Publications by authors named "Angela Di Giannatale"

33 Publications

Establishment and Characterization of a Cell Line (S-RMS1) Derived from an Infantile Spindle Cell Rhabdomyosarcoma with Fusion Transcript.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a cell line (S-RMS1) derived from a four-month-old boy with infantile spindle cell RMS harboring gene fusion. : Morphological and molecular characteristics of S-RMS1 were analyzed and compared with two RMS cell lines, RH30 and RD18. Whole genome sequencing of S-RMS1 and clinical exome sequencing of genomic DNA were performed. : S-RMS1 showed cells small in size, with a fibroblast-like morphology and positivity for MyoD-1, myogenin, desmin, and smooth muscle actin. The population doubling time was 3.7 days. Whole genome sequencing demonstrated that S-RMS1 retained the same genetic profile of the tumor at diagnosis. A Western blot analysis showed downregulation of AKT-p and YAP-p while RT-qPCR showed upregulation of endoglin and GATA6 as well as downregulation of TGFßR1 and Mef2C transcripts. : This is the first report of the establishment of a cell line from an infantile spindle cell RMS with SRF-NCOA2 gene fusion. S-RMS1 should represent a useful tool for the molecular characterization of this rare and almost unknown tumor.
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http://dx.doi.org/10.3390/ijms22115484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196948PMC
May 2021

Radiogenomics prediction for MYCN amplification in neuroblastoma: A hypothesis generating study.

Pediatr Blood Cancer 2021 Sep 18;68(9):e29110. Epub 2021 May 18.

UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.

Background: MYCN amplification represents a powerful prognostic factor in neuroblastoma (NB) and may occasionally account for intratumoral heterogeneity. Radiomics is an emerging field of advanced image analysis that aims to extract a large number of quantitative features from standard radiological images, providing valuable clinical information.

Procedure: In this retrospective study, we aimed to create a radiogenomics model by correlating computed tomography (CT) radiomics analysis with MYCN status. NB lesions were segmented on pretherapy CT scans and radiomics features subsequently extracted using a dedicated library. Dimensionality reduction/features selection approaches were then used for features procession and logistic regression models have been developed for the considered outcome.

Results: Seventy-eight patients were included in this study, as training dataset, of which 24 presented MYCN amplification. In total, 232 radiomics features were extracted. Eight features were selected through Boruta algorithm and two features were lastly chosen through Pearson correlation analysis: mean of voxel intensity histogram (p = .0082) and zone size non-uniformity (p = .038). Five-times repeated three-fold cross-validation logistic regression models yielded an area under the curve (AUC) value of 0.879 on the training set. The model was then applied to an independent validation cohort of 21 patients, of which five presented MYCN amplification. The validation of the model yielded a 0.813 AUC value, with 0.85 accuracy on previously unseen data.

Conclusions: CT-based radiomics is able to predict MYCN amplification status in NB, paving the way to the in-depth analysis of imaging based biomarkers that could enhance outcomes prediction.
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http://dx.doi.org/10.1002/pbc.29110DOI Listing
September 2021

Autophagy and Exosomes Relationship in Cancer: Friends or Foes?

Front Cell Dev Biol 2020 12;8:614178. Epub 2021 Jan 12.

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy.

Autophagy is an intracellular degradation process involved in the removal of proteins and damaged organelles by the formation of a double-membrane vesicle named autophagosome and degraded through fusion with lysosomes. An intricate relationship between autophagy and the endosomal and exosomal pathways can occur at different stages with important implications for normal physiology and human diseases. Recent researches have revealed that extracellular vesicles (EVs), such as exosomes, could have a cytoprotective role by inducing intracellular autophagy; on the other hand, autophagy plays a crucial role in the biogenesis and degradation of exosomes. Although the importance of these processes in cancer is well established, their interplay in tumor is only beginning to be documented. In some tumor contexts (1) autophagy and exosome-mediated release are coordinately activated, sharing the molecular machinery and regulatory mechanisms; (2) cancer cell-released exosomes impact on autophagy in recipient cells through mechanisms yet to be determined; (3) exosome-autophagy relationship could affect drug resistance and tumor microenvironment (TME). In this review, we survey emerging discoveries relevant to the exosomes and autophagy crosstalk in the context of cancer initiation, progression and recurrence. Consequently, we discuss clinical implications by targeting autophagy-exosomal pathway interaction and how this could lay a basis for the purpose of novel cancer therapeutics.
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http://dx.doi.org/10.3389/fcell.2020.614178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835528PMC
January 2021

Clinical, Genetic, and Prognostic Features of Adrenocortical Tumors in Children: A 10-Year Single-Center Experience.

