Maria Luisa Garrè

IRCCS Istituto G. Gaslini, Genova, Liguria, Italy

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Publications (101)292.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Fibrodyspasia ossificans progressiva is an autosomal dominant disease due to activating mutations in activin receptor type IA and characterized by progressive heterotopic ossification. Recently, the same non-synonymous heterozygous somatic mutations of ACVR1 have been identified in brain biopsies or autopsy of 24-27% of patients with a rare cerebral tumor, the diffuse intrinsic pontine glioma. We report the first case of a patient with FOP with incidental findings of an abnormal soft tissue mass surrounding the brainstem and causing obstructive hydrocephalus, associated with bilateral dentate lesions. Clinico-radiological course during 10 years of follow-up was consistent with a benign lesion, excluding an oncogenic role of ACVR1 mutations. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2015; DOI:10.1002/ajmg.a.37271 · 2.05 Impact Factor
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    ABSTRACT: Atypical teratoid/rhabdoid tumor (ATRT) is a rare embryonal tumor of the central nervous system with preponderance in very young children, the majority of whom are younger than 3 years of age at diagnosis. Historically, outcomes of this aggressive disease, even with extensive multimodal therapy, have been dismal. Recent improvements have come from therapies directed exclusively towards ATRT, but misdiagnosis or delays in the correct diagnosis lead to significantly worse survival rates. ATRTs most commonly occur supratentorially but have been described in virtually all central nervous system locations, including the cerebellopontine angle cistern, meninges, and spinal canal, and extradural locations. ATRTs originating from cranial nerves are rare. Here, we describe three cases of solitary ATRT arising from the 3rd cranial nerve (CN III) or close to its origin in the midbrain, all of which presented in patients within 6 months of birth, with isolated unilateral oculomotor nerve palsy and strikingly similar magnetic resonance imaging (MRI) features. These MRI features include IV contrast enhancement, relative T2 hyposignal, and restricted water diffusion on apparent diffusion coefficient images, findings which are consistent with angiogenesis and high cellularity, and hence, suggestive of malignancy. We conclude that ATRT should be placed high on the differential diagnosis list when encountering a young infant presenting with isolated, unilateral 3rd nerve palsy and a small, solitary tumor arising from CN III that demonstrates malignant conventional and diffusion-weighted imaging features on MRI.
    Journal of Neuro-Oncology 07/2015; DOI:10.1007/s11060-015-1787-0 · 2.79 Impact Factor
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    ABSTRACT: We report the finding of late persistent increased putaminal F-3,4-dihydroxyphenylalanine (DOPA) uptake following resection of a high-grade glioma involving the lateral portion of the ipsilateral precentral gyrus. Brain MRI findings were consistent with secondary putaminal degeneration. This F-DOPA PET phenomenon possibly represents elevated presynaptic dopamine function secondary to upregulation of the amino acid decarboxylase (AADC) activity, as a compensatory mechanism in response to cortical injury. In the setting of brain tumor surveillance, focal increased striatal F-DOPA uptake should be carefully interpreted in light of MRI findings and pathological changes related to corticostriatal connections.
    Clinical nuclear medicine 04/2015; DOI:10.1097/RLU.0000000000000798 · 2.86 Impact Factor
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    ABSTRACT: Primary intradural extramedullary ependymomas are very rare tumors and have never been described in children. We report on a 11-year-old girl presenting with a one-month history of neck pain, left arm weakness, paresthesia in the left hand fingers and gait disturbances. Admission MRI revealed an intradural extramedullary cystic lesion at the cervical level with craniospinal leptomeningeal nodules causing mild hydrocephalus. The multicystic lesion was surgically removed and neuropathological examination revealed a WHO Grade II ependymoma. The patient underwent adjuvant radiotherapy with progressive reduction of the metastatic nodules. At 2-year follow-up the patient was symptom-free with no evidence of recurrence on MRI. Although a rare entity, intradural extramedullary ependymomas should be included in the differential diagnosis of intradural extramedullary lesions also in children. Surgical treatment seems to play a pivotal role in the prognosis of these rare tumors, with a possible role for adjunctive radiotherapy in case of recurrence, anaplastic transformation, and metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.
