Vincristine, Irinotecan, and Bevacizumab in Relapsed Wilms Tumor With Diffuse Anaplasia.

The prognosis of relapsed Wilms tumor (WT) with diffuse anaplasia is dismal, therefore, novel therapeutic strategies need to be explored. We reported on 2 consecutive cases with relapsed anaplastic WT who presented a partial response after 2 courses of vincristine, irinotecan, and bevacizumab association. This regimen may have a role in the treatment of patients with anaplastic advanced WT.

Sudden benzodiazepine-induced resolution of post-operative pediatric cerebellar mutism syndrome: a clinical-SPECT study.

Post-operative pediatric cerebellar mutism syndrome (PPCMS) is a clinical syndrome arising from cerebellar injury and characterized by absence of speech and other possible symptoms and signs. Rare reports described some benefit after administration of dopamine agonist therapy, but no treatment has proven efficacy. In this paper, we report on the dramatic, sudden resolution of PPCMS induced by midazolam administration in a boy who underwent posterior fossa surgery for choroid plexus papilloma of the fourth ventricle. In addition to clinical improvement, post-midazolam single-photon emission computed tomography also demonstrated amelioration of brain perfusion.

Deep Sequencing the microRNA profile in rhabdomyosarcoma reveals down-regulation of miR-378 family members.

BACKGROUND: Rhabdomyosarcoma (RMS) is a highly malignant tumour accounting for nearly half of soft tissue sarcomas in children. MicroRNAs (miRNAs) represent a class of short, non-coding, regulatory RNAs which play a critical role in different cellular processes. Altered miRNA levels have been reported in human cancers, including RMS. METHODS: Using deep sequencing technology, a total of 685 miRNAs were investigated in a group of alveolar RMSs (ARMSs), embryonal RMSs (ERMSs) as well as in normal skeletal muscle (NSM). Q-PCR, MTT, cytofluorimetry, migration assay, western blot and immunofluorescence experiments were carried out to determine the role of miR-378a-3p in cancer cell growth, apoptosis, migration and differentiation. Bioinformatics pipelines were used for miRNA target prediction and clustering analysis. RESULTS: Ninety-seven miRNAs were significantly deregulated in ARMS and ERMS when compared to NSM. MiR-378 family members were dramatically decreased in RMS tumour tissue and cell lines. Interestingly, members of the miR-378 family presented as a possible target the insulin-like growth factor receptor 1 (IGF1R), a key signalling molecule in RMS. MiR-378a-3p over-expression in an RMS-derived cell line suppressed IGF1R expression and affected phosphorylated-Akt protein levels. Ectopic expression of miR-378a-3p caused significant changes in apoptosis, cell migration, cytoskeleton organization as well as a modulation of the muscular markers MyoD1, MyoR, desmin and MyHC. In addition, DNA demethylation by 5-aza-2'-deoxycytidine (5-aza-dC) was able to up-regulate miR-378a-3p levels with a concomitant induction of apoptosis, decrease in cell viability and cell cycle arrest in G2-phase. Cells treated with 5-aza-dC clearly changed their morphology and expressed moderate levels of MyHC. CONCLUSIONS: MiR-378a-3p may function as a tumour suppressor in RMS and the restoration of its expression would be of therapeutic benefit in RMS. Furthermore, the role of epigenetic modifications in RMS deserves further investigations.

Long-term follow-up of the "wait and see" approach to localized perinatal adrenal neuroblastoma.

BACKGROUND: Evidence-based guidelines for the management of localized perinatal adrenal neuroblastoma are not yet available. We describe our preliminary experience managing this tumor with a "wait and see" policy. METHODS: A single-center prospective study (February 2002 to December 2009) was conducted with 12 consecutive patients in whom an adrenal mass was detected antenatally or within the first 3 months of life. Diagnostic workup included the following investigations: measurement of urine catecholamine metabolites, imaging studies (ultrasonography, magnetic resonance imaging, or computed tomography), metaiodobenzylguanidine scintigraphy, and/or core needle biopsy. RESULTS: The male/female ratio was 1.4:1.0. Median tumor size at presentation was 29 mm (range 10-50 mm). Eight lesions were detected antenatally. Ten lesions were diagnosed as localized neuroblastoma. Of these ten lesions, four were excised because of parental preference (n = 2), tumor enlargement (n = 1) or tumor persistence (n = 1). The remaining six patients underwent watchful clinical observation, which showed progressive tumor shrinkage and complete regression within 10-39 months (median 12.5 months). The final two lesions were small predominantly cystic lesions without a clear-cut diagnosis. They were managed noninvasively. At an overall median follow-up of 109 months (range 30-122 months), all patients are alive and disease-free, although one patient progressed to stage 4 disease despite early excision of the primary tumor. CONCLUSIONS: Spontaneous regression of localized perinatal adrenal neuroblastoma occurs often, and a "wait and see" strategy seems justified in these small infants. Patients with enlarging or stable lesions that have persisted for several months may benefit from surgery, although prompt excision may not prevent tumor progression.

