Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry.

Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00-12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38-21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20-20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38-38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55-10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74-16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90-753.20) and soft tissue (SMR 453.00, 95% CI 203.50-1008.40), small intestine (SMR 1375.50, 95% CI 344.00-5499.70), nasal cavity (SMR 13.71, 95% CI 1.93-97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2-127.55).

Shortened time to recovery from chemotherapy induced neutropenia in pediatric patients with high dose combined cytokines.

Granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF) are cytokines which have been extensively administered as monotherapy to patients with a variety of hematopoietic disorders at dosages of 5 mcg/kg/day. Because their spectrum of activity is both singular and simultaneously overlapping, we postulated that combined therapy would be more advantageous than monotherapy. Since 1992 we have carried out a study of G-CSF and GM-CSF as monotherapy or in combination in pediatric patients with solid tumors following chemotherapy induced nadirs of 0-800 WBC/mm3. When combined, the cytokines were given twice per day at 2.5 or 5.0 mcg/kg. For the monotherapy groups, either cytokine at 5 mcg/kg or 10 mcg/kg was given once daily. The mean time to recovery from neutropenia nadir ranged from 6.6-8.2 days in patients receiving a total of 10 mcg/kg/day compared to 10.4-10.6 days in patients treated with 5 mcg/kg/day. Side effects were ephemeral eosinophilia. The dosage of 10 mcg/kg/day appears to be a better dosage for pediatric patients with a slight advantage in the combined twice a day schedule (6.6 days).

Health status and internal radiocontamination assessment in children exposed to the fallout of the Chernobyl accident.

The Chernobyl fallout caused release of radioisotope contaminants in a very large area that includes Belarus, the Ukraine, and the Russian Federation. In this study, the authors monitored the health status and level of internal contamination in 422 children who resided in the aforementioned areas and who were < or = 10 y of age at the time of the accident. The children came to Italy for a 1-mo period between 1991 and 1992. During this time, the children underwent pediatric checkups and biochemical, immunological, and thyroid analyses. All children underwent whole-body counter measurements, and urine radiotoxicological analysis was performed for 224 of them. The 24 children evacuated from Pripiat, a village very close to the Chernobyl reactor site, were selected for cytogenetic analysis. All of these children continue to have a detectable internal contamination of caesium radioisotopes. This condition is likely the result of ground and foodstuff contamination in the various areas. The children did not evidence overt pathologies related to ionizing radiation. However, minor alterations in immunological and thyroid parameters were observed in the group of the evacuated children. Traditional cytogenetic dosimetry was not possible, but the occurrence of acentric fragments was observed-indicating a persistent effect of continuous exposure to low doses of radiation.

Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age.

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

Toxicity of high-dose chemotherapy with etoposide, thiotepa and CY in treating poor-prognosis Ewing's sarcoma family tumors: the experience of the Bambino Gesù Children's Hospital.

We report the toxicity of high-dose chemotherapy (HDC) based on etoposide, thiotepa and CY (ETC) in children with poor-prognosis Ewing's sarcoma family tumors (ESFTs). A total of 26 patients with high-risk ESFT (metastasis or axis localization or tumor volume >200 ml or necrosis <95%) were reviewed. The conditioning was based on etoposide (600 mg/m(2)), thiotepa (750 mg/m(2)) and CY (120 mg/kg) followed by autologous BM or PBSC rescue. The conditioning regimen was well tolerated, without any toxic deaths. The median time from transplant to a neutrophil count of >0.5 x 10(9)/l was 10 days (range 6-27) and 22.5 days (range 9-114) for a plt count of >50 x 10(9)/l. Oral mucositis was recorded in 20 patients, grade 1/2 in 19 and grade 3 in the last patient. Diarrhea grade 1/2 was recorded in four patients and grade 1/2 liver toxicity in four patients. Sepsis was documented in four cases and skin toxicity in three. Lung and tubular toxicity, respectively, were reported in one patient each. We conclude that the ETC regimen presented a limited and manageable toxicity. Further studies would confirm the role of ETC in high-risk ESFT.

