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).

Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Italian Cooperative Group for Neuroblastoma.

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.

Features and outcome of neuroblastoma detected before birth.

BACKGROUND/PURPOSE: The growing use of routine ultrasonography during pregnancy is leading to an increasing number of prenatally diagnosed neuroblastomas. Optimal strategy has not yet been defined for these patients, because knowledge on this particular neuroblastoma (NB) population is still limited. However, definite guidelines are needed to avoid inadequate treatment. The authors analyzed the cases of antenatally detected NB (ADNB) reported in the Italian Neuroblastoma Registry during the past 6 years to elucidate the features of this subset of NB. METHODS: The Italian Neuroblastoma Registry was reviewed for the period January 1993 to December 1998 to collect clinical, radiographic, surgical, and histopathological data on ADNB cases. NB stage was evaluated according to INSS criteria. All patients had undergone imaging (computed tomography or magnetic resonance imaging) of the primary tumor and bone marrow biopsy before surgical resection. RESULTS: Seventeen patients were identified. Primary tumour site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1. All tumors were characterised by favourable histology according to Shimada classification. N-myc gene amplification was studied in 14 patients. N-myc amplification was detected only in a newborn with stage II-A NB, who died of massive bleeding 2 days after tumor resection. DNA index and 1p deletion were studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were observed in a newborn who subsequently died of disease progression despite surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently are alive and free of disease, and one with IV-S NB and short follow-up is alive with disease. CONCLUSIONS: Our data give evidence that in most cases infants with ADNB represent a subset of patients with excellent outcome. Aggressive treatment may not always be necessary. Infants with ADNB with unfavorable features should undergo early surgical excision, whereas patients with favourable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

Leukemia in a child with Wilms' tumor.

A case is described which illustrates an acute non-lymphocytic leukemia following multimodal control and apparent cure of Wilms' tumor. Literature cases are reviewed, and therapeutic inadequacies according to present protocols and their importance for the subsequent development of secondary leukemia are discussed.

Giant-cell pneumonia and lung tumorlets in a leukemic four-year-old child.

The authors report a case of a 4-year-old child whose death resulted from acute lymphoblastic leukemia (ALL) and giant-cell pneumonia. Typical lung tumorlets were occasionally observed. On electron microscopy study it was possible to demonstrate a large number of neurosecretory granules in the tumorlet's cells, identical to those present in Kulchitsky's cells. These studies suggest the occurrence of an abnormal immunitary process.

Undifferentiated (embryonal) sarcoma of the liver in childhood: results of a retrospective Italian study.

The clinical features and the treatment of undifferentiated (embryonal) sarcoma of the liver in 8 patients younger than 19 years old were analyzed. All these cases were registered in the retrospective multicentric study on childhood malignant tumors of the liver, conducted between 1983 and 1985 by the Italian Association of Pediatric Hematology Oncology. The age of the patients ranged from 94 to 190 months (median = 113.5 months); all children were males. An abdominal mass was the common presenting features. Abnormalities in hemogram and common liver tests were rarely reported. Angiography revealed various degrees of vascularization in these tumors. Two patients achieved a surgical complete remission (CR) at diagnosis; one patient achieved surgical CR after primary chemotherapy with vincristine, adriamycin, cyclophosphamide and 5-fluorouracil, which reduced the tumor volume and permitted surgical resection. Two of these patients are still in CR at 14 and 60 months after diagnosis; the third patient died of liver failure without evidence of recurrence 6 months after diagnosis. All of the other patients, who never achieved CR, died of disease. One was lost to follow-up, and one surgical death occurred. Reports of childhood undifferentiated sarcoma are reviewed.

Neurofibromatosis and malignant childhood cancers: a survey in Italy, 1970-83.

Neural tumors, Wilms' tumor, rhabdomyosarcoma and several types of leukemia have been previously described in association with neurofibromatosis (NF). In a nation-wide collection of cases in Italy, 15 children (0-14 years of age) with NF and cancer or leukemia were identified; 13 of them had been diagnosed with cancer between 1976-83. The expected number of children with cancer and NF in 1976-83 was 4.48. The distribution of tumor types was different from that found in the general population, with a higher proportion of tumors of neural crest origin as well as soft tissue sarcomas. In 7/15 the family history was positive for NF; in 5/7 the individuals affected included the mother and/or a maternal relative.

The outcome of Wilms' tumor in infants. Italy 1970-79.

Thirty-four infants under 1 year of age with Wilms' tumor were diagnosed and treated in 14 Italian pediatric oncology units during 1970-79. The 3-year survival rates decreased with higher group unilateral tumors: 95% in group I Wilms' tumor, 75% in group II and 20% in group III. The survival rates for children with group I and II Wilms' tumor were similar for those who were treated with surgery and chemotherapy and those who also received postoperative radiotherapy. During 1975-79 fewer patients with group I Wilms' tumor received radiotherapy (1 of 11) than during 1970-74 (4 of 6, p less than 0.05). All these children are alive at this writing.

