Luigi De Sio

Spindle cell (Kaposiform) hemangioendothelioma with Kasabach‐Merritt syndrome in an infant: Successful treatment with α‐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.

A multicenter, randomized, double blind placebo-controlled trial of amoxicillin/clavulanate for the prophylaxis of fever and infection in neutropenic children with cancer.

Aim of the study. To evaluate the effectiveness of oral amoxicillin/clavulanate (25 mg/kg every 12 h) for prevention of fever and/or infection in neutropenic children with cancer. Methods. Multicenter, prospective, randomized, double blind placebo-controlled trial. Results. In the intention-to-treat analysis, amoxicillin/clavulanate had a 12% benefit increase in terms of reduction in the incidence of febrile or infectious episodes, compared with placebo [44 of 83 (53%) vs. 55 of 84 (65%); 95% confidence interval, −28% to +3%;P = 0.101]. This benefit was also associated with a 30% increase in the probability of failure-free survival at Day 15 (P = 0.138). A logistic regression analysis showed the effect of prophylaxis to be relevant, especially in patients with leukemia or lymphoma and in those not receiving hematopoietic growth factors, with 17 and 15% absolute benefit increases (logistic P = 0.014 and 0.034, respectively). Compliance with oral drugs was good, with very few and nonsevere drug-related adverse events. Conclusions. In this study amoxicillin/clavulanate was associated with a detectable clinical effect in the reduction of fever and infection in neutropenic children with cancer, especially those with acute leukemia and not receiving growth factors; the study was not powered to demonstrate a statistically significant effect in the overall patient population.

Rhabdomyosarcoma in adolescents: A report from the AIEOP Soft Tissue Sarcoma Committee

In many types of cancer, the survival rates are reported to be less favorable for adolescents compared with younger children. To investigate whether this is true for adolescents with rhabdomyosarcoma (RMS), the results obtained in patients enrolled in protocols run by the Italian Soft Tissue Sarcoma Committee (STSC) were analyzed.

Antibiotic lock with vancomycin and urokinase can successfully treat colonized central venous catheters in pediatric cancer patients.

We used an antibiotic lock technique with vancomycin in combination with urokinase in 10 consecutive eligible children with Gram-positive catheter-related bacteremia persisting after appropriate intravenous antibiotics. Treatment was successful in sterilizing all colonized central venous catheters, avoiding device removal and delay of further chemotherapy. The antibiotic lock technique may represent a safe and effective therapeutic option in patients with selected, uncomplicated catheter-related bacteremias resistant to systemic antimicrobial therapy, particularly when maintaining a venous access is mandatory.

Clinical Significance of CXC Chemokine Receptor-4 and c-Met in Childhood Rhabdomyosarcoma

Purpose: The CXC chemokine receptor-4 (CXCR4)/stromal-derived factor-1 and c-Met/hepatocyte growth factor axes promote the metastatic potential of rhabdomyosarcoma cell lines in experimental models, but no data are available on their role in rhabdomyosarcoma tumors. The expressions of CXCR4 and c-Met were evaluated in primary tumors and isolated tumor cells in marrow, and were correlated with clinicopathologic variables and survival. Experimental Design: Forty patients with recently diagnosed rhabdomyosarcoma were retrospectively enrolled. CXCR4 and c-Met expression was investigated in primary tumors by immunohistochemistry, in isolated marrow-infiltrating tumor cells using double-label immunocytology. Results were expressed as the mean percentage of immunostained tumor cells. Results: CXCR4 and c-Met were expressed in ≥5% of tumor cells from 40 of 40 tumors, with 14 of 40 cases showing ≥50% of immunostained tumor cells (high expression). High CXCR4 expression correlated with alveolar histology (P = 0.006), unfavorable primary site (P = 0.009), advanced group (P < 0.001), marrow involvement (P = 0.007), and shorter overall survival and event-free survival (P < 0.001); high c-Met expression correlated with alveolar histology (P = 0.005), advanced group (P = 0.04), and marrow involvement (P = 0.02). In patients with a positive diagnosis for isolated tumor cells in marrow (n = 16), a significant enrichment in the percentage of CXCR4-positive (P = 0.001) and c-Met–positive (P = 0.003) tumor cells was shown in marrow aspirates compared with the corresponding primary tumors. Conclusions: CXCR4 and c-Met are widely expressed in both rhabdomyosarcoma subtypes and, at higher levels, in isolated marrow-infiltrating tumor cells. High levels of expression are associated with unfavorable clinical features, tumor marrow involvement and, only for CXCR4, poor outcome. In rhabdomyosarcoma, CXCR4 and c-Met represent novel exploitable targets for disease-directed therapy.

Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma

AIM The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma. PATIENTS AND METHODS Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered. RESULTS Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years. CONCLUSION Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.

Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.

Sporadic acute lymphocytic leukemia arising in a patient with neurofibromatosis and xanthogranulomatosis

We present a case report of a child who developed acute lymphoblastic leukemia, neurofibromatosis, optic glioma, and xanthogranulomatosis. This complex is unusual, not previously described, and appears to be a coincidence of different diseases. The importance of this case is that it may offer a clue to the genetic base of neurofibrosis syndromes including leukemic associations.

Abstract 3417: Ezh2 is up-regulated and correlates with Ki67 and CD31 expression in human pediatric rhabdomyosarcoma

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Rhabdomyosarcoma (RMS) is a pediatric tumor believed to originate from perturbations of the normal development of the muscle lineage. The Polycomb Group (PcG) protein Ezh2, which was originally implicated in inhibiting homeobox gene expression during embryonic development, was recently shown to act as a negative regulator of muscle differentiation. Moreover, Ezh2 is a histone methyltransferase that is aberrantly overexpressed in most human cancers. Comparing the level of the expression of Ezh2 in RMS cell lines, a small group of tumor samples with normal skeletal muscle myoblasts (SkMC), and normal muscle tissues, we have previously observed that Ezh2 is highly upregulated in rhabdomyosarcoma tumors (Ciarapica et al., 2009). The aim of this study was to characterize the relevance of Ezh2 expression in RMS. Ezh2 expression was analyzed by immunohistochemistry in a cohort of 32 RMS primary tumors and correlated with the expression of the cell proliferation marker, Ki67, and the angiogenic marker, CD31. Results of these expression studies were then correlated with the clinicopathological features of the tumor samples. No significant difference in the clinicopathological variables was observed between the two major histophatological groups of RMS, the most aggressive alveolar RMS (ARMS) and the embryonal RMS (ERMS). Ezh2 expression was not correlated with the clinical parameters of the cohorts, but strikingly, a significant positive correlation was observed between Ezh2 and Ki67 expression in the whole RMS sample (r0 = 0,560; p = 0,013). The number of the large vessels was correlated with the total number of vessels (r0= 0,730; p<0,0001) and with the expression of Ki67 (r0= 0,421; p=0,02). In ARMS samples, the number of large vessels was significantly correlated with the expression of Ezh2 (r0= 0,559; p=0,047), the total number of vessels (r0= 0,781; p=0,02), and the expression of Ki67 (r0= 0,738; p=0,004). This study confirmed our previous observation regarding the aberrantly high expression of Ezh2 in rhabdomyosarcoma tumors on a larger cohort of samples. Moreover, the present data established a positive correlation between Ezh2 expression and the proliferative and angiogenic potential of rhabdomyosarcoma neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3417.

Rhabdomyosarcoma associated hypertrophic osteoarthropathy in a child: detection by bone scintigraphy.

Hypertrophic osteoarthropathy (HOA) is characterized by digital clubbing, long bone periosteal reaction, and polyarthralgias. Primary familial HOA is very rare and is not associated with underlying disorders and has a good prognosis. Secondary pediatric nonneoplastic HOA is associated with cystic fibrosis, congenital heart disease, biliary atresia, and inflammatory bowel disease. Secondary neoplastic HOA may be associated with intra or extrathoracic tumors.A 5-year-old girl was admitted to our hospital for an abdominal mass, digital clubbing, and diffuse articular pain. The bone scan revealed symmetrical tracer uptake in the long bones. Upper and lower extremity x-rays were diagnostic for HOA. Paraneoplastic HOA in childhood accounts for not more than 12% of HOA paitents. HOA has been reported in 2 other cases of rhabdomyosarcoma.