Metastatic retinoblastoma: single institution experience over two decades.

BACKGROUND: Metastatic spread in retinoblastoma is a rare occurrence in developed countries but still associated with a poor prognosis. PATIENTS AND METHODS: Medical records of all metastatic retinoblastoma diagnosed during a 20-year period were retrospectively reviewed. RESULTS: Six patients out of 104 presented a metastatic disease with an incidence at diagnosis of 2%. Three had a metastatic disease at diagnosis, one patient a trilateral retinoblastoma and two a metastatic spread after enucleation. All but one were sporadic retinoblastoma. Central nervous system (CNS) involvement was reported in five patients, while one patient had an intraorbital lesion, and bone and bone marrow spread. Different treatment strategies were administered based on local treatment plus chemotherapy and radiotherapy with or without high-dose chemotherapy. An ifosfamide/carboplatin/etoposide regimen was administered in three patients resulting in a partial response. Out of six patients, four died, and two patients are alive at 60 and 63 months from diagnosis. Both children with a long follow-up were treated with high-dose chemotherapy. All but one of the patients with CNS involvement died; the survivor was a patient with pineal involvement. CONCLUSION: This retrospective review confirms a curable strategy based on local treatment and conventional plus high-dose chemotherapy. Patients with CNS involvement remain incurable.

[The echographic diagnosis of Candida albicans cystitis in childhood]. / Diagnosi ecografica di cistite da Candida albicans in età pediatrica.

Candida albicans infections are opportunistic and range from asymptomatic infections to life-threatening involvement, with a wide spectrum of clinical manifestations. Urinary tract involvement is usually secondary to systemic infection, although the kidney or the bladder may be primarily infected without other organs being involved. Renal fungus infections, most commonly due to Candida, are usually seen in patients with altered host resistance due to diabetes, malignancy, other chronic illnesses, or prolonged antibiotic, corticosteroid or immunosuppressive therapy. Herein we report on an immunosuppressed 12 years-old girl with Candida albicans cystitis diagnosed with US. Sonography demonstrated a discrete dense fluid-fluid interface within the bladder, mobile with changes in position. US was used to monitor the progress of therapy. Treatment is usually conservative, related to removing the precipitating factors (catheters, antibiotics, steroids). Indeed, in our case, the immunosuppressed patient needed aggressive therapy: i.v. fluconazole. Sonography 15 days after treatment showed a normal bladder, without significant sequelae or the formation of vesical concretions.

Role of deferoxamine in tumor therapy.

Several studies are consistent with the hypothesis that available iron may have some role in promoting tumor cell growth with different biological mechanisms. For this reason, several studies have been carried out to demonstrate the antitumor activity of deferoxamine (DFO), an iron chelator with a high affinity for ferritin-bound iron. In particular, the effects of DFO have been studied in patients with neuroblastoma, where ferritin is in part tumor derived and high concentrations correlate with poor outcome. To date, in vitro and in vivo studies demonstrating the antitumor effects of DFO are very promising, but further investigations are required to establish an exact role for DFO in the treatment of cancer.

D-CECaT: a breakthrough for patients with neuroblastoma.

