Transient global ventricular dysfunction in an adolescent affected by pancreatic adenocarcinoma.

BACKGROUND: Takotsubo cardiomyopathy (TC) is characterized by a transient decrease in ejection fraction and a reversible left ventricular dysfunction. The pathophysiology of TC is not completely understood. Heterogeneous and multifactorial mechanisms are involved: drugs, emotional and physical stress, genetic and hormonal factors. CASE PRESENTATION: A 17 year-old male with metastatic pancreatic adenocarcinoma, under chemotherapy containing 5-fluorouracil, presented severe left ventricular dysfunction requiring mechanical ventilation and inotropes administration. He completely recovered in 2 weeks. CONCLUSION: To our knowledge this is the first report of transient form of ventricular dysfunction, mimicking TC, in an adolescent. We believe that children and adolescents receiving 5-fluorouracil should be closely monitored and referred for investigation if they develop cardiac symptoms.

NRAS(Q61K) mutated primary leptomeningeal melanoma in a child: case presentation and discussion on clinical and diagnostic implications.

BACKGROUND: Primary melanocytic neoplasms are rare in the pediatric age. Among them, the pattern of neoplastic meningitis represents a peculiar diagnostic challenge since neuroradiological features may be subtle and cerebrospinal fluid analysis may not be informative. Clinical misdiagnosis of neoplastic meningitis with tuberculous meningitis has been described in few pediatric cases, leading to a significant delay in appropriate management of patients. We describe the case of a child with primary leptomeningeal melanoma (LMM) that was initially misdiagnosed with tuberculous meningitis. We review the clinical and molecular aspects of LMM and discuss on clinical and diagnostic implications. CASE PRESENTATION: A 27-month-old girl with a 1-week history of vomiting with mild intermittent strabismus underwent Magnetic Resonance Imaging, showing diffuse brainstem and spinal leptomeningeal enhancement. Cerebrospinal fluid analysis was unremarkable. Antitubercular treatment was started without any improvement. A spinal intradural biopsy was suggestive for primary leptomeningeal melanomatosis. Chemotherapy was started, but general clinical conditions progressively worsened and patient died 11 months after diagnosis. Molecular investigations were performed post-mortem on tumor tissue and revealed absence of BRAF(V600E), GNAQ(Q209) and GNA11(Q209) mutations but the presence of a NRAS(Q61K) mutation. CONCLUSIONS: Our case adds some information to the limited experience of the literature, confirming the presence of the NRAS(Q61K) mutation in children with melanomatosis. To our knowledge, this is the first case of leptomeningeal melanocytic neoplasms (LMN) without associated skin lesions to harbor this mutation. Isolated LMN presentation might be insidious, mimicking tuberculous meningitis, and should be suspected if no definite diagnosis is possible or if antitubercular treatment does not result in dramatic clinical improvement. Leptomeningeal biopsy should be considered, not only to confirm diagnosis of LMN but also to study molecular profile. Further molecular profiling and preclinical models will be pivotal in testing combination of target therapy to treat this challenging disease.

Comparison of two different conditioning regimens before autologous transplantation for children with high-risk neuroblastoma.

BACKGROUND: Although high-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma (NBL), the most effective conditioning regimen still remains to be identified. PATIENTS AND METHODS: Forty-one high-risk NBL entered into local protocol based on induction chemotherapy, surgery and HDC with either etoposide/thiotepa/cyclophophamide (ETC) or i.v. busulfan and L-PAM (Bu/L-PAM). RESULTS: Thirty-seven patients underwent HDC; 29 with ETC and 8 with Bu/L-PAM. No toxic deaths were recorded. The 5-year progression-free survival (PFS) of patients given ETC was 21% (95% confidence interval CI (9-36%), while PFS for patients given Bu/L-PAM was 88% (95% CI=39-98%) (p<0.05). In multivariate analysis, treatment with the ETC regimen predicted progression/recurrence with a hazard ratio (HR) of 16.8 (p<0.05), as well as MYCN amplification which had an HR of 4.4 (p<0.05). CONCLUSION: Although the number of studied cases is limited, our data suggest that in high-risk NBL the combination of Bu/L-PAM is superior to the ETC regimen.

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.

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

BACKGROUND: 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. METHODS: From 1988 through 2005, 643 patients were registered (567 children ages birth-14 years and 76 adolescents ages 15-19 years) and treated in 4 STSC protocols. The number of patients enrolled was compared with the expected number calculated from incidence rates derived from the Italian network of cancer registries. RESULTS: Only 27% of the expected number of adolescents with RMS were enrolled in the STSC trials. Compared with children, adolescents were found to have a longer interval from initial symptoms to diagnosis (8 weeks vs 4.6 weeks), more alveolar RMS (47.4% vs 32.6%), lymph node infiltration (39.1% vs 23.3%), and metastases at the time of diagnosis (30.7% vs 17.8%). The 2 age groups received similar treatments. The 5-year overall survival (OS) rate was 68.9% in children versus 57.2% in adolescents (P = .006), and the progression-free survival (PFS) rate was 64.3% in children versus 48.1% in adolescents (P = .0237). On multivariate analysis, age, tumor site, lymph node involvement, and metastases were found to be significant prognostic factors for OS and PFS. CONCLUSIONS: Survival for adolescents with RMS enrolled in STSC protocols appears to be satisfactory. The higher prevalence of unfavorable tumor characteristics noted among adolescents seems to explain their worse outcome compared with children. However, the limited number of adolescents enrolled in STSC studies is worrisome, and cooperation with oncologists who treat adults needs to be improved.

