Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease.

PURPOSE: Gorham-Stout disease is a very rare disorder characterized by progressive bone erosion and angiomatous proliferation; its etiopathogenesis is still unknown, and diagnosis is still performed by exclusion criteria. The alteration of bone remodeling activity has been reported in patients; in this study, we characterized circulating osteoclast and osteogenic precursors that could be important to better understand the osteolysis observed in patients. METHODS: Flow cytometry analysis of PBMC (Peripheral Blood Mononuclear Cells) was performed to characterize circulating osteoclast and osteogenic precursors in GSD patients (n = 9) compared to healthy donors (n = 55). Moreover, ELISA assays were assessed to evaluate serum levels of bone markers including RANK-L (Receptor activator of NF-κB ligand), OPG (Osteoprotegerin), BALP (Bone Alkaline Phosphatase) and OCN (Osteocalcin). RESULTS: We found an increase of CD16-/CD14+CD11b+ and CD115+/CD14+CD11b+ osteoclast precursors in GSD patients, with high levels of serum RANK-L that could reflect the increase of bone resorption activity observed in patients. Moreover, no significant alterations were found regarding osteogenic precursors and serum levels of BALP and OCN. CONCLUSION: The analysis of circulating bone cell precursors, as well as of RANK-L, could be relevant as an additional diagnostic tool for these patients and could be exploited for therapeutic purposes.

Expanding the spectrum of Gorham Stout disease exploring a single center pediatric case series.

Gorham-Stout Disease (GSD), also named vanishing bone disease, is an ultrarare condition characterized by progressive osteolysis with intraosseous lymphatic vessel proliferation and bone cortical loss. So far, about 300 cases have been reported. It may occur at any age but more commonly affects children and young adults. The aim of this study is to retrospectively review our internal patient series and to hypothesize a diagnostic-therapeutic protocol for earlier diagnosis and treatment. Clinical datasets from our center were examined to identify all GSD patients for collection and analysis. We identified 9 pediatric cases and performed a retrospective case-series review to examine and document both diagnosis and treatment. We found that delay in diagnosis after first symptoms played a critical role in determining morbidity and that multidisciplinary care is key for proper diagnosis and treatment. Our study provides additional insight to improve the critical challenge of early diagnosis and highlights a multidisciplinary treatment approach for the most appropriate management of patients with rare GSD disease. Although GSD is an ultrarare disease, physicians should keep in mind the main clinical features since neglected cases may result in potentially fatal complications.

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.

Elevated serum alpha-fetoprotein in Wilms tumor may follow the same pattern of other fetal neoplasms after treatment: evidence from three cases.

Alpha-fetoprotein (AFP) is a common tumoral marker in pediatric neoplasms; increased serum levels are usually encountered in tumors arising from tissues producing AFP during fetal life. However, elevation of such protein is rarely found in patients with Wilms tumor (WT). Three patients with WT and elevated serum AFP were studied over the course of the disease. One patient had left WT with invasion of aorto-caval lymph nodes and lung metastases. The second patient was referred to our center for abdominal recurrence of bilateral WT whereas the third showed right WT with inferior vena cava thrombosis. AFP levels demonstrated a trend parallel to decrease/increase of tumor size, with further elevation in patients with metastases. Elevated AFP serum levels in patients with WT could be related to peculiar histological features and serial dosage might be a useful diagnostic and prognostic test.

Temozolomide in resistant or relapsed pediatric solid tumors.

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

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.

A single-institution Wilms' tumor and localized neuroblastoma series.

Since January 1980, 120 children affected by Wilms' tumor have been treated at Bambino Gesù, mostly with multimodality treatment according to Société Internationale d'Oncologie Pediatrique (SIOP) protocols, including chemotherapy, surgery and radiotherapy in selected cases. This treatment approach emphasizes the role of preoperative (neoadjuvant) chemotherapy as opposed to the approach favored by the National Wilms' Tumor Study, which is focused on optimizing postoperative chemotherapy after primary surgery. Thus, using SIOP guidelines, staging occurs at the time of surgery, after chemotherapy administration. These differences will constitute the baseline for a comparison between the two experiences. Bilaterality, nephroblastomatosis, partial nephrectomy in unilateral Wilms' tumor and thrombosis of the vena cava are the main topics discussed. For the present study, the analysis was restricted to 98 consecutive cases diagnosed until December 1999, for whom at least 24 mo of follow-up is available. The more recent experience of treating resectable neuroblastoma in cooperative studies dates back to 1979, when the first Italian Cooperative Group Neuroblastoma protocol was introduced. This experience was continued within the frame of the first Localized Neuroblastoma European Study Group protocol (LNESG 94), and will be compared to North American Cooperative Group approaches and outcomes. Preoperative evaluation of surgical risk factors, intraoperative complications and their management, and long-term outcome will be discussed.

111 renal neoplasms of childhood: a clinicopathologic study.

