of paclitaxel and docetaxel in three human neuroblastoma (NB) cell lines, SH-SY5Y, BE(2)M17 and CHP100. Different exposure times (3, 6, 12, 24, 48 and 72 h) and different concentrations ranging from 0.1 nM to 10 microM were tested. Both paclitaxel and docetaxel show antineoplastic activity in human NB cell lines. Taxanes' antitumour activity varied among the different cell lines, CHP100 being the most sensitive and SH-SY5Y the least sensitive. Paclitaxel cytotoxicity appears schedule-dependent, with marked cell kill observed only for exposures of 24 h or longer. Docetaxel cytotoxicity was dependent upon prolonged exposure only in the SH-SY5Y cell line, while an exposure time of 3-6 h resulted in exponential cell kill in the other two cell lines. Docetaxel was more cytotoxic than paclitaxel with a mean ratio of (paclitaxel/docetaxel) IC50 values ranging from 2 to 11. For both taxanes, we observed good correlation between cytotoxic effect and percentage of cells blocked in G2/M phase. A cytotoxic effect occurred at concentrations comparable with those achieved in the plasma of patients treated with these agents in initial clinical trials. The full potential of prolonged infusion or repeated daily administrations of taxanes should be explored in clinical studies, and responses to taxanes in neuroblastoma should be assessed in paediatric phase II studies.

A new approach in the treatment of stage IV neuroblastoma using a combination of [131I]meta-iodobenzylguanidine (MIBG) and cisplatin.

The outlook for disseminated neuroblastoma (NB) continues to be dismal. NB is a radiosensitive tumour. Owing to its high concentration in NB lesions, [131I]meta-iodobenzylguanidine [131I]MIBG has the potential for specifically delivering very large radiation doses to the malignant cells. Encouraging results have been reported with [131I]MIBG used alone in patients resistant to conventional therapy and at diagnosis. We report the first attempt to explore the integration of this new treatment modality with chemotherapy. Among the drugs effective in NB, cisplatin was chosen because of its high degree of activity against NB, its mild haematological toxicity and the known synergism between cisplatin and radiation. 4 patients, 3 with relapsed, heavily pre-treated, progressive stage IV NB, and 1 with stage IV NB at diagnosis, all with a good [131I]MIBG uptake, were investigated with combined therapy (CO-TH). Two complete remissions and one partial remission were observed in these patients 4-6 weeks following only a single course of both cisplatin and [131I]MIBG at "standard" dosage. The only toxicity was haematological, which was significant and relatively long-lasting, but was not associated with any serious infections or bleeding tendency. The general condition of these patients during the entire study period was excellent. The fourth patient, investigated at diagnosis with a modified less intensive treatment, obtained a partial remission with mild haematological toxicity. During the subsequent courses of intensive multidrug chemotherapy, this patient showed haematological toxicity comparable with that experienced by patients treated with an identical drug combination, but without previous treatment with CO-TH. The provisional conclusion of this ongoing study is that this new form of CO-TH appears most effective in obtaining a rapid and excellent response in heavily pretreated relapsed patients with progressive disease, and should be further investigated in earlier stages of the disease.