[Wilms' tumor: reached progress and future prospects]. / Il tumore di Wilms: progressi ottenuti e prospettive future.

Wilms tumor, although rare, is the most frequent malignant renal tumor in children. With approximately 70 new cases diagnosed annually in Italy, it is important to collect these rare cases and to treat them in a uniform way. At the dawn of this century virtually all children with Wilms tumors died: today 95% of them survive; the treatment is carefully tailored to well defined risk factors (histology-stage-molecular markers) to minimize short and long-term toxicities. The object of this review is to describe the pathway to the progress. The most important step was to recognize that a single institution could not collect enough patients to answer complex questions, whereas this was possible for super-groups like the National Wilms Tumor Study Group (NWTSG) in the USA, the multinational SIOP study group in Europe, the United Kingdom group, the Italian group (CNR-AIEOP) and more recently the Brazilian one. Wilms tumor is the paradigm for the multimodal treatment of a pediatric malignant solid tumor, the development in surgical technique, the recognition of the sensitivity of Wilms tumor to irradiation and the availability of several chemotherapeutic agents led to a dramatic change in the prognosis for most patients. Much progress has been made in the study of histopatology of childhood renal tumors: the patients must be stratified into two groups, the favourable and the unfavourable histology, further subdivided into anaplasic tumors (focal or diffuse), clear cell tumors and rhabdoid tumors. The past few years have provided a breakthrough in understanding some of the genetic factors involved in Wilms' tumor: moreover, possible chromosomal prognostic factors have been identified: loss of heterozygosity of 16q markers and 1p markers. Today the results of the treatment of Wilms tumors are very good. In the NWTS-3 the four year relapse-free survival rate in stage 1 with favourable and with anaplastic histology was 92%, in stage 2 with favourable histology 88%, in stage 3 with favourable histology 79%, in stage 4 and in stage 2, 3 and 4 with unfavourable histology 71%. The Italian group has obtained less impressive results in the ¿80, but similar results in the first stage with the ¿92 protocol. There is a debate about the immediate nephrectomy preferred by NWTS and the preoperative strategies adopted by SIOP group. Successful treatment may be associated with many late effect: in patients cured of Wilms tumor the risk of congestive heart failure has been less than 1.7%, the risk of a second tumor less than 1%. The must important late effect remains the relapse of the disease: the risk is about 14-20%.

[Malignant tumors in children living in the province of Trieste, 1972-1993: descriptive epidemiology and the quality of diagnostic-therapeutic services]. / I tumori maligni nei bambini residenti nella provincia di Trieste, 1972-1993: epidemiologia descrittiva e qualità dei servizi diagnostico-terapeutici.

The study objectives were: 1) to analyse the incidence and death rates from cancer among children aged 0-14 years resident in the north-eastern Italian province of Trieste between 1972-1993, using data from the population-based Trieste Cancer Registry; 2) to evaluate the local diagnostic facilities by analysing the accuracy of histological diagnoses, the causes of delay in the diagnosis, and the interval between onset of symptoms and diagnosis of cancer; 3) to calculate the proportion of patients treated following the most effective therapy protocols known at the time of the tumour detection, and to compute the actuarial five-year survival rates since diagnosis. We recorded 123 new cases of cancer (93% microscopically verified) corresponding to a rate, age-standardized to the world population, of 161.9 (standard error [SE] = 15.1) per million child-years. The most common diagnostic group was that of primary brain tumours: 40 cases, rate = 51.0 (SE = 8.4). In 102 cases the diagnosis was made at hospitals in the province of Trieste, with a median time of seven days (25th-75th percentile = 1-16) between admission and diagnosis. In 37 cases the length of the interval between the advancing of the diagnostic hypothesis of cancer and the microscopic diagnosis ranged from eight to 57 days: 20% of the interval was spent in the identification of the lesion, 50% elapsed between the identification and the biopsy, and 30% was spent in performing the microscopic diagnosis. Out of 123 cases, 30 were partly treated or completely treated at centres not located in our province, i.e., at seven different Italian hospitals (14 cases), nine European hospitals (15 cases), and at one North-American centre (one case). The 40 children with brain tumours were spread among 12 institutions. The five-year survival rate increased from 52.4% (SE = 6.3) for the 63 children with cancers diagnosed in 1972-1981 to 62.5% (SE = 7.0) for the 48 with malignancies detected in 1982-1990.

[Hematopoietic stem cell transplantation in pediatric onco-hematology]. / Il trapianto di cellule staminali emopoietiche in onco-ematologia pediatrica.

Hematopoietic stem cell transplantation (HSCT) represents today an important therapeutic choice for several disorders of childhood: hematologic, metabolic and neoplastic pathologies can be treated with this strategy. The aim of this paper is to resume the latest history of HSCT, paying attention to the main changes and controversies, and its efficacy as far as concerns the major indications in pediatric oncohematology.