    World Neurosurgery 04/2015; DOI:10.1016/j.wneu.2015.04.002 · 2.42 Impact Factor
  • Radiotherapy and Oncology 12/2014; 111:S90-S91. DOI:10.1016/S0167-8140(15)30340-6 · 4.86 Impact Factor
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    ABSTRACT: Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important.
    Journal of Clinical Immunology 09/2014; 34(8). DOI:10.1007/s10875-014-0098-0 · 2.65 Impact Factor
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    ABSTRACT: We have recently reported that glioblastoma (GB) - initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (“responder” genetic profile) can be effectively and safely radio-sensitized by the ATM inhibitor KU60019. We report here on drug’s diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy towards pediatric GIC.Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by HPLC-MS. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hours, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hours after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the “responder” profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hours after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high grade gliomas. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2014; 136(6). DOI:10.1002/ijc.29121 · 5.01 Impact Factor
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    ABSTRACT: Atypical teratoid/rhabdoid tumor (AT/RT) of the Central Nervous System and malignant rhabdoid tumor of the kidney (MRTK) may present different response to chemotherapy and outcome. We describe the case of an infant with multifocal rhabdoid tumor with different behaviour and response to treatment depending on the anatomic site.
    Cancer Genetics 08/2014; 207(9). DOI:10.1016/j.cancergen.2014.08.003 · 2.42 Impact Factor
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    ABSTRACT: We report on a 9-years-old patient with mild intellectual disability, facial dimorphisms, bilateral semicircular canal dysplasia, periventricular nodular heterotopias, bilateral hippocampal malrotation and abnormal cerebellar foliation, who developed mild motor impairment and gait disorder due to a pilocytic astrocytoma of the spinal cord. Array-CGH analysis revealed two paternal inherited chromosomal events: a 484.3 Kb duplication on chromosome 15q26.3 and a 247 Kb deletion on 22q11.23. Further, a second de novo 1.5 Mb deletion on 22q11.21 occurred. Chromosome 22 at q11.2 and chromosome 15 at q24q26 are considered unstable regions subjected to copy number variations, i.e. structural alterations of genome, mediated by low copy repeat sequences or segmental duplications. The link between some structural CNVs, which compromise fundamental processes controlling DNA stability, and genomic disorders suggest a plausible scenario for cancer predisposition. Evaluation of the genes at the breakpoints cannot account simultaneously for the phenotype and tumour development in this patient. The two paternal inherited CNVs arguably are not pathogenic and do not contribute to the clinical manifestations. Similarly, although the de novo large deletion at 22q11.21 overlaps with the Di George (DGS) critical region and results in haploinsufficiency of genes compromising critical processes for DNA stability, this case lacks several hallmarks of DGS.
