Craniopharyngiomas are rare malformational tumours of low histological malignancy arising along the craniopharyngeal duct. The two histological subtypes, adamantinomatous craniopharyngioma (ACP) and ...papillary craniopharyngioma (PCP), differ in genesis and age distribution. ACPs are diagnosed with a bimodal peak of incidence (5-15 years and 45-60 years), whereas PCPs are restricted to adults mainly in the fifth and sixth decades of life. ACPs are driven by somatic mutations in CTNNB1 (encoding β-catenin) that affect β-catenin stability and are predominantly cystic in appearance. PCPs frequently harbour somatic BRAF
mutations and are typically solid tumours. Clinical manifestations due to increased intracranial pressure, visual impairment and endocrine deficiencies should prompt imaging investigations, preferentially MRI. Treatment comprises neurosurgery and radiotherapy; intracystic chemotherapy is used in monocystic ACP. Although long-term survival is high, quality of life and neuropsychological function are frequently impaired due to the close anatomical proximity to the optic chiasm, hypothalamus and pituitary gland. Indeed, hypothalamic involvement and treatment-related hypothalamic lesions frequently result in hypothalamic obesity, physical fatigue and psychosocial deficits. Given the rarity of these tumours, efforts to optimize infrastructure and international collaboration should be research priorities.
This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy.
Following ...treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board.
From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy-number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion.
Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART.
.
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age ...permits, radiotherapy), median survival is 17 months
. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs.
), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT
, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
Childhood-onset craniopharyngiomas are rare embryonic tumours of low-grade histological malignancy. Novel insights into the molecular pathogenesis of human adamantinomatous craniopharyngioma have ...started to unveil the possibility of testing novel treatments targeting pathogenic pathways. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and in severe neuroendocrine sequelae. Quality of survival in patients with craniopharyngioma with hypothalamic involvement is impaired by severe obesity, physical fatigue and non-optimal psychosocial development. Patients with craniopharyngioma involving hypothalamic structures have reduced 20-year overall survival, but overall and progression-free survival are not related to the degree of surgical resection. Irradiation is effective in the prevention of tumour progression and recurrence. For favourably localized craniopharyngiomas, the preferred treatment of choice is to attempt complete resection with preservation of visual, hypothalamic and pituitary function. For unfavourably localized tumours in close proximity to optic and/or hypothalamic structures, a radical neurosurgical strategy attempting complete resection is not recommended owing to potential severe sequelae. As expertise has been shown to have an impact on post-treatment morbidity, medical societies should establish criteria for adequate professional expertise for the treatment of craniopharyngioma. On the basis of these criteria, health authorities should organize the certification of centres of excellence that are authorized to treat and care for patients with this chronic disease.
Ependymoma with YAP1‐MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying ...YAP1‐MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1‐MAMLD1 fusion was documented by RT‐PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo‐rosettes, small to medium‐sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot‐like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1‐MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1–11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow‐up, 4.84 years). In this to date, largest series of ependymomas with YAP1‐MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.
Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty ...years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies.
Hypothalamic syndrome Müller, Hermann L; Tauber, Maithé; Lawson, Elizabeth A ...
Nature reviews. Disease primers,
04/2022, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such ...as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling. However, these are mostly ineffective and no medications that are specifically approved for the treatment of HS are available. Specific challenges in HS are because the syndrome represents an adverse effect of different diseases, and that diagnostic criteria, aetiology, pathogenesis and management of HS are not completely defined.
We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 ...compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.
•Group3 medulloblastoma neurospheres were screened with FDA-approved drugs•Pemetrexed and gemcitabine inhibited mouse and human G3 and mouse SHH MBs in vitro•Pemetrexed and gemcitabine increased survival of mice bearing mouse and human G3 MB•Pemetrexed and gemcitabine did not affect survival of mice bearing mouse SHH MB
Group3 medulloblastoma (G3 MB) exhibits a high incidence of metastasis and poor patient prognosis. Morfouace et al. report that combination therapy with pemetrexed and gemcitabine, two drugs already in clinical use, effectively inhibits the proliferation of G3 MB that overexpresses MYC.
Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the
SMARCE1
gene has been ...reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (
n
= 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (
n
= 42). Targeted DNA sequencing revealed
SMARCE1
mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (
n
= 14) in comparison to those with meningioma WHO grade 2 (
n
= 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the
SMARCE1
gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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