[Bilateral adrenal neuroblastoma of multicentric origin]. / Neuroblastoma surrenale bilaterale di origine polifocale.

Bilateral neuroblastoma is extremely rare. In the literature few cases are reported which are mostly considered to represent metastases rather than multicentric tumoral occurrence. A case of bilateral adrenal neuroblastoma is reported; given its various aspects, and especially the prognosis features, this tumor is, in our opinion, of a multicentric origin.

[Computerized tomography of the skull in children with lymphoblastic leukemia treated with prophylactic cranial radiation]. / Tomografia computerizzata del cranio in bambini con leucemia acuta linfoblastica sottoposti ad irradiazione cranica profilattica.

Thirty asymptomatic patients with acute lymphoblastic leukemia who had received prophylactic cranial irradiation (16 pts had 2400 cGy, 14 pts 1800 cGy) and intrathecal methotrexate were studied by computed tomography of the brain 60 to 148 months after initiation of prophylaxis. Three of 30 (10%) patients presented abnormal findings: widening of frontal subarachnoid space (1 patient), little area of decreased attenuation coefficient (1 patient), and intracerebral calcifications (1 patient Tomography abnormalities could be detected either in patients treated with 2400 cGy and in those treated with 1800 cGy. None of our patients showed central nervous system dysfunctions on physical examination. The results of our study suggest that tomography findings have a poor clinical significance.

[Neuroblastoma. Tumor rupture as an unfavorable prognostic factor]. / Neuroblastoma. Rottura tumorale come fattore prognosticamente sfavorevole.

Since there is little information regarding the possible prognostic significance of tumor rupture in localized neuroblastoma, we have analyzed the clinical courses of 163 children registered from 1979-1990 in 12 italian pediatric oncology Centers participating in the Neuroblastoma Cooperative Group of the A.I.E.O.P. (Italian Association for Paediatric Haematology-Oncology). Ten instances (6%) of tumor rupture were described. Ruptures occurred preoperatively in one child, during the operation in 9; among these 9, two were provoked by the surgeon to allow radical tumor excision, 7 were accidental. Of these 10 children, 7 relapsed at 3-25 months (median, 8 months) from diagnosis. Relapses were local in 5 children (2 of the 5 died), disseminated in one (who died), local + disseminated in one (presently alive with disease). Two local relapses were followed by bony or haematologic spread at 4 and 8 months, respectively. Of the 7 children who relapsed, 2 are alive in complete remission at 29, 100 months, respectively; two are alive with disease at 3 and 65 months, 3 died at 8, 15 and 24 months, respectively. We conclude that rupture of a localized neuroblastoma is a factor predisposing to relapse and may compromise the chance of cure. The surgeon should be aware of the risks connected with this complication and make any effort to avoid it.

Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant.

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication of hematopoietic stem cell transplantation (HSCT) affecting 9.6-17.3 % of cases. 200 HSCT, performed between January 1995 and March 2013 in our Paediatric HSCT Centre in Trieste, were retrospectively analysed to evaluate the frequency of VOD and to identify the associated risk factors. The frequency of VOD according to the Seattle criteria was 17 %, within the range reported in literature. The mortality rate was 37.5 % (75 out of 200 transplantations) in the general population and 73.5 % (25 out of 34) in VOD patients (p < 0.05). Veno-occlusive disease significantly decreased from 38 % (1995-2000) to 8 % (2007-2013) p < 0.05. Univariate and multivariate analyses identified sepsis and pre-transplant ferritin levels above 1000 ng/ml as two significant risk factors for VOD, while the use of tacrolimus appeared to be associated with a lower VOD risk. Veno-occlusive disease still remains an important cause of transplant-related mortality even if it appears to have decreased over the last few years.

Allogeneic bone marrow transplantation in hematologic disorders of childhood: new trends and controversies.

Bone marrow transplantation (BMT) represents an important therapeutic choice for several kinds of disorders: hematologic, metabolic and neoplastic pathologies can be treated with this strategy. The aim of this article is to describe the main indications for allogeneic BMT in haematologic disorders of childhood and possible problems related to this procedure. We consider only hematologic aspects, paying particular attention to unusual disorders of infancy as myelodysplastic syndromes and aplastic anemia. We also consider quality of life after a BMT in patients with sickle cell anemia and thalassemia major and compare this with quality of life of patients receiving chronic periodic blood transfusions.

Efficacy of diazoxide in preventing hypoglycemia in a child affected by hypopituitary dwarfism.

An observation is reported of the efficacy of diazoxide (10 mg/kg/24 h) in the prevention of hypoglycemic crises in a child with growth hormone deficiency. The success of the therapy may be attributed to a reduction of glucose uptake induced by the drug, rather than to the inhibition of insulin secretion which is already depressed in subjects affected by growth hormone deficiency. The availability of a drug with no serious and irreversible side effects, capable of preventing hypoglycemic crises in patients with hormone deficiency, seems to be important whenever it is not possible to immediately start a replacement therapy.