In view of the high relapse rate following chemotherapy for patients with advanced neuroblastoma (NB) and primitive neuroectodermal tumors (PNET), we designed a novel chemotherapy program which incorporated the iron chelator deferoxamine. The purpose of the deferoxamine was to sensitize the cells to standard chemotherapy. The D-CECaT regimen contained (in mg/m2): deferoxamine 4500 during days 1-5; cyclophosphamide 600 mg over days 6 and 7; etoposide 300 mg over days 7 and 8; carboplatin 100 mg over days 7 and 8; and thiotepa 30 mg over days 6-8. Between October 1989 and May 1992 we entered 23 advanced NB and two PNET patients. Sepsis occurred in four courses, nausea and vomiting in 30 courses, and 50 courses required blood and platelets. Responses observed in previously untreated patients with stage III NB: six out of six CR (17+ to 41+ months), with stage IV NB, nine out of 11 CR (14+ to 28+ months), two out of 11 VGPR (22+ months), with stage IV PNET two out of two CR (1+ to 35+ months). With previously treated and failed stage IV NG, two out of six VGPR for 19+ and 20 months, and four out of six PR 1, 8, 9 and 11 months. Median survival for 19 new patients was 22+ months (6 to 41+ months; two patients in CR died at 7 months during adjuvant autologous marrow transplant). In conclusion, D-CECaT is an effective initial cytoreductive regimen for advanced stage NB/PNET patients. Additional patients and studies are required to determine its use as an alternative to autologous bone marrow transplantation.

Isolation and molecular characterisation of the gene encoding the cytoplasmic ribosomal protein S28 in Prunus persica [L.]] Batsch.

RT-PCR was performed on peach (Prunus persica [L.] Batsch) RNA to isolate cDNAs corresponding to transcripts which are differentially expressed in leaves borne on basal and apical shoots. A gene was identified which was more highly expressed in the leaves of basal shoots, and codes for the cytoplasmic protein S28 present in the small ribosomal subunit. The 5' leader regions of RPS28 mRNAs were found to harbour 8-11 pyrimidine tracts, which suggested similarities to regulatory stretches that control the translation of mRNAs for ribosomal proteins in animals. The peach S28 is encoded by two intron-containing genes, which are both transcribed in mitotically active tissues such as developing leaves and roots. In situ hybridisation to shoot vegetative apices and the measurement of nucleus/nucleolus ratios indicated that RPS28 expression was confined to areas undergoing active cell division. The mature RPS28 mRNA was detected as a single species in actively dividing tissues such as apical tips, developing leaves, vegetative buds, stamens, developing fruits and roots. In contrast, accumulation of a precursor RNA, in the presence of the mature product, was found in fully expanded leaves and subtending stems, while only the precursor species was detected in several late-stage tissues. This phenomenon suggested that expression of the mature RNA is controlled at the level of splicing and turnover of the precursor RNA. This is similar to the mode of regulation of ribosomal protein genes in animals.

Amount and organization of the heterochromatin in Olea europaea and related species.

The amount and spatial organization of the heterochromatin in nuclei of the shoot meristem and the frequency in the nuclear DNA of sequences belonging to a family of tandem repeats were investigated in cultivars of Olea europaea and related species. Significant differences between Olea species and between cultivars of O. europaea were observed: (i) in the spatial organization of the heterochromatin in interphase nuclei as determined by the number and surface area of the chromocentres; (ii) in genome size; and (iii) in the amount of condensed chromatin as measured by cytophotometry carried out at different thresholds of optical density. DNA elements belonging to a family of tandem repeats about 80 bp in length (OeTaq80 repeats) were isolated from the genomic DNA of an olive cultivar. It was shown: (i) by nucleotide sequence comparisons, that these repeats display variability in structure even within the same array, where different elements may share no more than 74% homology; (ii) by in situ hybridization, that OeTaq80-related DNA sequences are mainly localized in the heterochromatin at the chromosome ends; (iii) by dot-blot hybridization experiments, that these sequences are highly represented in the genome of all the olive cultivars and the majority of Olea species studied, and that their frequency may differ significantly even between olive cultivars; and (iv) by calculating the copy number of OeTaq80-related sequences per haploid (1C) genome, that the redundancy of these DNA elements may differ significantly between the genomes tested. It is suggested that the inter- and intraspecific changes in the nuclear and genomic traits observed can contribute to the understanding of the phylogenetic relationships between Olea species and in defining parameters to be exploited in varietal identification within cultivated olives.