Angela Tamburini

Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3-10.0) after progression and 14.4% (95% CI 10.5-18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status (P<0.001) and a non-abdominal primary site (P=0.034 for progression, and P=0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse (P<0.001). Probability of survival increased by era of diagnosis. Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.

Pediatric peripheral blood progenitor cell collection: haemonetics MCS 3P versus COBE Spectra versus Fresenius AS104

BACKGROUND: An increasing number of apheresis machines are becoming available for peripheral blood progenitor cell (PBPC) collection in children. STUDY DESIGN AND METHODS: At the Childrens Hospital of Florence (Italy), three apheresis machines were evaluated: MCS 3P (Haemonetics) (10 procedures in 4 patients, aged 10–12 years, weight 23.5‐64 kg), Spectra, (COBE) (8 procedures in 3 patients, aged 4–17 years, weight 19–59 kg), and AS104 (Fresenius) (24 procedures in 9 patients, aged 2–16 years, weight 13.6‐60 kg). For PBPC quantitative analysis, CD34 cytofluorimetry was employed. Relevant variables analyzed included efficiency of CD34+ cell extraction and enrichment, mononuclear cell purity and red cell contamination of the apheresis components, and platelet count decreases after leukapheresis. RESULTS: No significant differences in CD34+ cell‐extraction abilities were found. However, the AS104 provided consistently purer leukapheresis components in terms of mononuclear cell and CD34+ cell enrichment (441 +/− 59%, vs. 240 +/− 35% and 290 +/− 42% for MCS 3P and Spectra, respectively). Postapheresis platelet counts dropped the least with the AS104. The smallest patient who underwent apheresis with MCS 3P (the only machine working on discontinuous flow and hence with greater volume shifts) weighed 23.5 kg and tolerated the procedure well, with no signs of hemodynamic instability. No significant complications were observed. CONCLUSION: All machines seem to have comparable PBPC extraction efficiency, but the AS104 seems to give the component with the greatest PBPC enrichment. This feature might be relevant for further ex vivo cell processing (CD34+ cell selection, expansion, and so on).

G-CSF serum pharmacokinetics during peripheral blood progenitor cell mobilization: neutrophil count-adjusted dosage might potentially improve mobilization and be more cost-effective

The optimal dosing schedule of G-CSF for peripheral blood progenitor cell (PBPC) mobilization is still under investigation although many centers use 10 μg/kg/day in a single subcutaneous dose. However, G-CSF clearance increases with increasing absolute neutrophil count (ANC). Hence a G-CSF dosage adjusted to ANC might be a reasonable approach. We measured G-CSF trough serum levels by sandwich ELISA assay at different ANCs in eight patients undergoing treatment with filgrastim at 10 μg/kg/day in a single subcutaneous dose. A total of 26 samples were analyzed, and a strong correlation between increasing ANC and decreasing G-CSF levels was found by linear regression analysis (P < 0.0003, r2 = 0.4199). For ANC values above 5000/μl the trough serum levels, ie 24 h after administration, were consistently below the level that provides maximal clonogenic precursor stimulation in vitro (10 ng/ml). Serial serum G-CSF measurements performed in three patients at 0, 3, 6, 9 and 24 h after G-CSF administration, showed a reduction of the area under the curve (AUC) with increasing ANC. For an ANC of 20000/μl or greater, the G-CSF serum level fell under the maximal in vitro stimulation threshold of 10 ng/ml within 12 h. This preliminary pharmacokinetic data seems to suggest that an ANC-adjusted G-CSF dosing schedule might improve the design of PBPC mobilization regimens.

In vivo cytoreduction studies and cell sorting-enhanced tumor-cell detection in high-risk neuroblastoma patients: Implications for leukapheresis strategies

PURPOSEnTo improve autologous leukapheresis strategies in high-risk neuroblastoma (NB) patients with extensive bone marrow involvement at diagnosis.nnnPATIENTS AND METHODSnAnti-G(D2) immunocytochemistry (sensitivity, 1 in 10(5) to 10(6) leukocytes) was used to evaluate blood and bone marrow disease at diagnosis and during the recovery phase of the first six chemotherapy cycles in 57 patients with stage 4 NB and bone marrow disease at diagnosis. A total of 42 leukapheresis samples from the same patients were evaluated with immunocytology, and in 24 of these patients, an anti-G(D2) immunomagnetic enrichment step was used to enhance tumor-cell detection.nnnRESULTSnTumor cytoreduction was much faster in blood compared with bone marrow (3.2 logs after the first cycle and 2.1 logs after the first two cycles, respectively). Bone marrow disease was often detectable throughout induction, with a trend to plateau after the fourth cycle. By direct anti-G(D2) immunocytology, a positive leukapheresis sample was obtained in 7% of patients after either the fifth or sixth cycle; when NB cell immunomagnetic enrichment was applied, 25% of patients had a positive leukapheresis sample (sensitivity, 1 in 10(7) to 10(8) leukocytes).nnnCONCLUSIONnStandard chemotherapy seems to deliver most of its in vivo purging effect within the first four cycles. In patients with overt marrow disease at diagnosis, postponing hematopoietic stem-cell collection beyond this point may not be justified. Tumor-cell clearance in blood seems to be quite rapid, and earlier collections via peripheral-blood leukapheresis might be feasible. Immunomagnetically enhanced NB cell detection can be highly sensitive and can indicate whether ex vivo purging should be considered.

