Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with ...enhanced levels of the c-MYC oncogene (MB
Group3
) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MB
Group3
stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MB
Group3
stem cells
,
and a combined anti-autophagy and anti-STAT3 approach impacts the MB
Group3
outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MB
Group3
.
Abstract Background Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood tumor with dismal prognosis. Emerging molecular signatures have paved the way for stereotactic biopsy in selected Centers. ...We present our experience in DIPG stereotactic needle biopsy using the Robotic Stereotactic Assisted system (ROSA™) in a consecutive pediatric series. Methods All stereotactic biopsy procedures for DIPG performed during the last year at our Institution were considered. All procedures were carried out using the ROSA™ surgical assistant through a precoronary approach. All children underwent a post-operative CT scan to document possible surgical complications and confirm the site of biopsy. Post-operative clinical changes were recorded to test morbidity of the procedure. Results In the last year we performed 7 pontine needle biopsies. Specimens were diagnostic and useful for molecular analysis in all cases. No surgical complications were observed. One child showed a transient neurological worsening related to the biopsy that resolved within 2 weeks. The combination of the precoronary approach and use of the stereotactic ROSA™ system allowed single-session surgeries in all cases. Conclusions Pontine biopsy for DIPG is a safe procedure in selected Centers. The advantages of the single-session procedure we described might be of particular interest in the pediatric setting.
DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the
gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the ...age of 60.
variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir).
gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.
Purpose of the Report
Paediatric diffuse high-grade gliomas (PDHGG) are rare central nervous system neoplasms lacking effective therapeutic options. Molecular imaging of tumour metabolism might ...identify novel diagnostic/therapeutic targets. In this study, we evaluated the distribution and the dosimetry aspects of
64
CuCuCl
2
in PDHGG subjects, as copper is a key element in cellular metabolism whose turnover may be increased in tumour cells.
Material and Methods
Paediatric patients with PDHGG were prospectively recruited.
64
CuCuCl
2
PET/CT was performed 1 h after tracer injection; if the scan was positive, it was repeated 24 and 72 h later. Lesion standardised uptake value (SUV) and target-to-background ratio (TBR) were calculated. Tumour and organ dosimetry were computed using the MIRD algorithm. Each patient underwent an MRI scan, including FLAIR, T2-weighted and post-contrast T1-weighted imaging.
Results
Ten patients were enrolled (median age 9, range 6–16 years, 6 females). Diagnoses were diffuse midline gliomas (
n
= 8, 5 of which with H3K27 alterations) and diffuse hemispheric gliomas (
n
= 2). Six patients had visible tracer uptake (SUV: 1.0 ± 0.6 TBR: 5 ± 3.1).
64
CuCuCl
2
accumulation was always concordant with MRI contrast enhancement and was higher in the presence of radiological signs of necrosis. SUV and TBR progressively increased on the 24- and 72-h acquisitions (
p
< 0.05 and
p
< 0.01, respectively). The liver and the abdominal organs received the highest non-target dose.
Conclusions
64
CuCuCl
2
is a well-tolerated radiotracer with reasonably favourable dosimetric properties, showing selective uptake in tumour areas with visible contrast enhancement and necrosis, thus suggesting that blood–brain barrier damage is a pre-requisite for its distribution to the intracranial structures. Moreover, tracer uptake showed an accumulating trend over time. These characteristics could deserve further analysis, to determine whether this radiopharmaceutical might have a possible therapeutic role as well.
Background:
Diffuse intrinsic pontine glioma (DIPG) is a fatal disease with a median overall survival (OS) of less than 12 months after diagnosis. Radiotherapy (RT) still remains the mainstay ...treatment. Several other therapeutic strategies have been attempted in the last years without a significant effect on OS. Although radiological imaging is the gold standard for DIPG diagnosis, the urgent need to improve the survival has led to the reconsideration of biopsy with the aim to better understand the molecular profile of DIPG and support personalized treatment.
Methods:
In this study, we present a single-center experience in treating DIPG patients at disease progression combining targeted therapies with standard of care. Biopsy was proposed to all patients at diagnosis or disease progression. First-line treatment included RT and nimotuzumab/vinorelbine or temozolomide. Immunohistochemistry-targeted research included study of mTOR/p-mTOR pathway and BRAFv600E. Molecular analyses included polymerase chain reaction, followed by Sanger sequences and/or next-generation sequencing.
Results:
Based on the molecular profile, targeted therapy was administered in 9 out of 25 patients, while the remaining 16 patients were treated with standard of care. Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (5/9), PI3K/AKT/mTOR pathway and BRAFv600E (1/9), ACVR1 (2/9) and PDGFRA (1/9); no severe side effects were reported during treatment. Response to treatment was evaluated according to Response Assessment in Pediatric Neuro-Oncology criteria, and the overall response rate within the cohort was 66%. Patients treated with targeted therapies were compared with the control cohort of 16 patients. Clinical and pathological characteristics of the two cohorts were homogeneous. Median OS in the personalized treatment and control cohort was 20.26 and 14.18 months, respectively (p = 0.032). In our experience, the treatment associated with the best OS was everolimus.