    Molecular Cytogenetics 05/2014; 7:31. DOI:10.1186/1755-8166-7-31 · 2.66 Impact Factor
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    ABSTRACT: Infiltrative astrocytomas (IAs) represent a group of astrocytic gliomas ranging from low-grade to highly malignant, characterized by diffuse invasion of the brain parenchyma. When compared with their adult counterpart, pediatric IAs may be considered biologically distinct entities; nevertheless, similarly to those in adults they represent a complex oncologic challenge. The aim of this study was to investigate the diagnostic role, clinical contribution, and prognostic value of fused (18)F-3,4-dihydroxyphenylalanine ((18)F-DOPA) PET/MR images in pediatric supratentorial IAs. Pediatric patients with supratentorial IAs involving at least 2 cerebral lobes, either newly diagnosed or with suspected disease progression, prospectively underwent (18)F-DOPA PET and conventional MR imaging, performed within 10 d of each other. (18)F-DOPA PET data were interpreted qualitatively and semiquantitatively, fusing images with MR images. PET scans were classified as positive if tumors identified on MR imaging exhibited tracer uptake above the level of the corresponding contralateral normal brain. Maximum standardized uptake values, tumor-to-normal contralateral tissue ratios, and tumor-to-normal striatum ratios were calculated for all tumors. Correlations between the degree and extent of (18)F-DOPA uptake, MR imaging tumor characteristics, and histologic results were investigated. The contribution of (18)F-DOPA PET/MR image fusion was considered relevant if it enabled one to select the most appropriate biopsy site, discriminate between disease progression and treatment-related changes, or influence treatment strategy. The patient's outcome was finally correlated with (18)F-DOPA uptake. Thirteen patients (8 boys and 5 girls) were included (5 diffuse astrocytomas, 2 anaplastic astrocytomas, 5 gliomatosis cerebri, and 1 glioblastoma multiforme). The (18)F-DOPA uptake pattern was heterogeneous in all positive scans (9/13), revealing metabolic heterogeneities within each tumor. Significant differences in terms of (18)F-DOPA uptake were found between low- and high-grade lesions (P < 0.05). The diagnostic and therapeutic contribution of (18)F-DOPA PET/MR image fusion was relevant in 9 of 13 patients (69%). (18)F-DOPA uptake correlated significantly with progression-free survival (P = 0.004). Our results indicate that (18)F-DOPA PET/MR image fusion may be a reliable imaging biomarker of pediatric IAs. Information gathered by this combined imaging approach can be readily transferred to the everyday practice and may help clinicians to better stratify patients with IAs, especially diffuse astrocytomas and gliomatosis cerebri, for diagnostic, therapeutic, and prognostic purposes.
    Journal of Nuclear Medicine 03/2014; 55(5). DOI:10.2967/jnumed.113.125500 · 5.56 Impact Factor
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    ABSTRACT: 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.
    Journal of Neuro-Oncology 02/2014; 117(2). DOI:10.1007/s11060-014-1390-9 · 2.79 Impact Factor
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    ABSTRACT: Background The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days.Methods Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment.ResultsMedian age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%).ConclusionsTMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.
    Neuro-Oncology 01/2014; 16(5). DOI:10.1093/neuonc/not320 · 5.29 Impact Factor
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    ABSTRACT: Tuberous sclerosis complex is a genetic, multisystemic disorder characterized by circumscribed benign lesions (hamartomas) in several organs, including brain. This is the result of defects in the TSC1 and/or TSC2 tumor suppressor genes, encoding the hamartin-tuberin complex that inhibits the mammalian target of rapamycin pathway. Specific inhibitors of this pathway have been shown to reduce the volume of subependymal giant cell astrocytomas associated with tuberous sclerosis. Congenital lymphedema is rarely seen in association with tuberous sclerosis, with only a few reported cases. Although this association can be coincidental, the dysgenetic lymphatic system can represent a hamartia as a consequence of gene mutation. We describe a child with congenital lymphedema in tuberous sclerosis and associated subependymal giant cell astrocytoma who experienced lymphangitis under treatment with mammalian target of rapamycin inhibitors. Because our patient did not show worsening of lymphedema, congenital lymphedema does not seem to be a contraindication for this therapy.
    Journal of child neurology 09/2013; 29(9). DOI:10.1177/0883073813499969 · 1.67 Impact Factor
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    ABSTRACT: Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency. Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l1l2 that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR. We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs, but still point to an active involvement of TGF-beta signaling pathway in the PA development and pick out some hitherto unreported genes worthy of further investigation for the mixed glial-neuronal tumours. The identification of a brain region-specific gene signature suggests that LGGs, with similar pathological features but located at different sites, may be distinguishable on the basis of cancer genetics. Molecular fingerprinting seems to be able to better sub-classify such morphologically heterogeneous tumours and it is remarkable that mixed glial-neuronal tumours are strikingly separated from PAs.