PURPOSE: The aim of this study was to perform a clinicopathologic evaluation of a single pediatric institution renal tumor series. Most patients were treated within the frame of 3 consecutive SIOP trials, which included preoperative chemotherapy as their main feature. METHODS: Medical records and diagnoses of 111 patients were reviewed. The association of pathologic features with outcome was investigated by means of the Kaplan-Meier method, the Cox model, and a logistic multivariate analysis. Comparison among different trial results was carried out. RESULTS: In 98 patients (88%), nephroblastoma was diagnosed, followed by 6 adult-type renal tumors, 3 cystic nephromas, 2 mesoblastic nephromas, and 2 clear cell sarcomas. For nephroblastoma, a statistically significant correlation between grade and both disease-free survival rate and 5-year survival rate, and between stage and overall survival rate was shown. Lymph node involvement, local relapse, nephrogenic rests, and older age at presentation appeared to be less important prognostic factors. Tumor spillage was very sensitive to chemo or radiotherapy. No significant difference in outcome was observed among different trials. CONCLUSIONS: Wilms' tumor was the most frequent neoplasm and resulted in a 5-year cure rate of 90%. Clinical course was influenced mainly by diffuse anaplasia and, to a minor extent, by lymph node involvement. Because some tumors followed an unpredictable course, it is likely that also other biological factors played a significant role.

Spindle cell (Kaposiform) hemangioendothelioma with Kasabach-Merritt syndrome in an infant: successful treatment with alpha-2A interferon.

A two-month-old infant developed a vascular tumor of the right flank which upon biopsy proved to be a spindle cell hemangioendothelioma. The increased capillary bed characterizing the neoplasm caused a severe thrombocytopenia together with a consumption coagulopathy (Kasabach-Merritt syndrome). The patient, who was dependent on platelet transfusions, improved quickly after interferon alpha-2a was given at the dosage of 3,000,000 U/m2, with resolution of the Kasabach-Merritt syndrome after three weeks and a 75% decrease of the tumor volume within three months of treatment.

Comparison of the diagnostic and prognostic value of biological markers in neuroblastoma. Proposal for a common methodology of analysis. SENSE group.

BACKGROUND: The prognosis of pediatric neuroblastoma depends both on clinical presentation and on certain cellular and molecular characteristics. Screening programs have been initiated in infants of less than one year of age, based on the hypothesis that neuroblastoma progresses from early to late clinical stages through a classical multistep process linked to an accumulation of molecular abnormalities. However, recent analyses suggest that most cases discovered by screening are low stage tumors considered as dysembryogenetic residues devoid from major abnormalities and that high-grade tumors with molecular abnormalities are unrelated diseases. AIM OF THE REVIEW: To confirm one or the other hypothesis, and eventually identify biological factors possibly responsible for the initiation and progression of the disease, it is of utmost importance that all investigators agree on biological criteria for analysis when neuroblastoma tissue is available in screened and unscreened populations. This paper reviews the biological tools available for prognosis in neuroblastoma, the priority for analysis of biological markers according to both methodological reliability and feasibility, and the conditions of tissue storage for further analysis of these biological markers. CONCLUSION: The standardized biological evaluation of neuroblastoma will allow to collect sufficient data for multivariate analysis; such analysis is now fundamental if one wants to clearly define the respective impacts of biological abnormalities on neuroblastoma progression.

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.

An improved technique for peripheral blood stem cell collection in small patients.

Peripheral Blood Stem Cell collection in adults is a consolidated method for autografting. The same procedure is less easily performed in pediatric patients due to low weight, vascular access problems and anticoagulant side effects. Great efforts have been made to overcome technical difficulties and make apheresis in children a reliable and safe procedure.

Functionally active ganglioneuroma with increased plasma and urinary catecholamines and positive iodine 131-meta-iodobenzylguanidine scintigraphy.

Ganglioneuromas are usually considered not to be functionally active. Studies of their catecholamine excretory pattern and of their imaging by means of the adrenergic tracing agent 131-I-MIBG have been therefore sparse. We report on a case of secretory ganglioneuroma, as demonstrated by the increased urinary excretion of the catecholamine metabolites HVA and VMA, increased plasma dopamine and epinephrine levels, and positive 131-I-MIBG scintigraphy. We must therefore be aware that a functionally active tumor is not necessarily a neuroblastoma, and that the diagnosis should be biopsy proven.

A pilot study of high-dose carboplatin and pulsed etoposide in the treatment of childhood solid tumors.

Carboplatin was administered at 1,000 mg/m2/course in combination with etoposide at 300 mg/m2/course to 23 patients aged 5 months to 16 years. Five patients were affected by neuroblastoma, four by CNS tumors, three by Ewing's sarcoma, two by rhabdomyosarcoma, two by malignant teratoma, two by Wilms' tumor, two by head and neck carcinoma, one by hepatoblastoma, one by synovial sarcoma, and one by Langerhans-cell histiocytosis. Eleven patients were pretreated, seven of them with high-dose cisplatin. The overall response rate was 7/11 (64%) for pretreated and 10/12 (83%) for previously untreated patients. Myelosuppression was the main side effect, with anemia and thrombocytopenia more pronounced than leukopenia. Gastrointestinal toxicity and ototoxicity were very mild; nephrotoxicity and neurotoxicity other than hearing loss were not observed. In children with malignant tumors, the therapeutic activity of carboplatin at high doses, even in combination chemotherapy, deserves further studies.