Use of percutaneous radial artery catheter for peripheral blood progenitor cell collection in pediatric patients.

BACKGROUND : Leukapheresis procedures require adequate flow rates, which in children may frequently involve invasive vascular access placement.

Incidence and survival cancer trends in children and adolescents in the provinces of Florence and Prato (central Italy), 1985-1997

Aims and background The incidence of childhood and adolescent cancers has been increasing during the last decades in most Western countries. Improvements in cancer survival rates have also been observed according to the availability of more efficient therapies. Methods and study design A total of 518 cancer cases (age, 0–19 years) incident in the period 1985–1997 in the Tuscany Cancer Registry area, corresponding to the Provinces of Florence and Prato (Central Italy), were analyzed. Incidence rates and estimated annual percentage change were computed according to sex, 5-year age groups and diagnostic groups of the International Classification for Childhood Cancer. All patients were actively followed at 31.12.1998, and 5-year survival rates were computed for cases diagnosed in 1985–1990 and 1991–1997. Results Overall age-standardized incidence rates were 186.7/106 for males and 175.4 for females. In 1991–1997, standardized incident rates were 50.8 for leukemias, 44.6 for lymphomas, and 34.3 for CNS tumors. There was a marked increasing trend for lymphomas that grew at a yearly rate of +12.1% and less evident increasing tendency for leukemias, CNS tumors and carcinomas. The overall survival rate was 88% at one year, 78% at 3 years, and 74% at 5 years. A slight improving tendency in survival was evident over time. Conclusions The study pointed out that in the examined area, during 1985–1997, there was a significant increasing incidence trend for lymphomas. Survival rates were as high as in other Western countries – evidence of the high level of diagnostic and treatment services in the area.

High-dose chemotherapy with autologous stem cell rescue for treatment of retinoblastoma: Report of five cases

RB is a primarily pediatric cancer arising from the retina, initiated by biallelic loss of the RB1 gene. We report five children with bilateral RB (n = 3), extra‐ocular disseminated RB, or disseminated relapsed RB, who were treated with tandem high‐dose chemotherapy and autologous stem cell rescue. All patients received at least 2.2 × 106/kg CD34+ (median, 3.9 × 106/kg) cells. The preparative regimen for course 1 was carboplatin, thiotepa, etoposide, and for course 2, CM and melphalan. ANC of at least 0.5 × 109/L occurred at a median of 11 days (range, 10–12) and 15 days (range, 12–16) after the first and second procedure, respectively. Platelet engraftment occurred at a median of 13 days (range, 12–17) and 15 days (range, 14–22) after the first and second procedure, respectively. All of the five patients treated remain alive and disease free at the last follow‐up time, ranging between 21 and 44 months after completion of autologous transplant. Additional therapy was required in one patient, in whom enucleation had to be performed because of early disease relapse, refractory to local therapy. Intensification of chemotherapy with repeated high‐dose chemotherapy and autologous rescue appears an acceptable choice in selected cases with bilateral or extra‐ocular disease, either recurrent or refractory.

Urinary endothelin-1-like immunoreactivity excretion in Wilms' tumor survivors.

BackgroundWe evaluated urinary endothelin (ET)-1-like Immunoreactivity (uET-1xa0L) excretion in Wilms tumor (WT) survivors and investigated its relationships with glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Glomerular hemodynamics were also assessed by Gomez formulae.MethodsSeventeen WT survivors underwent renal sequential scintigraphy for residual kidney function determination including ERPF and GFR. Forty-five healthy individuals were selected as the control group. uET-1xa0L was measured by radioimmunoassay from the 24-h urine collection.ResultsIn WT survivors, uET-1xa0L excretion was significantly higher than in controls. Significant correlations were found between uET-1xa0L and ERPF and GFR. Cluster analysis, applied on uET-1xa0L, identified two different patient groups. Between them, GFR and ERPF were significantly different. No significant difference existed between the two clusters for age and sex, elapsed time from nephrectomy, treatment, or nephrectomy side. Applying Gomez formulae, significant difference was found for afferent and total renal resistance.ConclusionsAccording to our results, uET-1xa0L seems to be a marker of glomerular injury in patients with renal mass loss revealing renal overload condition. The uET-1xa0L role in renal damage progression and hemodynamic glomerular worsening in nephrectomized patients should be proven by prospective long-term follow-up studies, even for potential ET-1 receptor antagonist therapeutic use.