Surgical treatment of congenital rhabdoid tumor in a 10-day-old newborn.

BACKGROUND: Malignant rhabdoid tumors are rare and aggressive tumors of pediatric age. The primary tumor can occur in different localizations, but it mainly involves kidney, soft tissue, or central nervous system. It has been associated to a poor diagnosis. METHODS: The authors present the case of a 10-day-old newborn affected by a bulky nasofronto-orbitary neoplasm. The patient underwent radical surgical treatment and further excision of a preauricular metastasis combined with postoperative chemotherapy treatment. RESULTS: The authors adopted a diagnostic and therapeutic protocol according to international guidelines, not without difficulty because the first histological report showed esthesioneuroblastoma. The rarity and aggresivity of rhabdoid tumor and the precocity of onset in our patient presented a difficulty to define prognostic factors and survival rates, as well as therapeutic plan of treatment. CONCLUSIONS: The authors underline the importance of a correct prenatal diagnosis and an early surgical treatment to reach the complete healing of the patient.

Marriage and parenthood among childhood cancer survivors: a report from the Italian AIEOP Off-Therapy Registry.

BACKGROUND: The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. DESIGN AND METHODS: We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. RESULTS: During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women CONCLUSIONS: Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

Staged Image-guided Robotic Radiosurgery and Deferred Chemotherapy to Treat a Malignant Glioma During and After Pregnancy.

A 26-year-old pregnant woman with a fast-growing malignant deep-seated brain glioma was offered a therapeutic abortion to allow subsequent surgical resection. This option was refused by the mother, but the fast tumor growth placed the life of both mother and child at risk. A staged CyberKnife radiosurgery treatment was then planned, aiming to provide at least temporary tumor growth control and allow a safe delivery while keeping the doses received by the fetus well below the allowed doses. Growth control and the safe delivery of a healthy child were achieved after this first treatment. An intensive chemotherapy program based on the combination of Avastin, irinotecan, and Temodal was then started. Recurring tumor growth was treated with a second CyberKnife procedure while continuing the above chemotherapy protocol. At 43 months after the second CyberKnife procedure, the tumor had disappeared on magnetic resonance imaging. Neither mother nor child showed the neurological sequelae. Staged radiosurgery and deferred chemotherapy proved to be a safe and effective treatment to allow the delivery of a healthy child and the long-term control of an aggressive brain glioma.

Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors.

PURPOSE: Clinicobiological characteristics of neuroblastic tumor (NT) expressing c-kit tyrosine kinase receptor and/or its ligand, stem cell factor (SCF), are debated. This study aimed at investigating the clinicobiological features of primary NTs expressing c-kit and/or SCF in order to define the clinical relevance of selective therapeutic targeting. EXPERIMENTAL DESIGN: c-Kit and SCF expression was studied in 168 NTs using immunohistochemistry and in 106 of 168 using Northern blot. Quantitative determination of c-kit expression in 54 additional NTs was also done using real-time reverse transcription-PCR. Correlations between c-kit and SCF expression and clinicobiological features were analyzed using chi2 test, univariate, and multivariate regression analyses. RESULTS: c-Kit protein was detected in 21 of 168 NTs (13%) and its mRNA in 23 of 106 NTs (22%). SCF protein was shown in 30 of 106 NTs (28%) and its mRNA in 33 of 106 NTs (31%). No mutations in exon 11 of c-kit gene were identified. By univariate analysis, c-kit and SCF expression correlated with advanced stage, MYCN amplification, and 1p36 allelic loss. Cox simple regression analysis showed that overall survival probability was 17% in the c-kit-positive subset versus 68% in the negative (P < 0.001), 43% in the SCF-positive subset versus 78% in the negative (P < 0.001). When using real-time reverse transcription-PCR, significant levels of c-kit mRNA were found in 35 of 54 NTs (65%), but the correlations with clinicobiological features were no longer documented. CONCLUSIONS: c-Kit expression can be detected in the majority of primary NTs. High levels of expression are preferentially found in tumors with unfavorable clinicobiological variables. c-Kit may represent a useful therapeutic target in a subset of otherwise untreatable NTs.