Front Oncol 2020 15;10:554388. Epub 2020 Oct 15.

Department of Paediatric Haematology/Oncology Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Pediatric adrenocortical tumors (ACTs) are very rare endocrine neoplasms in childhood. In this study, we performed a retrospective analysis of children with ACT treated at our institution by examining clinical and genetic disease features, treatment strategies, and outcomes. We retrospectively analyzed a cohort of 13 children treated at the Bambino Gesù Children's Hospital from November 2010 to March 2020. The median age at diagnosis was 17 months (range = 0-82 months). The female: male ratio was 3.3/1. Mixed symptomatology (>1 hormone abnormality) was the most common presentation (46.1%). In three cases, the tumor was detected during prenatal or perinatal echographic screening. All patients presented with localized disease at diagnosis and underwent total adrenalectomy. Six patients were identified as having malignancies according to the Wieneke scoring system, five benign, and two undetermined. Seven patients underwent mitotane adjuvant therapy for 12 months. There was metastatic disease in three patients, with no correlation with age or Wieneke score. The most common sites of metastases were the liver and lungs. Metastatic patients were treated with surgery ( = 2), mitotane ( = 1), chemotherapy ( = 2) associated with anti-EGFR ( = 1), or immunotherapy with anti-PD1 (pembrolizumab) ( = 1); two patients achieved complete disease remission. Overall 2- and 5-year survival rates were 100%, with a median follow-up of 5 years (range = 2-9.5 years). Two- and 5-year disease free survival was 76.9 and 84.6%, respectively (95% confidence interval = -66.78-114.76 months). All patients are alive, 12 without disease, and one with stable disease. Genetic analyses showed TP53 germline mutations in six of eight patients analyzed (five inherited, one ). One patient had Beckwith-Wiedemann syndrome, with mosaic paternal uniparental disomy of chromosome 11, in both neoplastic and healthy adrenal tissue. We report the cases of 13 patients treated for ACT, including 12 aged <4 years at diagnosis, with a relative short time from symptoms onset. Our cohort experienced an excellent prognosis. TP53 mutation was found in 75% of tested patients (6/8) confirming the need to perform genetic tests and familial counseling in this disease.
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http://dx.doi.org/10.3389/fonc.2020.554388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593337PMC
October 2020

Integration of Multiple Platforms for the Analysis of Multifluorescent Marking Technology Applied to Pediatric GBM and DIPG.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, 00146 Rome, Italy.

The intratumor heterogeneity represents one of the most difficult challenges for the development of effective therapies to treat pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG). These brain tumors are composed of heterogeneous cell subpopulations that coexist and cooperate to build a functional network responsible for their aggressive phenotype. Understanding the cellular and molecular mechanisms sustaining such network will be crucial for the identification of new therapeutic strategies. To study more in-depth these mechanisms, we sought to apply the Multifluorescent Marking Technology. We generated multifluorescent pGBM and DIPG bulk cell lines randomly expressing six different fluorescent proteins and from which we derived stable optical barcoded single cell-derived clones. In this study, we focused on the application of the Multifluorescent Marking Technology in 2D and 3D in vitro/ex vivo culture systems. We discuss how we integrated different multimodal fluorescence analysis platforms, identifying their strengths and limitations, to establish the tools that will enable further studies on the intratumor heterogeneity and interclonal interactions in pGBM and DIPG.
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http://dx.doi.org/10.3390/ijms21186763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555235PMC
September 2020

Neuroblastoma-secreted exosomes carrying miR-375 promote osteogenic differentiation of bone-marrow mesenchymal stromal cells.

J Extracell Vesicles 2020 Jun 3;9(1):1774144. Epub 2020 Jun 3.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Bone marrow (BM) is the major target organ for neuroblastoma (NB) metastasis and its involvement is associated with poor outcome. Yet, the mechanism by which NB cells invade BM is largely unknown. Tumour microenvironment represents a key element in tumour progression and mesenchymal stromal cells (MSCs) have been recognized as a fundamental part of the associated tumour stroma. Here, we show that BM-MSCs isolated from NB patients with BM involvement exhibit a greater osteogenic potential than MSCs from non-infiltrated BM. We show that BM metastasis-derived NB-cell lines secrete higher levels of exosomal miR-375, which promotes osteogenic differentiation in MSCs. Of note, clinical data demonstrate that high level of miR-375 correlates with BM metastasis in NB patients. Our findings suggest, indeed, a potential role for exosomal miR-375 in determining a favourable microenvironment in BM to promote metastatic progression. MiR-375 may, thus, represent a novel biomarker and a potential target for NB patients with BM involvement.
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http://dx.doi.org/10.1080/20013078.2020.1774144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448845PMC
June 2020

A Chart Review on the Feasibility and Safety of the Vincristine Irinotecan Pazopanib (VIPaz) Association in Children and Adolescents With Resistant or Relapsed Sarcomas.