Conclusion:
Despite the small simple size of our study, our data suggest a prognostic advantage and a safe profile of targeted therapies in DIPG patients, and we strongly advocate to reconsider the role of biopsy for these patients.
Low-grade gliomas (LGG) are the most common central nervous system tumors in children. Prognosis depends on complete surgical resection. For patients not amenable of gross total resection (GTR) new ...approaches are needed. The
mutation V600E is critical for the pathogenesis of pediatric gliomas and specific inhibitors of the mutated protein, such as Vemurafenib, are available. We investigated the safety and efficacy of Vemurafenib as single agent in pediatric patients with V600E
LGG. From November 2013 to May 2018, 7 patients have been treated in our Institution; treatment was well-tolerated, the main concern being dermatological toxicity. The best responses to treatment were: 1 complete response, 3 partial responses, 1 stable disease, only one patient progressed; in one patient, the follow-up is too short to establish the clinical response. Two patients discontinued treatment, and, in both cases, immediate progression of the disease was observed. In one case the treatment was discontinued due to toxicity, in the other one the previously assessed
V600E mutation was not confirmed by further investigation. Two patients, after obtaining a response, progressed during treatment, suggesting the occurrence of resistance mechanisms. Clinical response, with improvement of the neurologic function, was observed in all patients a few weeks after the therapy was started. Despite the limitations inherent to a small and heterogeneous cohort, this experience, suggests that Vemurafenib represents a treatment option in pediatric patients affected by LGG and carrying
mutation V600E.
Medulloblastoma is the most common malignant pediatric brain tumor. Medulloblastoma should not be viewed as a single disease, but as a heterogeneous mixture of various subgroups with distinct ...characteristics. Based on genomic profiles, four distinct molecular subgroups are identified: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. Each of these subgroups are associated with specific genetic aberrations, typical age of onset as well as survival prognosis. Magnetic resonance imaging (MRI) is performed for all patients with brain tumors, and has a key role in the diagnosis, surgical guidance and follow up of patients with medulloblastoma. Several studies indicate MRI as a promising tool for early detection of medulloblastoma subgroups. The early identification of the subgroup can influence the extent of surgical resection, radiotherapy and chemotherapy targeted treatments. In this article, we review the state of the art in MRI-facilitated medulloblastoma subgrouping, with a summary of the main MRI features in medulloblastoma and a brief discussion on molecular characterization of medulloblastoma subgroups. The main focus of the article is MRI features that correlate with medulloblastoma subtypes, as well as features suggestive of molecular subgroups. Finally, we briefly discuss the latest trends in MRI studies and latest developments in molecular characterization.
Background and purpose: Differentiating pediatric posterior fossa (PF) tumors such as medulloblastoma (MB), ependymoma (EP), and pilocytic astrocytoma (PA) remains relevant, because of important ...treatment and prognostic implications. Diffusion kurtosis imaging (DKI) has not yet been investigated for discrimination of pediatric PF tumors. Estimating diffusion values from whole-tumor-based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and assess DKI accuracy in discriminating among pediatric PF tumors. Materials and methods: We retrospectively analyzed 34 children (M, F, mean age 7.48 years) with PF tumors who underwent preoperative examination on a 3 Tesla magnet, including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor, the ROI of the area of maximum tumor diameter, and a small 5 mm ROI. The automated analysis pipeline included inter-observer variability, statistical, and machine learning (ML) analyses. We evaluated inter-observer variability with coefficient of variation (COV) and Bland–Altman plots. We estimated DKI metrics accuracy in discriminating among tumor histology with MANOVA analysis. In order to account for class imbalances, we applied SMOTE to balance the dataset. Finally, we performed a Random Forest (RF) machine learning classification analysis based on all DKI metrics from the SMOTE dataset by partitioning 70/30 the training and testing cohort. Results: Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14), and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics and were used for the analysis. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p < 0.001). SMOTE generated 11 synthetic observations (10 EP and 1 PA), resulting in a balanced dataset with 45 instances (34 original and 11 synthetic). ML analysis yielded an accuracy of 0.928, which correctly predicted all but one lesion in the testing set. Conclusions: VOI-based measurements presented improved repeatability compared to ROI-based measurements across all diffusion metrics. An ML classification algorithm resulted accurate in discriminating PF tumors on a SMOTE-generated dataset. ML techniques based on DKI-derived metrics are useful for the discrimination of pediatric PF tumors.
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