    BMC Cancer 08/2013; 13(1):387. DOI:10.1186/1471-2407-13-387 · 3.32 Impact Factor
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    ABSTRACT: Microarray-based comparative genomic hybridization (array-CGH) led to the discovery of genetic abnormalities among patients with complex phenotype and normal karyotype. Also several apparently normal individuals have been found to be carriers of cryptic imbalances, hence the importance to perform parental investigations after the identification of a deletion/duplication in a proband. Here, we report the molecular cytogenetic characterization of two individuals in which the microdeletions/duplications present in their parents could have predisposed and facilitated the formation of de novo pathogenic different copy number variations (CNVs). In family 1, a 4-year-old girl had a de novo pathogenic 10.5 Mb duplication at 15q21.2q22.2, while her mother showed a 2.262 Mb deletion at 15q13.2q13.3; in family 2, a 9-year-old boy had a de novo 1.417 Mb deletion at 22q11.21 and a second paternal deletion of 247 Kb at 22q11.23 on the same chromosome 22. Chromosome 22 at band q11.2 and chromosome 15 at band q11q13 are considered unstable regions. We could hypothesize that 15q13.2q13.3 and 22q11.21 deletions in the two respective parents might have increased the risk of rearrangements in their children. This study highlights the difficulty to make genetic counseling and predict the phenotypic consequences in these situations.
    PLoS ONE 03/2013; 8(3):e57910. DOI:10.1371/journal.pone.0057910 · 3.23 Impact Factor
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    ABSTRACT: Background We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s).Methods Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy.ResultsPatients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival.Conclusions Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.
    Neuro-Oncology 03/2013; 15(6). DOI:10.1093/neuonc/not019 · 5.29 Impact Factor
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    ABSTRACT: Persons with Down syndrome (DS) uniquely have an increased frequency of leukemias but a decreased total frequency of solid tumors. The distribution and frequency of specific types of brain tumors have never been studied in DS. We evaluated the frequency of primary neural cell embryonal tumors and gliomas in a large international data set. The observed number of children with DS having a medulloblastoma, central nervous system primitive neuroectodermal tumor (CNS-PNET) or glial tumor was compared to the expected number. Data were collected from cancer registries or brain tumor registries in 13 countries of Europe, America, Asia and Oceania. The number of DS children with each category of tumor was treated as a Poisson variable with mean equal to 0.000884 times the total number of registrations in that category. Among 8,043 neural cell embryonal tumors (6,882 medulloblastomas and 1,161 CNS-PNETs), only one patient with medulloblastoma had DS, while 7.11 children in total and 6.08 with medulloblastoma were expected to have DS. (p 0.016 and 0.0066 respectively). Among 13,797 children with glioma, 10 had DS, whereas 12.2 were expected. Children with DS appear to be specifically protected against primary neural cell embryonal tumors of the CNS, whereas gliomas occur at the same frequency as in the general population. A similar protection against neuroblastoma, the principal extracranial neural cell embryonal tumor, has been observed in children with DS. Additional genetic material on the supernumerary chromosome 21 may protect against embryonal neural cell tumor development.
    Journal of Neuro-Oncology 01/2013; 112(1). DOI:10.1007/s11060-012-1041-y · 2.79 Impact Factor
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    ABSTRACT: Glioneuronal tumours are a group of primary brain neoplasms of relatively recent acquisition in the World Health Organization (WHO) Classification of the Central Nervous System tumours. In diagnostic practice it is still possible to encounter glioneuronal tumours that cannot be placed into any of the well-defined WHO categories despite a growing list of entities. We have recently published four paediatric cases of diffuse leptomeningeal tumours that cannot be easily classified in the currently used CNS WHO classification, but which have histological and immunohistochemical criteria to be considered as glioneuronal tumours. The clinical, neuroradiological and pathological long-term follow-up of an unusual diffuse leptomeningeal glioneuronal tumour is presented herein.
    Pathologica 12/2012; 104(6):428-31.

Publication Stats

1k Citations
292.49 Total Impact Points

Institutions

  • 1987–2014
    • IRCCS Istituto G. Gaslini
      • Department of Experimental and Laboratory Medicine
      Genova, Liguria, Italy
  • 2009
    • Università degli Studi di Genova
      Genova, Liguria, Italy
  • 2005
    • CRO Centro di Riferimento Oncologico di Aviano
      Aviano, Friuli Venezia Giulia, Italy