Existing drug delivery methods have not led to a significant increase in survival for patients with malignant primary brain tumors. While the combination of conventional therapies consisting of ...surgery, radiotherapy, and chemotherapy has improved survival for some types of brain tumors (e.g., WNT medulloblastoma), other types of brain tumors (e.g., glioblastoma and diffuse midline glioma) still have a poor prognosis. The reason for the differences in response can be largely attributed to the blood–brain barrier (BBB), a specialized structure at the microvasculature level that regulates the transport of molecules across the blood vessels into the brain parenchyma. This structure hampers the delivery of most chemotherapeutic agents for the treatment of primary brain tumors. Several drug delivery methods such as nanoparticles, convection enhanced delivery, focused ultrasound, intranasal delivery, and intra-arterial delivery have been developed to overcome the BBB in primary brain tumors. However, prognosis of most primary brain tumors still remains poor. The heterogeneity of the BBB in primary brain tumors and the distinct vasculature of tumors make it difficult to design a drug delivery method that targets the entire tumor. Drug delivery methods that combine strategies such as focused ultrasound and nanoparticles might be a more successful approach. However, more research is needed to optimize and develop new drug delivery techniques to improve survival of patients with primary brain tumors.
Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling ...to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Radiotherapy, often combined with concurrent chemotherapy is palliative, with 1-year, 2-year, and 5-year overall survival of 42·3%, 9·6%, and 2·2%, respectively.1 Multiple clinical trials ...investigating systemic cytotoxic chemotherapy and novel agents have thus far not changed these poor overall survival rates.2,3 In most solid cancers, as well as in high-grade gliomas located in other parts of the brain, extensive safe surgery is an essential determinant of disease control, often in combination with adjuvant (or neoadjuvant) chemotherapy, radiotherapy, or both. In the treatment of most cancers, repeated adjuvant and neoadjuvant systemic treatments seem to achieve improved tumour control. ...implantable convection-enhanced delivery systems that allow for repeated infusions of drugs or drug combinations are currently being investigated.6 The timing of convection-enhanced delivery in diffuse intrinsic pontine glioma, especially before, during, after, or perhaps even as a replacement for radiotherapy should be investigated further in clinical trials, preferably involving international collaborative groups. Conversely, if local disease control leads to improved overall survival, this might result in larger numbers of patients showing metastatic disease at progression or relapse, which might ultimately require convection-enhanced delivery to be part of a multimodal treatment strategy, in combination with additional therapeutic avenues that have yet to be explored, such as systemic drugs and targeted agents with better BBB penetrance, as well as other innovative therapies (eg, CART-cell or dendritic cell therapies).
Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and ...radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation ...could provide cues to improve outcome prediction and therapeutic approaches.
Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes.
We identified DAB2IP, a member of the RAS-GTPase-activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death.
These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis.
The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). ...Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.
Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection.
We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival.
These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.
Introduction
This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor ...erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG).
Methods
Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m
2
) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m
2
) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed.
Results
Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5–10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m
2
. Median sPFS was 3.2 months (range 1.0–10.9), and median OS was 13.8 months (range 9.3–33.0). Overall QoL was stable during treatment.
Conclusions
Daily erlotinib is safe and well tolerated in doses up to 85 mg/m
2
when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.
Background
Survivors of childhood brain tumors are prone to sleep and neurocognitive problems. Effective interventions to improve neurocognitive functioning are largely lacking. In general, sleep ...problems are negatively related to neurocognitive functioning, but this relationship is unclear in survivors of childhood brain tumors. Therefore, the occurrence of sleep problems, potential risk factors, and the relation between sleep and executive functioning were evaluated.
Procedure
Baseline data of a randomized controlled trial on the effectiveness of neurofeedback were used. Childhood brain tumor survivors 8‐18 years of age with parent‐reported neurocognitive complaints ≥2 years after treatment were eligible. Parents completed the Sleep Disturbance Scale for Children. Executive functioning was assessed by parents and teachers (Behavior Rating Inventory of Executive Functioning). Multiple linear regression analyses were used to examine sociodemographic and medical characteristics and emotional difficulties and hyperactivity/inattention (Strength and Difficulties Questionnaire) as potential risk factors for sleep problems, and to assess the association between sleep and executive functioning.
Results
Forty‐eight percent of survivors (n = 82, 7.0 ± 3.6 years post diagnosis, age 13.8 ± 3.2 years) had sleep problems and scored significantly worse than the norm on the subscales Initiating and Maintaining Sleep, Excessive Somnolence, and the total scale (effect sizes 0.58‐0.92). Emotional problems and/or hyperactivity/inattention were independent potential risk factors. Sleep problems were associated with worse parent‐reported executive functioning.
Conclusions
Sleep problems occur among half of childhood brain tumor survivors with neurocognitive problems, and are associated with worse executive functioning. Future studies should focus on the development of sleep interventions for this population, to improve sleep as well as executive functioning.
Abstract Background Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first ...progression. Methods At first progression, 31 children with DIPG, aged 2–16 years, underwent re-irradiation (dose 19.8–30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Results Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3–6 months: 4.0 versus 2.7; P < .01; 6–12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4–5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27–.54; P < .01) and re-irradiation (corrected hazard ratio = .18–.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). Conclusions The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability.
Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in ...children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0-6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter- and intratumoral heterogeneity of uptake, and 89Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89Zr-bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P = 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion:89Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89Zr-bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment.
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