Evaluation of carboplatin pharmacokinetics in pediatric oncology by means of inductively coupled plasma mass spectrometry.

Carboplatin is widely used in pediatric oncology to treat different tumors. Aim of the present study was to assess the potential of sector field inductively coupled plasma mass spectrometry (SF-ICPMS) in evaluating the area under the plasma platinum concentration vs time curve in pediatric patients presenting solid tumors and treated with carboplatin 349-1000 mg m-2. Seventeen patients were enrolled and 23 courses of chemotherapy were evaluated. Plasma was ultrafiltered and free carboplatin was measured in ultrafiltrates as platinum by SF-ICP-MS. Comparison was made between different equations to obtain a target AUC. Limits of detection and of quantification, intra- and inter-day repeatability of the measurements, recovery of the 'free-carboplatin' confirmed SF-ICP-MS as a reliable technique in the quantification of serum platinum in anticancer carboplatin-based therapies.

(18)F-DOPA Positron Emission Tomography in Medulloblastoma: 2 Case Reports.

BACKGROUND: Medulloblastoma (MDB) is an aggressive embryonal brain tumor, with underlying altered genetics and biological pathways that account for very heterogeneous natural histories and clinical behaviors. Positron emission tomography (PET) using radiolabeled amino acids provides important metabolic information for the diagnosis of cerebral glioma but only a few data are available on amino acid PET in MDB. In particular, no cases of MDB imaging with 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine (F-DOPA) have previously been described. CASE DESCRIPTION: Two patients with different histologic subtypes of MDB were referred for F-DOPA PET to define the extent and metabolic degree of their diseases. The patients had a newly diagnosed large-cell/anaplastic MDB and a fourth relapse of classic MDB, respectively. F-DOPA PET was unremarkable in the first case; F-DOPA uptake was low in the second patient with the tumor/background ratio as high as 1.29. Comparison was made with magnetic resonance imaging, which showed fluid-attenuated inversion recovery positive diseases. Aggressive tumor growth was shown in the clinical course of both patients. CONCLUSIONS: The 2 cases reported here suggest that sensitivity of F-DOPA PET in MDB can be low. However, more comprehensive data are needed to conclude on the overall accuracy of F-DOPA PET in MDB.

DNMT3B in vitro knocking-down is able to reverse embryonal rhabdomyosarcoma cell phenotype through inhibition of proliferation and induction of myogenic differentiation.

Aberrant DNA methylation has been frequently observed in many human cancers, including rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. To date, the expression and function of the de novo DNA methyltransferase (DNMT) 3B in RMS have not yet been investigated. Our study show for the first time a significant up-regulation of DNMT3B levels in 14 RMS tumour samples and 4 RMS cell lines in comparison to normal skeletal muscle. Transfection of RD and TE671 cells, two in vitro models of embryonal RMS (ERMS), with a synthetic DNMT3B siRNA decreased cell proliferation by arresting cell cycle at G1 phase, as demonstrated by the reduced expression of Cyclin B1, Cyclin D1 and Cyclin E2, and by the concomitant up-regulation of the checkpoint regulators p21 and p27. DNMT3B depletion also impaired RB phosphorylation status and decreased migratory capacity and clonogenic potential. Interestingly, DNMT3B knock-down was able to commit ERMS cells towards myogenic terminal differentiation, as confirmed by the acquisition of a myogenic-like phenotype and by the increased expression of the myogenic markers MYOD1, Myogenin and MyHC. Finally, inhibition of MEK/ERK signalling by U0126 resulted in a reduction of DNMT3B protein, giving evidence that DNMT3B is a down-stream molecule of this oncogenic pathway.Taken together, our data indicate that altered expression of DNMT3B plays a key role in ERMS development since its silencing is able to reverse cell cancer phenotype by rescuing myogenic program. Epigenetic therapy, by targeting the DNA methylation machinery, may represent a novel therapeutic strategy against RMS.

Detection and clinical significance of disseminated tumour cells at diagnosis in bone marrow of children with localised rhabdomyosarcoma.