Front Oncol 2020 6;10:1228. Epub 2020 Aug 6.

Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Pediatric patients with relapsed or refractory sarcomas have poor outcome and need novel therapies that provide disease control while maintaining an acceptable quality of life. The safety of vincristine, irinotecan, and pazopanib (VIPaz) association has not yet been published in this population. A chart review was conducted in children and adolescents with relapsed or refractory bone and soft tissue sarcomas who received VIPaz in our institution. One hundred sixty-six patients with a diagnosis of soft or bone sarcoma were admitted to our hospital in the period between March 2015 and August 2018, 30 were relapsed or resistant. Seventeen out of 30 resistant or relapsed patients (median age, 14 years) received 114 VIPaz cycles (median six cycles per patient, range 1-17). Sixteen courses (15%) resulted in gastrointestinal toxicity with Grade two diarrhea; 35 courses (30%) resulted in Grade ≥3 neutropenia. One patient presented Grade two hypothyroidism after nine courses, and another one had Grade two hyperbilirubinemia after 12 courses. Two and five patients required a 25% dose reduction of irinotecan (because of diarrhea) and pazopanib (because of neutropenia four and hyperbilirubinemia 1), respectively. No patient experienced heart failure, hypertension, nor posterior reversible encephalopathy syndrome. Pneumothorax was not reported in any case even in lung metastatic patients. After two and four VIPaz cycles, we observed one complete response (CR), five partial responses (PRs), seven stable diseases (SDs), and four progressive diseases (PDs). With a median follow-up of 15 months (range 3-32), five out of 17 (29%) patients were alive, and four patients were in continuous CR after 12 VIPaz cycles. The VIPaz regimen might be a safe option in children and adolescents with relapsed or refractory sarcomas otherwise unable to be enrolled in other clinical trials; on the other hand, the efficacy of pazopanib observed cannot be sustained from the current study.
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http://dx.doi.org/10.3389/fonc.2020.01228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425124PMC
August 2020

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

Cell 2020 08 13;182(4):1044-1061.e18. Epub 2020 Aug 13.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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http://dx.doi.org/10.1016/j.cell.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522766PMC
August 2020

Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa075. Epub 2020 Jun 9.

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.

Background: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation.

Methods: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922).

Results: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m weekly for vinblastine with 230 mg/m BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67).

Conclusions: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.
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http://dx.doi.org/10.1093/noajnl/vdaa075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344116PMC
June 2020

Proteomic Profiling of Retinoblastoma-Derived Exosomes Reveals Potential Biomarkers of Vitreous Seeding.

Cancers (Basel) 2020 06 12;12(6). Epub 2020 Jun 12.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Pediatrico Bambino Gesù, Piazza Sant'Onofrio 4, 00165 Rome, Italy.

Retinoblastoma (RB) is the most common tumor of the eye in early childhood. Although recent advances in conservative treatment have greatly improved the visual outcome, local tumor control remains difficult in the presence of massive vitreous seeding. Traditional biopsy has long been considered unsafe in RB, due to the risk of extraocular spread. Thus, the identification of new biomarkers is crucial to design safer diagnostic and more effective therapeutic approaches. Exosomes, membrane-derived nanovesicles that are secreted abundantly by aggressive tumor cells and that can be isolated from several biological fluids, represent an interesting alternative for the detection of tumor-associated biomarkers. In this study, we defined the protein signature of exosomes released by RB tumors (RBT) and vitreous seeding (RBVS) primary cell lines by high resolution mass spectrometry. A total of 5666 proteins were identified. Among these, 5223 and 3637 were expressed in exosomes RBT and one RBVS group, respectively. Gene enrichment analysis of exclusively and differentially expressed proteins and network analysis identified in RBVS exosomes upregulated proteins specifically related to invasion and metastasis, such as proteins involved in extracellular matrix (ECM) remodeling and interaction, resistance to anoikis and the metabolism/catabolism of glucose and amino acids.
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http://dx.doi.org/10.3390/cancers12061555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352325PMC
June 2020

DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor () Alterations.