Bevacizumab in pediatric patients: how safe is it?

BACKGROUND: Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). The safety profile of bevacizumab was evaluated in a cohort of children with either recurrent or poor-prognosis malignancies. PATIENTS AND METHODS: Bevacizumab was administered intravenously at the dosage of 5-10 mg/kg every 14-28 days alone or in combination with other agents. Toxicity was reported according to common toxicity criteria version 4. RESULTS: Seventeen patients received a total of 156 bevacizumab doses (median 5 doses/pt) for a median treatment duration of 2 months (range 1-21). Grade II-III lymphopenia was recorded in 10 patients, while grade III proteinuria and grade I epistaxis occurred in one patient each. Grade III wound dehiscence was observed in one case and 3 severe adverse events (SAEs) were recorded: one reversible posterior leukoencephalopathy syndrome (RPLS) with grade IV seizures and grade IV hypertension, one grade IV hypertension and a post-operative grade IV entero-cutaneous fistula. CONCLUSION: In the present cohort, the overall incidence of SAEs (17%) was higher than previously reported, thus, further studies should be justified to better characterize the safety profile of bevacizumab in the pediatric population.

Microscopic neoplastic thrombosis in localised nephroblastoma: does it influence outcome?

INTRODUCTION: Microscopic neoplastic thrombosis (MNT) is reported to occur frequently in Wilms tumour (WT). The aim of this study is to determine whether MNT influences prognosis in localised WT. PATIENTS AND METHODS: Records and slides of 80 consecutive, unselected, localised WT patients were retrospectively reviewed. All patients received chemotherapy before surgery according to SIOP Protocol. The median follow-up was 9 years (range 0.5-25.8). The Kaplan-Meier method and the Cox proportional hazard model were applied. RESULTS: MNT was present in 14 (18%) cases. Out of 14 patients with MNT, 6 presented macroscopic thrombosis and 5 had either blastemal predominance or anaplastic histology. The 5-year overall survival (OS) and progression-free survival (PFS) for the whole population were 95% (95% confidence interval, CI, 87-98%) and 91% (95% CI 82-96%), respectively. The 5-year OS and PFS for MNT positive patients were 92% (95% CI 57-99%) and 77% (95% CI 44-92%), while the 5-year OS and PFS for MNT negative patients were 96% (95% CI 87-99%) and 94% (95% CI 85-98%), respectively; the difference was statistically significant (p<0.05) for PFS. In multivariate analysis, only the presence of anaplasia retained significance with a hazard ratio (HR) of 14.8 and 12.9 (p<0.05) for recurrence and death, respectively. CONCLUSION: These data suggest that the presence of MNT increases the risk of recurrence. MNT is associated with well-known prognostic factors, such as macroscopic thrombosis (possibly representing regression of macroscopic involvement) and anaplasia. Further prospective studies are needed to clarify the role of MNT as independent prognostic factor.

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.

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.

Pancreatitis as an unusual presentation of rhabdomyosarcoma.

The most common etiologies of acute pancreatitis in children are trauma, multi-system disease, drugs, infections, idiopathic and congenital anomalies of the pancreaticobiliary system. Acute pancreatitis is rarely associated with underlying childhood malignancies. We report a 12-year-old male with acute pancreatitis as the presenting symptom of an alveolar metastatic rhabdomyosarcoma.

A multimodal strategy based on surgery, radiotherapy, ICE regimen and high dose chemotherapy in atypical teratoid/rhabdoid tumours: a single institution experience.

PURPOSE: Atypical Teratoid/Rhabdoid Tumour is a rare and aggressive childhood tumour. The outcome of a series treated with the same multimodal strategy was reported. PATIENTS: The patients were treated with surgery, 2 courses of ifosfamide/carboplatin/etoposide(ICE), 2 courses of cyclophosphamide/etoposide/carboplatino/thiotepa (CECAT) or 2 other ICE courses, high dose chemotherapy (HDC) and radiotherapy. RESULTS: Eight patients underwent primary surgery achieving a complete removal in 3. Progressive disease (PD) occurred in 2/8 patients during ICE courses and in 3/4 during CECAT courses. After 4 courses 5 patients presented a PD. HDC was performed in 3 patients followed by local radiotherapy. The Kaplan Meier OS and EFS probability at 5 years are, respectively, 50% (CI 11-80%) and 33% (CI 6-66%). CONCLUSION: A strategy based on surgery, including a second surgical look, and on radiotherapy appears the best option. ICE regimen and HDC correlate with good prognosis in some patients but this approach needs further evaluation.

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.

Synovial sarcoma of children and adolescents: the prognostic role of axial sites.