Identification of patients with a poor prognosis for non-metastatic rhabdomyosarcoma (RMS) remains a clinical challenge. Prospective analysis for the presence of disseminated RMS cells in bone marrow at diagnosis, using immunocytochemistry, with MyoD1 and myogenin as markers, was carried out. Thirty-seven patients treated on RMS88 and RMS96 Italian protocols underwent staging investigations, and in addition marrow examination for occult tumour cells. All patients had negative marrow involvement using cytomorphology, but 10/37 were positive with immunostaining. With a median follow-up of 46 months (range, 12-115), 7 patients had died and 30 were disease-free. Overall survival probability was 92% in patients with no occult marrow infiltration, 47% with occult marrow infiltration (P=0.001); event-free survival probability was 89% in the former and 50% in the latter (P=0.01). Disseminated tumour cells are indicative of disease spread and are significantly linked to recurrence at distant sites and poorer outcome. Marrow examination at diagnosis using immunocytochemistry may be an additional tool to modulate treatment.

Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Aberrant expression of Anaplastic Lymphoma Kinase (ALK) and MET gene has been implicated in the malignant progression of RMS, especially in the alveolar subtype. This observation suggests that crizotinib (PF-02341066), a kinase inhibitor against ALK and MET, may have a therapeutic role in RMS, although its antitumour activity in this malignancy has not yet been studied. METHODS: RH4 and RH30 alveolar RMS (ARMS) cell lines were treated with crizotinib and then assessed by using proliferation, viability, migration and colony formation assays. Multiple approaches, including flow cytometry, immunofluorescence, western blotting and siRNA-based knock-down, were used in order to investigate possible molecular mechanisms linked to crizotinib activity. RESULTS: In vitro treatment with crizotinib inhibited ALK and MET proteins, as well as Insulin-like Growth Factor 1 Receptor (IGF1R), with a concomitant robust dephosphorylation of AKT and ERK, two downstream kinases involved in RMS cell proliferation and survival. Exposure to crizotinib impaired cell growth, and accumulation at G2/M phase was attributed to an altered expression and activation of checkpoint regulators, such as Cyclin B1 and Cdc2. Crizotinib was able to induce apoptosis and autophagy in a dose-dependent manner, as shown by caspase-3 activation/PARP proteolytic cleavage down-regulation and by LC3 activation/p62 down-regulation, respectively. The accumulation of reactive oxygen species (ROS) seemed to contribute to crizotinib effects in RH4 and RH30 cells. Moreover, crizotinib-treated RH4 and RH30 cells exhibited a decreased migratory/invasive capacity and clonogenic potential. CONCLUSIONS: These results provide a further insight into the molecular mechanisms affected by crizotinib in ARMS cells inferring that it could be a useful therapeutic tool in ARMS cancer treatment.

Burkitt's Lymphoma Presented as Advanced Ovarian Cancer without Evidence of Lymphadenopathy: CT and MRI Findings.

Burkitt's lymphoma is a rare non-Hodgkin's lymphoma which can occasionally involve the ovary and may cause confusion for the clinician since its presentation might mimic other much more frequent tumors. We present a case of a 23-year-old woman with sporadic Burkitt's lymphoma presented as advanced ovarian cancer with bilateral ovarian masses, peritoneal carcinomatosis, ascites, and marked elevation of CA-125. Liver involvement and atypical bone lesions, such as the cranial vault and the iliac wing, were also detected without evidence of lymphadenopathy. We describe the MRI and CT findings of simultaneous ovarian and bone lesions, which have never been reported in literature in a patient with Burkitt's lymphoma, before and after one cycle of chemotherapy. In evaluating any ovarian neoplasm in a young woman, Burkitt's lymphoma should be considered as a possibility, particularly if associated with bone lesions. MRI is the most useful tool to characterize the ovarian lesions and suggest the diagnosis before the histopathological results.

Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry.

AIM: Presenting features, treatment and outcome of 134 newborns with neuroblastoma diagnosed over a 27-year period are described. METHODS: Analyses were performed on the entire cohort and on patients distributed over three periods of diagnosis. RESULTS: Twenty-seven tumours (20.1%) were detected prenatally. Localised disease prevailed (65.7%) with an increase of stage 1 patients over time from 18.8% to 46.5%. Disseminated disease accounted for 34.3% of tumours with only one stage 4 and 45 stage 4S. Five-year overall survival (OS) of the entire cohort was 88.3%. Five/88 patients with localised disease died, including three who died of complications (OS, 95.3%). The only stage 4 patient survived. Eleven/45 stage 4S patients died, including 7/18 symptomatic and 4/27 asymptomatic (OS, 74.1%). CONCLUSION: The outcome of neuroblastoma in newborns is excellent. In localised tumours, surgery-related deaths outnumbered deaths due to disease. Symptomatic stage 4S patients were at greater risk of dying.