Int J Mol Sci 2020 Mar 6;21(5). Epub 2020 Mar 6.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors in the pediatric population. Molecular techniques are instrumental for the categorization and differential diagnosis of these tumors. A subgroup of recently identified soft tissue sarcomas with undifferentiated round cell morphology was characterized by Capicua transcriptional receptor () rearrangements. Recently, an array-based DNA methylation analysis of undifferentiated tumors with small blue round cell histology was shown to provide a highly robust and reproducible approach for precisely classifying this diagnostically challenging group of tumors. We describe the case of an undifferentiated sarcoma of the abdominal wall in a 12-year-old girl. The patient presented with a voluminous mass of the abdominal wall, and multiple micro-nodules in the right lung. The tumor was unclassifiable with current immunohistochemical and molecular approaches. However, DNA methylation profiling allowed us to classify this neoplasia as small blue round cell tumor with alterations. The patient was treated with neoadjuvant chemotherapy followed by complete surgical resection and adjuvant chemotherapy. After 22 months, the patient is disease-free and in good clinical condition. To put our experience in context, we conducted a literature review, analyzing current knowledge and state-of-the-art diagnosis, prognosis, and clinical management of rearranged sarcomas. Our findings further support the use of DNA methylation profiling as an important tool to improve diagnosis of non-Ewing small round cell tumors.
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http://dx.doi.org/10.3390/ijms21051818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084764PMC
March 2020

Pediatric gastrointestinal stromal tumor: Report of two novel patients harboring germline variants in SDHB and SDHC genes.

Cancer Genet 2020 02 16;241:61-65. Epub 2019 Dec 16.

Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and rarely occur in pediatric patients. 85% of pediatric GISTs and 15% of adult GISTs lack of KIT or PDGFRA mutations. 40% of these "wild-type" GISTs present loss of function mutations in genes encoding for the subunits of the succinate dehydrogenase (SDH) complex. Germline mutations in SDH complex genes have been described in patients with the Carney-Stratakis syndrome (CSS), a rare inherited condition that predisposes to GIST and paraganglioma. We report two pediatric patients with multifocal GIST, harboring respectively a novel and a previously reported loss-of-function germline variant, in SDHC and SDHB genes.
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http://dx.doi.org/10.1016/j.cancergen.2019.12.002DOI Listing
February 2020

Exosomal MiRNAs in Pediatric Cancers.

Int J Mol Sci 2019 Sep 17;20(18). Epub 2019 Sep 17.

Department of Pediatric Hematology/Oncology, IRCCS, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.

MicroRNAs (miRNAs) have generated great attention in oncology as they play a fundamental role in the regulation of gene expression and their aberrant expression is present in almost all types of tumors including pediatric ones. The discovery that miRNAs can be transported by exosomes, which are vesicles of 40-120 nm involved in cellular communication, that are produced by different cell types, and that are present in different biological fluids, has opened the possibility of using exosomal miRNAs as biomarkers. The possibility to diagnose and monitor the progression and response to drugs through molecules that can be easily isolated from biological fluids represents a particularly important aspect in the pediatric context where invasive techniques are often used. In recent years, the idea of liquid biopsy as well as studies on the possible role of exosomal miRNAs as biomarkers have developed greatly. In this review, we report an overview of all the evidences acquired in recent years on the identification of exosomal microRNAs with biomarker potential in pediatric cancers. We discuss the following herein: neuroblastoma, hepatoblastoma, sarcomas (osteosarcoma, Ewing's sarcoma and rhabdoid tumors, and non-rhabdomyosarcoma soft tissue sarcoma), brain tumors, lymphomas, and leukemias.
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http://dx.doi.org/10.3390/ijms20184600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770697PMC
September 2019

Exosomes in Systemic Sclerosis: Messengers Between Immune, Vascular and Fibrotic Components?

Int J Mol Sci 2019 09 4;20(18). Epub 2019 Sep 4.

Unit of Endocrinology, Department of Movement, Human and Health Sciences, Università degli Studi di Roma "Foro Italico", Piazza Lauro de Bosis, 600135 Rome, Italy.

Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered incurable and is associated with a high risk of mortality, which is related to fibrotic events. An early diagnosis is useful for preventing complications, and targeted therapies reduce disease progression and ameliorate patients' quality of life. Nevertheless, there are no validated biomarkers for early diagnosis with predictive prognostic value. Exosomes are membrane vesicles, transporting proteins and nucleic acids that may be delivered to target cells, which influences cellular behavior. They play important roles in cell-cell communication, both in physiological and pathological conditions, and may be useful as circulating biomarkers. Recent evidences suggest a role for these microvesicles in the three main aspects related to the pathogenesis of SSc (immunity, vascular damage, and fibrosis). Moreover, exosomes are of particular interest in the field of nano-delivery and are used as biological carriers. In this review, we report the latest information concerning SSc pathogenesis, clinical aspects of SSc, and current approaches to the treatment of SSc. Furthermore, we indicate a possible role of exosomes in SSc pathogenesis and suggest their potential use as diagnostic and prognostic biomarkers, as well as therapeutic tools.
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http://dx.doi.org/10.3390/ijms20184337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770454PMC
September 2019

Expression profiles of exosomal miRNAs isolated from plasma of patients with desmoplastic small round cell tumor.

Epigenomics 2019 04 20;11(5):489-500. Epub 2018 Dec 20.

Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant' Onofrio, 4, 00165 Rome, Italy.

Aim: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive mesenchymal tumor, lacking biomarkers for diagnosis, treatment stratification and prognosis. We investigated the exosomal miRNA profile in plasma samples collected from DSRCT patients, evaluating their potential as circulating biomarkers for this tumor.

Patients & Methods: We isolated exosomes from plasma of three DSRCT adolescents and four age-matched healthy controls; expression of circulating miRNAs was quantified by qPCR.

Results: We identified 55 miRNAs significantly modulated compared with healthy controls. Among these miRNAs, 14 were highly dysregulated in at least one patient and 5 were expressed in all patients.

Conclusion: To our knowledge, this is the first report describing exosomal miRNAs as promising biomarkers to characterize disease status in DSRCT patients.
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http://dx.doi.org/10.2217/epi-2018-0179DOI Listing
April 2019

Circulating Biomarkers for Tumor Angiogenesis: Where Are We?

Curr Med Chem 2020 ;27(14):2361-2380

Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy.

Background: In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment.

Objectives: The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy.

Results: We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling.

Conclusion: Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.
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http://dx.doi.org/10.2174/0929867325666180821151409DOI Listing
July 2020

Congenital Extra-Ventricular (Ganglio)Neurocytoma of the Brain Stem: A Case Report.

Front Pediatr 2018 11;6:108. Epub 2018 May 11.

Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy.

Extraventricular neurocytoma (EVN) is an extremely rare tumor of neuroglial origin with a tendency toward ganglionic or glial differentiation. In the 2016 World Health Organization Classification, EVN was classified as a grade II tumor and described as a neoplasm with good outcome. However, the presence of cellular atypia is an important unfavorable prognostic factor. Here, we describe the first case of a patient with a congenital EVN localized in the brainstem. After a sub-total resection, his disease rapidly progressed despite several chemotherapies, including molecular targeting approaches. He died 13 months after diagnosis. In conclusion, we report an atypical case of EVN presenting an extremely aggressive behavior, despite the absence of cellular atypia. The brainstem origin and the age of the patient may have represented two important prognostic factors for our patient.
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http://dx.doi.org/10.3389/fped.2018.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958410PMC
May 2018

Congenital Rhabdomyosarcoma: a different clinical presentation in two cases.

BMC Pediatr 2018 05 15;18(1):166. Epub 2018 May 15.

Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.

Background: Rhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4-2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported.

Case Presentation: We describe two cases with congenital RMS treated at Bambino Gesù Children's Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up.

Conclusions: RMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613-20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets.
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http://dx.doi.org/10.1186/s12887-018-1128-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953406PMC
May 2018

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma.

BMC Cancer 2018 01 5;18(1):31. Epub 2018 Jan 5.

Department of Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4, 00165, Rome, Italy.

Background: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31.

Methods: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients.

Results: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio.

Conclusion: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.
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http://dx.doi.org/10.1186/s12885-017-3947-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755407PMC
January 2018

Intraspinal mesenchymal chondrosarcoma: report of a pediatric case and literature review.

Tumori 2017 Nov 15;103(Suppl. 1):e66-e72. Epub 2017 Nov 15.

Department of hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome - Italy.

Purpose: Mesenchymal chondrosarcoma (MCS) is an aggressive variant of chondrosarcoma and is a rare tumor, particularly within the pediatric population. Commonly, MCS originates in the bone, but it can also arise in extraskeletal sites, such as the brain and the intraspinal area. Due to the rarity of this tumor, there are no guidelines for its optimal treatment.