BACKGROUND: The outcome of patients with non-extremity synovial sarcoma (SS) is generally worse than that of patients with limb tumours. METHODS: The present study analysed a series of 115 consecutive SS patients treated in Italian paediatric protocols (period 1979-2005), mainly focusing on the 30 cases arising from 'axial' sites (16 head-neck, 8 trunk, 4 lung-pleura and 2 retroperitoneum). RESULTS: Initial gross resection was achieved in 40% of axial cases and in 80% of limb SS (p<0.0001). Five-year EFS and overall survival (OS) were, respectively, 43.3% and 55.1% for axial SS, and 69.6% (p=0.0068) and 84.0% (p=0.0004) for extremity SS. Local progression/recurrence was the cause of treatment failure in 75% of relapsing patients axial disease. CONCLUSIONS: Our findings emphasise that children and adolescents with SS originating at non-extremity locations have a worse prognosis than those with limb SS. Tumour site should be considered when defining a risk-adapted treatment strategy for SS.

Pleuropulmonary blastoma, a distinctive neoplasm of childhood: report of three cases.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare, aggressive dysontogenetic neoplasm affecting children. It was identified as a distinct entity by Manivel in 1988 and later subdivided into three types on the basis of the histological pattern, with increasing malignancy from type I (cystic) through type II (solid/cystic) to type III (solid). OBJECTIVE: To report on the imaging findings, clinical presentation, and differential diagnosis, mainly cystic malformations. MATERIALS AND METHODS: We evaluated three children, age 2-4 years, with PPB. RESULTS: One patient presented with unresolving pneumothorax and a multicystic mass, another with a mixed fluid/solid lesion, and the last with a solid heterogeneous mass. CONCLUSION: Despite its rarity, PPB should be considered in the evaluation of cystic or solid masses in children with respiratory distress. Plain film radiography alone is unable to distinguish between PPB and cystic malformations. CT represents the gold standard, although MRI can show the imaging features of solid enhancing nodules inside fluid-filled cavities, a mass causing lung compression, mediastinal shift, frequent pleural effusion, and no chest wall invasion. No preoperative imaging can reliably differentiate between congenital cystic lesions and PPB type I.

High histologic and overall response to dose intensification of ifosfamide, carboplatin, and etoposide with cyclophosphamide, doxorubicin, and vincristine in patients with high-risk Ewing sarcoma family tumors: the Bambino Gesù Children's Hospital experience.

BACKGROUND: Ewing sarcoma (ES) and extraosseous ES/primitive neuroectodermal tumors (PNET) share histopathologic features of the ES family of tumors (ESFT). The authors report on their results from a regimen of ifosfamide, carboplatin, and etoposide (ICE) with cyclophosphamide, doxorubicin, and vincristine (CAV) dose intensification in patients with high-risk ESFT. METHODS: Since 1990, patients with ESFT and with 1 or more of the following risk factors were reviewed: tumor volume > 200 mL, tumor site with a poor prognosis, and pulmonary and/or bone marrow metastases. RESULTS: Thirty-six patients with ESFT who were involved in the study were divided into 2 arms of 18 patients each. One group received treatment with various regimens, and the other group received treatment with ICE plus CAV. The disease was brought under control more rapidly in the latter patients, for whom surgery was more easily feasible, and up to 90% of patients achieved a major response, with an estimated 3-year overall survival rate of 67% +/- 12%. CONCLUSIONS: The current results showed that ICE plus CAV was tolerated well and was effective in the studied subset of tumors, indicating that dose intensification correlates with better disease control, a high percentage of necrosis, and conservative surgery in patients with high-risk ESFT.

Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group.

PURPOSE: To assess the value of chemotherapy and radiotherapy in children with malignant peripheral nerve sheath tumors (MPNSTs) and to identify risk factors associated with outcome. PATIENTS AND METHODS: A total of 167 untreated eligible patients enrolled onto the Italian and German studies between 1975 and 1998 entered this analysis. Seventeen percent of patients had neurofibromatosis type 1 (NF1). Chemotherapy was administered to 74% of patients; radiotherapy was administered to 38% of patients. RESULTS: With a median follow-up of 7 years, 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 37%, respectively. The 5-year OS and PFS by Intergroup Rhabdomyosarcoma Study (IRS) groupings were as follows: group I, 82% and 61%; group II, 62% and 37%; group III, 32% and 27%; group IV, 26% and 21%, respectively. Univariate analysis identified IRS groups, size, invasiveness, primary site, age, and presence of NF1 as prognostic factors; multivariate analysis identified absence of NF1, tumor invasiveness T1, IRS groups I to II and extremity of primary site as independent favorable factors for OS. A trend was observed toward a benefit from radiotherapy after initial gross resection. The overall response rate to primary chemotherapy, including minor responses, in group III patients was 45%. CONCLUSION: MPNST is an aggressive tumor for which complete surgical resection is the mainstay of successful treatment. Postoperative radiotherapy may have a role in improving local control in patients with minimal residual tumor. The reported responses to primary chemotherapy suggest that it may be effective in patients with tumor considered unresectable at diagnosis.

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.

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.