Conservative therapy in intraocular retinoblastoma: response/recurrence rate.

PURPOSE: To evaluate the response/recurrence rate and the outcome in intraocular retinoblastoma treated with chemoreduction and focal therapy, the authors performed a retrospective review of their patients. METHODS: The series included 46 newly diagnosed patients with unilateral or bilateral intraocular retinoblastoma (58 eyes) receiving carboplatin/etoposide chemotherapy associated with focal therapy (laser or cryotherapy). The mean follow-up was 53 months (range 11-125). RESULTS: Fifty-one eyes (88%) presented with complete response after four to eight courses of chemotherapy combined with focal treatment. The response rate was 100% in group 1, 94% in group 2, 100% in group 3, 83% in group 4, and 70% in group 5 (5 vs. 1-4, P < 0.03; 5-4 vs. 1-3, P < 0.025). Twenty-nine eyes (57%) relapsed after a mean of 7 months (range 2-36). The relapse rate was 30% in group 1, 27.% in group 2, 67% in group 3, 80% in group 4, and 100% in group 5 (5 vs. 1-4, P < 0.001; 4-5 vs. 1-3, P < 0.001). Seven of 18 cases achieved a second complete response with further conservative treatment (total courses 8-14). Twenty-nine eyes (50%) were treated without external-beam radiotherapy or enucleation: 90% in group 1, 69% in group 2, 67% in group 3, 33% in group 4, and 6% in group 5 (5 vs. 1-4, P < 0.01; 5-4 vs. 1-3, P < 0.001). Ten eyes (17%) required external-beam radiotherapy and 21 eyes (36%) enucleation. The ocular salvage rate was 67%. CONCLUSIONS: Although all groups of patients with intraocular retinoblastoma responded to carboplatin/etoposide chemotherapy associated with focal therapy, all the cases in group 5 relapsed. This approach is questionable in group 5, in which could be justified to delay aggressive treatment in a very young child.

Tropisetron: optimal dosage for children in prevention of chemotherapy-induced vomiting.

The antiemetic efficacy and tolerability of Tropisetron (Navoban, Novartis Pharma Switzerland AG, Bern), a selective 5-hydroxytriptamine receptor antagonist, has been assessed in the prevention of acute vomiting in children receiving chemotherapy for solid tumors. Tropisetron iv was given 30 min before administration of chemotherapy at a dose of 5 mg in children <20 kg body weight and at a dose of 10 mg in those >20 kg. A total of 50 children were studied in 189 courses of chemotherapy. Control of emesis was defined as total in absence of acute vomiting, as major if 1 or 2 events of acute vomiting occurred, and as not controlled if >2 events of acute vomiting occurred. Response was studied, taking into account Tropisetron dosage, degree of emetogenicity of the chemotherapeutic agents in pretreated and non-pretreated patients, and according to age groups. Tropisetron, administered in a single daily dose of 8-12 mg/m(2), was found to be very effective in completely controlling acute emesis in 92% of the courses of moderately and highly emetogenic chemotherapy administered to pediatric patients with solid tumors. Moreover, Tropisetron, at this dosage, did not lead to any adverse effects.

Nutritional status in childhood malignancies.

In children affected by tumor, nutritional status is important to sustain aggressive chemotherapy and to support normal growth during and after therapy. The aim of this study was to investigate the prevalence of nutritional status disorders in a sample of pediatric oncology day-hospital patients. We measured weight and height in patients affected by solid tumors on or off therapy at short-term follow-up (1-24 mo). The study was performed at a pediatric oncology day-hospital over a period of 20 consecutive days. A suitable computer package was used to estimate relative body weight (%RBW) and body mass index (BMI) for each patient. Thereafter, the same sample was divided into four weight classes (underweight, normal weight, overweight, and obese) according to %RBW and BMI. Moreover, patients were divided into two groups: on and off therapy. In the off-therapy group, no patient was underweight; in the on-therapy group, 26.3% and 15.8% of patients were underweight (not significant) according to %RBW and BMI, respectively. The prevalence of overweight (overweight ++obese) according to %RBW was 36.9% in the on-therapy group and 52.9% in the off-therapy group (P < 0.05); whereas the prevalence of overweight according to BMI was 21% in the on-therapy group and 35.3% in the off-therapy group (P = 0.05). These preliminary data suggest that, in pediatric oncology, nutritional assessment is required to provide nutritional strategies in on-therapy patients whose underweight status prevalence is impressive or in off-therapy children in whom the causes of overweight should be explored.