Methods: We report a case of intradural extramedullary MCS, located at the T11-T12 level, in a 14-year-old male. The tumor was documented by magnetic resonance imaging and treated with gross total resection (GTR) without adjuvant treatment. We further reviewed the relevant pediatric literature and discussed the management and outcome of intracranial and intraspinal MCS.

Results: The patient's follow-up showed no evidence of disease 2 years from diagnosis. A total of 51 cases of intracranial and intraspinal MCS have been reported (24 intraspinal and 27 intracranial). Recurrence has been described in only 4 patients with intraspinal MSC, and among them 3 received adjuvant chemotherapy and radiotherapy. GTR seems to reduce the risk of recurrence and, due to a higher cancer-mortality rate for these patients, adjuvant chemotherapy and radiotherapy are recommended in case aggressive surgery is not possible.

Conclusions: According to our single experience, we would suggest that adjuvant therapy might be unnecessary in cases where a localized MCS undergoes GTR. Chemotherapy and radiotherapy should be recommended when GTR cannot be obtained. Further studies are needed to investigate a standard treatment approach for this rare tumor.
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http://dx.doi.org/10.5301/tj.5000689DOI Listing
November 2017

MicroRNAs in Neuroblastoma: Biomarkers with Therapeutic Potential.

Curr Med Chem 2018 Feb;25(5):584-600

Department of Hematology/Oncology, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.

Background: Neuroblastoma is the most common extracranial solid tumor in infancy. The majority of children have a disseminated disease at diagnosis with bone marrow as the most common site of metastasis. Although several prognostic factors have been defined (i.e. age, stage, histology, recurrent genetic anomalies), the identification of non-invasive biomarkers for disease follow-up and therapy monitoring is indeed still a clinical need. Aberrant regulation of microRNAs (miRNAs) expression has been implicated in several malignancies.

Objectives: In this mini-review, we describe the recent findings about miRNAs in neuroblastoma, both in the tumor and circulation, with particular focus on those involved in tumor progression and drug resistance. Furthermore, we will discuss the use of specific miRNAs as potential therapeutic tools in this tumor.

Results: Several miRNAs have been identified to be down- or up-regulated in primary tumors and have been associated with MYCN amplification, differentiation, dissemination and chemoresistance. Little evidence is available in the literature about circulating miRNAs which are of particular interest as potential biomarkers for liquid biopsy.

Conclusion: Identification of body-fluid markers for non-invasive diagnosis, risk stratification, treatment monitoring and tumor follow-up, is gaining growing interest, especially in the pediatric field. miRNAs are suitable candidates as biomarkers in neuroblastoma but further investigations are needed to expand knowledge regarding their role in this malignancy to design specific approaches of miRNAs-mediated therapies.
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http://dx.doi.org/10.2174/0929867324666171003120335DOI Listing
February 2018

Proteomic Analysis of Neuroblastoma-Derived Exosomes: New Insights into a Metastatic Signature.

Proteomics 2017 Dec 12;17(23-24). Epub 2017 Sep 12.

Department of Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Around 70% of patients with metastatic disease at diagnosis present bone-marrow infiltration, which is considered a marker of poor outcome; however, the mechanism underlying this specific tropism has to be elucidated. Tumor-derived exosomes may support metastatic progression in several tumors by interacting with the microenvironment, and may serve as tumor biomarkers. The main objective of this study is to identify an exosomal signature associated with NB metastatic bone-marrow dissemination. Therefore, the proteomic cargo of exosomes isolated from NB cell lines derived from primary tumor and bone-marrow metastasis is characterized. The comparison among exosomal proteins show 15 proteins exclusively present in primary tumor-derived exosomes, mainly involved in neuronal development, and 6 proteins in metastasis-derived exosomes related to cancer progression. Significant proteins obtain with statistical analysis performed between the two groups, reveal that primary tumor exosomes contain a higher level of proteins involved in extra-cellular matrix (ECM) assembly and adhesion, as well as in neuronal development. Exosomes isolated from bone-marrow metastasis exhibit proteins involved in ameboidal cell migration and mitochondrial activity. This work suggests that proteomic profiling of NB-derived exosomes reflects the tumor stage and may be considered as potential tumor biomarker.
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http://dx.doi.org/10.1002/pmic.201600430DOI Listing
December 2017

Nano-Delivery in Pediatric Tumors: Looking Back, Moving Forward.

Anticancer Agents Med Chem 2017 ;17(10):1328-1343

Bambino Gesu Children's Hospital, IRCCS-Department of Pediatric Hematology/Oncology and Stem Cell Transplantation Rome. Italy.

