Amedeo A. Azizi

Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma

Alveolar soft part sarcoma is a rare tumour of unknown histogenesis. Although tumour growth is slow and often asymptomatic, vascular invasion and metastatic dissemination (especially to the brain and lung) take place early in the course of disease. Resection is the treatment of choice and could lead to complete remission. If complete resection is not possible, the prognosis of alveolar soft part sarcoma is poor, since conventional cytotoxic chemotherapy regimens have little effi cacy in most patients. Therefore, alternative treatment approaches are needed. We report tumour regression in a patient with disseminated alveolar soft part sarcoma during antiangiogenic treatment with the antibody against vascular endothelial growth factor (VEGF), bevacizumab. An 8-year-old boy presented with a 2-week history of headaches in July, 2003. The boy was in good general condition, but physical examination revealed minor gait ataxia, dysdiadochokinesis, bilateral pyramidal signs, papilloedema, and homonymous hemianopsia. MRI of the brain detected three solid contrast-enhancing lesions in the left cerebellum (3·2×3·7 cm), left occipital lobe (4·8×3·7×5·2 cm), and left parietal lobe (1·3×1 cm). Digital subtraction angiography showed all lesions to be highly vascularised. No notable fi ndings were seen in MRI of the spinal cord. A multislice CT of the thorax and abdomen revealed 15 intra pulmonary lesions (the largest measur ing 2·7×2·8 cm). Whole-body MRI detected a lesion (2·4×1·2 cm) in the left psoas muscle, which was regarded as the primary site. Resection of the infratentorial tumour was undertaken to prevent brain-stem compression. Histopathological examination of the tissue revealed tumour cells arranged in solid nests and separated by thin sinusoidal vessels, characteristic of alveolar soft part sarcoma (fi gure 1A). The Lancet Oncol 2006; 7: 521–23

Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors

Median survival time of recurrent embryonal brain tumors is short regardless of salvage chemotherapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularization by interfering with tumor angiogenesis at various levels.

Atypical teratoid rhabdoid tumor: improved long-term survival with an intensive multimodal therapy and delayed radiotherapy. The Medical University of Vienna Experience 1992-2012.

Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease‐specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV‐ATRT) consisting of three 9‐week courses of a dose‐dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high‐dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5‐year overall survival (OS) and event‐free survival (EFS) for all 22 consecutive patients was 56.3 ± 11.3% and 52.9 ± 11.0%, respectively. For MUV‐ATRT regimen‐treated patients (cohort A) 5‐year OS was 100% and EFS was 88.9 ± 10.5%. For patients treated differently (cohort B) 5‐year OS and EFS were 28.8 ± 13.1%. All nine MUV‐ATRT regimen‐treated patients are alive for a median of 76 months (range: 16–197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV‐ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1–M3 stage disease allowing postponement of radiotherapy until after HDCT.

Feasibility and tolerability of bevacizumab in children with primary CNS tumors

Bevacizumab, an antibody to the vascular endothelial growth factor, has demonstrated anti‐cancer activity in a number of solid tumors. Fear of intratumoral hemorrhage, however, has slowed its introduction into the treatment of central nervous system (CNS) tumors. Currently, only a small number of children with gliomas received bevacizumab.

Pharmacokinetics and Safety of Intrathecal Liposomal Cytarabine in Children Aged <3 Years

