ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemo... more ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemotherapeutics are lacking and 5-year survival rates remain poor at approximately 50%. Previous studies have shown that the majority of ependymomas possess telomerase, an enzyme that maintains telomere length and permits limitless growth potential. The objective of this study was to elucidate whether telomerase is an effective therapeutic target in ependymoma using the telomerase inhibitors MST-312 and Imetelstat. Paediatric ependymoma cell lines R254 and BXD-1425EPN were treated for 72 hours with MST-312 in parallel with telomerase-negative control cells. R254 ependymoma cells were also treated with Imetelstat for 17 weeks in parallel with mismatch control and untreated cells. Cell number, apoptosis (TUNEL), senescence (beta-galactosidase), telomerase activity (telomere repeat amplification protocol), cell cycle arrest (flow cytometry) and DNA damage (immunofluorescence (gammaH2AX)) was assessed following telomerase inhibition by either compound. MST-312 telomerase inhibition reduced proliferation by 50%, increased γH2AX associated DNA damage 2.2-fold and induced a marked increase in G2 cell populations in both R254 and BXD-1425EPN ependymoma cells but not in telomerase-deficient control cells. Imetelstat treatment of R254 ependymoma cells decreased proliferation after 6 weeks and induced growth arrest following 15 weeks of treatment while no effect was observed in mismatch control or untreated cells. The observed growth arrest was associated with an 80% increase in senescence and 20% decrease in viability. These findings suggest that telomerase inhibition may represent a potential therapeutic strategy for paediatric ependymoma.
International Journal of Radiation Oncology Biology Physics, Oct 1, 2013
photocoagulation, and thermotherapy. Following plaque radiation therapy, there was a total of 33/... more photocoagulation, and thermotherapy. Following plaque radiation therapy, there was a total of 33/255 recurrences (12.9%), with 26/33 recurrences occurring within the first year. The median time to recurrence was 4.5 months. Sixty-five patients (25.5%) underwent enucleation due to poor vision, pain or viable tumor, with 44/65 of the surgeries occurring within the first year and 18/65 within 5 years after plaque treatment. The median time to enucleation was 7 months. The actuarial local recurrence rates at 1 year, 5 year, and 10 year were 10.2%, 11.8%, and 12.2%, respectively, while actuarial rates for enucleation were 17.3%, 24.3% and 24.7%, respectively. Radiation-related complications included cataracts (n Z 64), non-proliferative retinopathy (n Z 46), maculopathy (n Z 26), retinal neovascularization (n Z 25), glaucoma (n Z 9), and vitreous hemorrhage (n Z 2). Conclusions: Plaque radiation therapy is effective for the management of retinoblastoma with 88% tumor control at 10 years. The choice of iodine125 provides deeper tumor penetration compared to other focal organpreserving therapies, yet limits full ocular and systemic exposure, resulting in beneficial local control. The majority of local failures occur within the first year after plaque brachytherapy. ICRB groups B and C are the bestsuited candidates (basal diameter less than 16 mm and thickness less than or equal to 9 mm). Author Disclosure: N.R. Patel: None. J. Emrich: None. N. Ghodasara: None. F. Troicki: None. L. Komarnicky-Kocher: None. C.L. Shields: None. S. Kaliki: None. A. Mashayekhi: None. S.E. Lally: None. J.A. Shields: None.
BackgroundHippocampal avoidance (HA) has been shown to preserve cognitive function in adult patie... more BackgroundHippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole‐brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri‐hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri‐hippocampal relapse in pediatric patients with medulloblastoma (MB).Methods and materialsWe identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri‐hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ‐1), 6 to 10 mm (HZ‐2), and >10 mm (HZ‐3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard‐risk patients with MB were planned using either volumetric‐modulated arc therapy (VMAT) or i...
Background Survivors of pediatric medulloblastoma experience long-term morbidity associated with ... more Background Survivors of pediatric medulloblastoma experience long-term morbidity associated with the toxic effects of postoperative radiotherapy (RT). Proton RT limits radiation dose to normal tissues thereby reducing side effects of treatment while maintaining high cure rates. However, long-term data on disease outcomes and long-term effects of proton RT remain limited. Methods One hundred seventy-eight pediatric medulloblastoma patients treated with proton RT between 2002 and 2016 at the Massachusetts General Hospital comprise the cohort of patients who were treated with surgery, radiation therapy, and chemotherapy. We evaluated event-free survival (EFS), overall survival (OS), and local control using the Kaplan-Meier method. The cumulative incidence of brainstem injury and secondary malignancies was assessed. Results Median follow-up was 9.3 years. One hundred fifty-nine patients (89.3%) underwent a gross total resection (GTR). The 10-year OS for the entire cohort, standard-risk ...
BACKGROUNDProton therapy may reduce cognitive deficits after radiotherapy among brain tumor survi... more BACKGROUNDProton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case‐matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period.METHODSAmong 88 consecutive patients with standard‐risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One‐way analyses of variance were performed to compare the Full‐Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts.RESULTSNeurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The ...
e21029 Background: Though the majority of pediatric medulloblastoma patients treated with surgery... more e21029 Background: Though the majority of pediatric medulloblastoma patients treated with surgery, radiotherapy and chemotherapy are cured, HRQoL is impaired. Methods: Patients enrolled on a phase ...
ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemo... more ABSTRACT Ependymomas represent the third most common paediatric brain tumour, yet effective chemotherapeutics are lacking and 5-year survival rates remain poor at approximately 50%. Previous studies have shown that the majority of ependymomas possess telomerase, an enzyme that maintains telomere length and permits limitless growth potential. The objective of this study was to elucidate whether telomerase is an effective therapeutic target in ependymoma using the telomerase inhibitors MST-312 and Imetelstat. Paediatric ependymoma cell lines R254 and BXD-1425EPN were treated for 72 hours with MST-312 in parallel with telomerase-negative control cells. R254 ependymoma cells were also treated with Imetelstat for 17 weeks in parallel with mismatch control and untreated cells. Cell number, apoptosis (TUNEL), senescence (beta-galactosidase), telomerase activity (telomere repeat amplification protocol), cell cycle arrest (flow cytometry) and DNA damage (immunofluorescence (gammaH2AX)) was assessed following telomerase inhibition by either compound. MST-312 telomerase inhibition reduced proliferation by 50%, increased γH2AX associated DNA damage 2.2-fold and induced a marked increase in G2 cell populations in both R254 and BXD-1425EPN ependymoma cells but not in telomerase-deficient control cells. Imetelstat treatment of R254 ependymoma cells decreased proliferation after 6 weeks and induced growth arrest following 15 weeks of treatment while no effect was observed in mismatch control or untreated cells. The observed growth arrest was associated with an 80% increase in senescence and 20% decrease in viability. These findings suggest that telomerase inhibition may represent a potential therapeutic strategy for paediatric ependymoma.
International Journal of Radiation Oncology Biology Physics, Oct 1, 2013
photocoagulation, and thermotherapy. Following plaque radiation therapy, there was a total of 33/... more photocoagulation, and thermotherapy. Following plaque radiation therapy, there was a total of 33/255 recurrences (12.9%), with 26/33 recurrences occurring within the first year. The median time to recurrence was 4.5 months. Sixty-five patients (25.5%) underwent enucleation due to poor vision, pain or viable tumor, with 44/65 of the surgeries occurring within the first year and 18/65 within 5 years after plaque treatment. The median time to enucleation was 7 months. The actuarial local recurrence rates at 1 year, 5 year, and 10 year were 10.2%, 11.8%, and 12.2%, respectively, while actuarial rates for enucleation were 17.3%, 24.3% and 24.7%, respectively. Radiation-related complications included cataracts (n Z 64), non-proliferative retinopathy (n Z 46), maculopathy (n Z 26), retinal neovascularization (n Z 25), glaucoma (n Z 9), and vitreous hemorrhage (n Z 2). Conclusions: Plaque radiation therapy is effective for the management of retinoblastoma with 88% tumor control at 10 years. The choice of iodine125 provides deeper tumor penetration compared to other focal organpreserving therapies, yet limits full ocular and systemic exposure, resulting in beneficial local control. The majority of local failures occur within the first year after plaque brachytherapy. ICRB groups B and C are the bestsuited candidates (basal diameter less than 16 mm and thickness less than or equal to 9 mm). Author Disclosure: N.R. Patel: None. J. Emrich: None. N. Ghodasara: None. F. Troicki: None. L. Komarnicky-Kocher: None. C.L. Shields: None. S. Kaliki: None. A. Mashayekhi: None. S.E. Lally: None. J.A. Shields: None.
BackgroundHippocampal avoidance (HA) has been shown to preserve cognitive function in adult patie... more BackgroundHippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole‐brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri‐hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri‐hippocampal relapse in pediatric patients with medulloblastoma (MB).Methods and materialsWe identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri‐hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ‐1), 6 to 10 mm (HZ‐2), and >10 mm (HZ‐3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard‐risk patients with MB were planned using either volumetric‐modulated arc therapy (VMAT) or i...
Background Survivors of pediatric medulloblastoma experience long-term morbidity associated with ... more Background Survivors of pediatric medulloblastoma experience long-term morbidity associated with the toxic effects of postoperative radiotherapy (RT). Proton RT limits radiation dose to normal tissues thereby reducing side effects of treatment while maintaining high cure rates. However, long-term data on disease outcomes and long-term effects of proton RT remain limited. Methods One hundred seventy-eight pediatric medulloblastoma patients treated with proton RT between 2002 and 2016 at the Massachusetts General Hospital comprise the cohort of patients who were treated with surgery, radiation therapy, and chemotherapy. We evaluated event-free survival (EFS), overall survival (OS), and local control using the Kaplan-Meier method. The cumulative incidence of brainstem injury and secondary malignancies was assessed. Results Median follow-up was 9.3 years. One hundred fifty-nine patients (89.3%) underwent a gross total resection (GTR). The 10-year OS for the entire cohort, standard-risk ...
BACKGROUNDProton therapy may reduce cognitive deficits after radiotherapy among brain tumor survi... more BACKGROUNDProton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case‐matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period.METHODSAmong 88 consecutive patients with standard‐risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One‐way analyses of variance were performed to compare the Full‐Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts.RESULTSNeurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The ...
e21029 Background: Though the majority of pediatric medulloblastoma patients treated with surgery... more e21029 Background: Though the majority of pediatric medulloblastoma patients treated with surgery, radiotherapy and chemotherapy are cured, HRQoL is impaired. Methods: Patients enrolled on a phase ...
Uploads