Recent advances in the treatment of pediatric tumors led to an improvement of survival in this population. As a result, many pediatric survivors experience long-term effects that impact their quality of life. Therefore, it is extremely important to identify new treatment approaches that may target the tumor minimizing the drug-related side effects. Over the past 10 years, remarkable advances in nanomedicine have provided several potential tools for cancer treatment. Recently, there has been a growing interest towards therapeutic nanocarriers in the pediatric field, since they represent a new strategy to enhance the drug efficacy and reduce the toxicity. Various nanoformulations have been developed to improve the targeting and the release of antitumor compound to cancer cells in pediatric tumors and clinical trials have been conducted or are ongoing. Exosomes are nanometer-sized vesicles that play a crucial role in mediating intercellular communication. Thanks to to their intrinsic cell targeting properties, stability in the circulation, and bio-compatibility, they are emerging as new promising vehicles both for drugs and biological therapeutics. Moreover, these nanovesicles are a reservoir of potential diagnostic and prognostic markers. In this review, we describe recent advances in the treatment of pediatric tumors through nanodelivery system with particular attention to neuroblastoma, soft-tissues/bone sarcomas and pediatric brain tumors. Furthermore, we explore the potential role of exosomes as an effective option of nanodelivery providing insights into their characteristics in pediatric tumors and their use in adult clinical trials.
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http://dx.doi.org/10.2174/1871520617666170103101141DOI Listing
October 2017

Anomalous vascularization in a Wnt medulloblastoma: a case report.

BMC Neurol 2016 Jul 15;16:103. Epub 2016 Jul 15.

Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4 - 00165, Rome, Italy.

Background: Medulloblastoma is the most common malignant brain tumor in children. To date only few cases of medulloblastoma with hemorrhages have been reported in the literature. Although some studies speculate on the pathogenesis of this anomalous increased vascularization in medulloblastoma, the specific mechanism is still far from clearly understood. A correlation between molecular medulloblastoma subgroups and hemorrhagic features has not been reported, although recent preliminary studies described that WNT-subtype tumors display increased vascularization and hemorrhaging.

Case Presentation: Herein, we describe a child with a Wnt-medulloblastoma presenting as cerebellar-vermian hemorrhagic lesion. Brain magnetic resonance imaging (MRI) showed the presence of a midline posterior fossa mass with a cystic hemorrhagic component. The differential diagnosis based on imaging included cavernous hemangioma, arteriovenous malformation and traumatic lesion. At surgery, the tumor appeared richly vascularized as documented by the preoperative angiography.

Conclusions: The case we present showed that Wnt medulloblastoma may be associated with anomalous vascularization. Further studies are needed to elucidate if there is a link between the hypervascularization and the Wnt/β-catenin signaling activation and if this abnormal vasculature might influence drug penetration contributing to good prognosis of this medulloblastoma subgroup.
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http://dx.doi.org/10.1186/s12883-016-0632-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946170PMC
July 2016

Tumour exosome integrins determine organotropic metastasis.

Nature 2015 Nov 28;527(7578):329-35. Epub 2015 Oct 28.

Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden.

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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http://dx.doi.org/10.1038/nature15756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788391PMC
November 2015

Primary cutaneous and subcutaneous Ewing sarcoma.

Pediatr Blood Cancer 2015 Sep 20;62(9):1555-61. Epub 2015 Apr 20.

MD, Pediatric and Adolescent Oncology, Gustave Roussy, 114 Rue Eduard Vaillant, 94805, Villejuif, France.

Background: Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization.

Procedure: Retrospective study (1996-2012) on 56 patients.

Results: Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/53). Thirty and 25 patients received chemotherapy according to Euro-Ewing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1-15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n = 3, metastatic n = 1). Survival was excellent: 5y-OS and 5y-EFS were 93.8% (95%CI = 83-98%) and 88.5% (95%CI-= 77-95), respectively.

Conclusions: Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities.
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http://dx.doi.org/10.1002/pbc.25535DOI Listing
September 2015

The new deal: a potential role for secreted vesicles in innate immunity and tumor progression.

Front Immunol 2015 24;6:66. Epub 2015 Feb 24.

Children's Cancer and Blood Foundation Laboratories, Department of Pediatrics, Weill Cornell Medical College , New York, NY , USA ; Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.