AbstractBackground and objective: Liposomal cytarabine (DepoCyte®) is a slow-release formulation for intrathecal application, ensuring prolonged drug exposure. Although there is an urgent need for new treatment options for infants with leptomeningeal dissemination of a malignant brain tumour, there are no clinical and pharmacokinetic data available on this drug for children aged <3 years. The objective of this pilot study was to determine the feasibility, safety and pharmacokinetics of cytarabine after intrathecal administration of liposomal cytarabine 25 mg in patients aged <3 years. Patients and methods: Six male patients with a mean age of 21 months and CNS primitive neuroectodermal tumours (n = 3) or atypical teratoid/rhabdoid tumours (n = 3) were included. Liposomal cytarabine (25 mg) was administered intraventricularly. One patient also received the drug by lumbar puncture. Dexamethasone was used concomitantly for 3–5 days to prevent arachnoiditis. Cerebrospinal fluid (CSF) and plasma samples were collected before administration of liposomal cytarabine and 1 hour, 12 hours, 24 hours, 1 week and 2 weeks post-dosing. Noncompartmental pharmacokinetic analysis of CSF and plasma was performed. Results: Liposomal cytarabine was generally well tolerated; only grade 2 headache occurred in one patient. After intraventricular administration of cytarabine 25 mg, free and encapsulated drug concentrations above the cytotoxic drug level of 0.1 μg/mL were detectable in the CSF for at least 7 days and up to 14 days post-dosing. The average elimination half-lives were 56.7 hours for encapsulated cytarabine and 59.3 hours for free cytarabine. After intralumbar administration, the elimination half-life of free cytarabine, measured in the ventricular CSF during two courses in one patient, was significantly shorter (32.7 hours). Conclusion: Application of liposomal cytarabine with concomitant dexamethasone appears to be safe and well tolerated in children aged <3 years. Drug exposure in infants aged <3 years after an intraventricular dose of 25 mg is comparable to that after administration of 50 mg in adult patients and 35 mg in older children.

Tumor stabilization under treatment with imatinib in progressive hypothalamic‐chiasmatic glioma

Hypothalamic‐chiasmatic gliomas (HCG) account for up to 20% of tumors in patients under the age of 3 years. While most children respond to chemotherapy, alternative treatment approaches are needed for those with progressive disease refractory to chemotherapy.

Vascular endothelia growth factor targeted therapy may improve the effect of dendritic cell-based cancer immune therapy.

Glioblastoma (GBM) is the most com-mon and most lethal subtype of glioma and, despite advances, therapy prognosis re-mains poor with a median survival of ~15 months and a 2-year survival rate of 26% [1]. Standard therapy consists of tumor re-section, radiation and chemotherapy and a majority of patients receive antiangioge-netic therapy with the humanized anti-vas -cular endothelial growth factor monoclonal antibody bevacizumab as second-line ther-apy. In a randomized Phase II clinical trial we use an individualized cancer immune therapy concept based on dendritic cells (DC-CIT) as add on to first-line therapy [2]. Our cancer vaccine AV0113 is comprised of two main components: Type 1 dendritic cells, that are characterized by the secretion of the immune regulatory molecule IL-12 to polarize the immune system towards a cy-tolytic immune response, are derived from the patient’s monocytes and are pulsed with tumor antigens, that are extracted from the patient’s autologous tumor tissue. AV0113 represents a fully individualized somatic cell therapy.

Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain

Background Ependymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma. Methods We determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas. Results In posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q. Conclusion Taken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.

Identification of c-myc-dependent proteins in the medulloblastoma cell line D425Med

High c-myc levels are linked to poor prognosis in medulloblastoma (MB), and it was the aim of the current study to search for c-myc-dependent proteins in the MB cell line D425Med. For this purpose D425Med cells and cells with knocked-down c-myc (by siRNA) were analysed by a gel-based differential proteomics study using mass spectrometry. Heterogeneous nuclear ribonucleoproteins C1/C2, heterogeneous nuclear ribonucleoprotein A/B, stathmin, endoplasmic reticulum protein ERp29 precursor and guanidinoacetate N-methyltransferase were c-myc dependently expressed. Signalling, the protein machinery, metabolism and endoplasmic reticulum function may be affected and these results enable studying tumour tissue for these proteins as potential dignity markers or pharmacological targets.

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

The cellular composition of H3K27M gliomas Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) are an aggressive type of childhood cancer with few options for treatment. Filbin et al. used a single-cell sequencing approach to study the oncogenic programs, genetics, and cellular hierarchies of H3K27M-glioma. Tumors were mainly composed of cells resembling oligodendrocyte precursor cells, whereas differentiated malignant cells were a smaller fraction. In comparison with other gliomas, these cancers had distinct oncogenic programs and stem cell–like profiles that contributed to their stable tumor-propagating potential. The analysis also identified a lineage-specific marker that may be useful in developing therapies. Science, this issue p. 331 Single-cell analyses of H3K27M glioma defines a putative developmental hierarchy that differs from other gliomas. Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.