Tumors must evade the immune system to survive and metastasize, although the mechanisms that lead to tumor immunoediting and their evasion of immune surveillance are far from clear. The first line of defense against metastatic invasion is the innate immune system that provides immediate defense through humoral immunity and cell-mediated components, mast cells, neutrophils, macrophages, and other myeloid-derived cells that protect the organism against foreign invaders. Therefore, tumors must employ different strategies to evade such immune responses or to modulate their environment, and they must do so prior metastasizing. Exosomes and other secreted vesicles can be used for cell-cell communication during tumor progression by promoting the horizontal transfer of information. In this review, we will analyze the role of such extracellular vesicles during tumor progression, summarizing the role of secreted vesicles in the crosstalk between the tumor and the innate immune system.
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http://dx.doi.org/10.3389/fimmu.2015.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338782PMC
March 2015

Patients in pediatric phase I and early phase II clinical oncology trials at Gustave Roussy: a 13-year center experience.

J Pediatr Hematol Oncol 2015 Mar;37(2):e102-10

Departments of *Pediatric and Adolescent Oncology †Biostatistics and Epidemiology ‡Radiology §CNRS UMR 8203 Vectorology and Anticancer Therapeutics, Université Paris-Sud 11, Gustave Roussy, Villejuif, France.

In the European Union, the pediatric medicines regulation in 2007 modified significantly the access to new agents in pediatric oncology. Early oncology trials are still thought to be associated with limited benefit and substantial risk. We report the characteristics and outcome of patients below 21 years enrolled in investigational trials in the Pediatric and Adolescent Department at Gustave Roussy between January 2000 and December 2012. A total of 235 patients (median age, 10.4 [0.8 to 20.7] y) were included in 26 trials (16 cytotoxic and 10 targeted agents) for a total of 260 inclusions. A total of 117 patients (50%) had brain tumors and 68 (29%) had various soft tissue and bone sarcoma. Thirteen of the 106 patients in a phase I trial experienced dose-limiting toxicity. Main severe toxicity was hematologic; none had toxic death. Grade 3 to 4 toxicities were associated with combination trials, cytotoxic agent, and at least 1 previous line of therapy. Thirty patients (12%) had objective response and 42 (16%) had stable disease for >4 months. Median overall survival was 9.0 months (95% CI, 7.5-10.5) and 73% of patients received further anticancer treatment. Phase I to II pediatric oncology trials are safe, associated with clinical benefit, and can be successfully integrated in current relapse strategies.
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http://dx.doi.org/10.1097/MPH.0000000000000237DOI Listing
March 2015

Natural history of cavernous malformations in children with brain tumors treated with radiotherapy and chemotherapy.

J Neurooncol 2014 Apr 11;117(2):311-20. Epub 2014 Feb 11.

Neuro-Oncology, Istituto Giannina Gaslini, Genova, Italy,

Cavernous malformations (CM) are cerebral irradiation-related late complications. Little is known about their natural history and the pathogenetic role of concomitant chemotherapy. We present a retrospective, single-institution study of 108 children affected with medulloblastoma, ependymoma, or germinoma treated with radio- and chemotherapy. The frequency, clinical and radiological presentations, and outcomes were analyzed to investigate the relationship among radiation dose, associated chemotherapy, age, latency and localization of radiation-induced CM. 100 out of 108 children were treated with radiotherapy for primary brain tumor; 34 (27 with medulloblastoma and 7 with other histologies) out of 100 patients developed CM. No significant relationship was found between CM and gender (p = 0.70), age (p = 0.90), use of specific chemotherapy (standard versus high-dose, p = 0.38), methotrexate (p = 0.49), and radiation dose (p = 0.45). However, CM developed more frequently and earlier when radiotherapy was associated with methotrexate (70 % of cases). Radiation-induced CM prevailingly occurred in the cerebral hemispheres (p = 0.0001). Only 3 patients (9 %) were symptomatic with headache. Three patients underwent surgery for intra- or extra-lesional hemorrhage. CM was confirmed by histopathology for all 3 patients. The vast majority of radiation-induced CM is asymptomatic, and macro-hemorrhagic events occur rarely. Concomitant therapy with methotrexate seems to favor their development. We recommend observation for asymptomatic lesions, while surgery should be reserved to symptomatic growth or hemorrhage.
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http://dx.doi.org/10.1007/s11060-014-1390-9DOI Listing
April 2014

Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.

Eur J Cancer 2014 Jan 7;50(1):170-7. Epub 2013 Sep 7.

Hôpital des Enfants, 330 Avenue de Grande Bretagne, 31059 Toulouse Cedex 9, France. Electronic address:

Purpose: To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma.

Patients And Methods: This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently.

Results: Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia.

Conclusion: Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.
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http://dx.doi.org/10.1016/j.ejca.2013.08.012DOI Listing
January 2014
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