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1.
Artigo em Inglês | MEDLINE | ID: mdl-32634544

RESUMO

PURPOSE: Methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is associated with improved treatment response and survival in patients with Glioblastoma (GB), but the necessary pathological specimen can be non-diagnostic. In this study, we assessed whether radiomics features from pre-treatment 18F-DOPA PET imaging could be used to predict pathologic MGMT status. METHODS: This study included 86 patients with newly diagnosed GB, split into three groups (training, validating, predicting). We performed radiomics analysis on 18F-DOPA PET images by extracting features from two tumor-based contours: a "Gold" contour of all abnormal uptake per expert Nuclear Medicine physician, and an "HGG" contour based on a T/N > 2.0 representing the most aggressive components. Feature selection was performed by comparing the weighted feature importance and filtering with bivariate analysis. Optimization of model parameters was explored using grid search with selected features. The stability of the model with increasing input features was also investigated for model robustness. The model predictions were then applied by comparing the overall survival (OS) probability of the GB patients with unknown MGMT status vs those with known MGMT status. RESULTS: A radiomics signature was constructed to predict MGMT methylation status. Using features extracted from HGG contour alone with a Random Forest model, we achieved 80% ± 10% accuracy for 95% confidence level in predicting MGMT status. The prediction accuracy was not improved with the addition of the Gold contour or with more input features. The model was applied to the patients with unknown MGMT methylation status. The prediction results are consistent with what is expected using OS as a surrogate. CONCLUSIONS: This study suggests that 3 features from radiomics modeling of 18F-DOPA PET imaging can predict the MGMT methylation status with reasonable accuracy. It may provide valuable therapeutic guidance for patients where MGMT testing is inconclusive or non-diagnostic.

2.
J Clin Oncol ; : JCO1902983, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32706640

RESUMO

PURPOSE: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

4.
J Neurooncol ; 148(1): 89-95, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32303974

RESUMO

PURPOSE: Stereotactic radiosurgery (SRS) is commonly performed after surgical resection of brain metastases to reduce the chance of local tumor recurrence while maintaining cognitive function. Target delineation in these cases is typically based off T1-weighted post-gadolinium MRI (T1Gd). In this study, we report outcomes for patients having postoperative SRS in which the planning target volume (PTV) was based on T2-weighted MRI (T2W). METHODS: Sixty-two consecutive patients having single-fraction SRS after brain metastases resection were retrospectively reviewed. Excluded were patients with prior whole brain radiation therapy, multiple resection cavities, and small cell pathologies. RESULTS: The median time from surgery to SRS was 11 days; 26 patients (42%) had SRS ≤ 7 days. The median PTV was 8.0 cm3; the median margin dose was 18 Gy. The crude rates of local tumor control (LC), leptomeningeal disease (LMD), distant brain recurrence (DBR), and radiation necrosis (RN) were 85%, 19%, 37%, and 2%, respectively. The 1-year LC, LMD, DBR, and RN rates were 88%, 25%, 36%, and 0%, respectively. No tumor or dosimetric factor was associated with LC. Sub-total tumor resection was a risk factor for LMD (HR 5.11, P = 0.003), whereas patients with multiple brain metastases had a greater risk of DBR (HR 2.88, P = 0.01). The median PTV was smaller compared to the median PTV based off the consensus guidelines utilizing T1Gd MRI (8.0 cm3 vs. 9.1 cm3, P = 0.004). CONCLUSION: T2W MRI provided accurate resection cavity delineation even in the early postoperative period and was associated with decreased PTV compared to T1Gd MRI in the majority of cases.

5.
Int J Radiat Oncol Biol Phys ; 107(4): 720-725, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251755

RESUMO

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

6.
Int J Radiat Oncol Biol Phys ; 106(5): 905-911, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001382

RESUMO

PURPOSE: The proposed Radiation Oncology Alternative Payment Model (RO-APM) released on July 10, 2019, represents a dramatic shift from fee-for-service (FFS) reimbursement in radiation therapy (RT). This study compares historical revenue at Mayo Clinic to the RO-APM and quantifies the effect that disease characteristics may have on reimbursement. METHODS AND MATERIALS: FFS Medicare reimbursements were determined for patients undergoing RT at Mayo Clinic from 2015 to 2016. Disease categories and payment episodes were defined as per the RO-APM. Average RT episode reimbursements were reported for each disease site, except for lymphoma and metastases, and stratified by stage and disease subcategory. Comparisons with RO-APM reimbursements were made via descriptive statistics. RESULTS: A total of 2098 patients were identified, of whom 1866 (89%) were categorized per the RO-APM; 840 (45%) of those were aged >65 years. Breast (33%), head and neck (HN) (14%), and prostate (11%) cancer were most common. RO-APM base rate reimbursements and sensitivity analysis range were lower than historical reimbursement for bladder (-40%), cervical (-34%), lung (-28%), uterine (-26%), colorectal (-24%), upper gastrointestinal (-24%), HN (-23%), pancreatic (-20%), prostate (-16%), central nervous system (-13%), and anal (-10%) and higher for liver (+24%) and breast (+36%). Historical reimbursement varied with stage (stage III vs stage I) for breast (+57%, P < .01), uterine (+53%, P = .01), lung (+50%, P < .01), HN (+24%, P = .01), and prostate (+13%, P = .01). Overall, for patients older than 65 years of age, the RO-APM resulted in a -9% reduction in total RT reimbursement compared with historical FFS (-2%, -15%, and -27% for high, mid, and low adjusted RO-APM rates). CONCLUSIONS: Our findings indicate that the RO-APM will result in significant reductions in reimbursement at our center, particularly for cancers more common in underserved populations. Practices that care for socioeconomically disadvantaged populations may face significant reductions in revenue, which could further reduce access for this vulnerable population.


Assuntos
Neoplasias/patologia , Neoplasias/radioterapia , Radioterapia (Especialidade)/economia , Idoso , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias/economia , Mecanismo de Reembolso
7.
J Clin Oncol ; 38(10): 1019-1029, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32058845

RESUMO

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

8.
Neuro Oncol ; 22(6): 830-837, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32002556

RESUMO

BACKGROUND: The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. METHODS: Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. RESULTS: For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter <5 cm and baseline Mini-Mental State Examination (MMSE) >27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter <5 cm, patients who had gross total resection, and patients with baseline MMSE >27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. CONCLUSIONS: Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

9.
Int J Radiat Oncol Biol Phys ; 106(2): 255-260, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31654784

RESUMO

PURPOSE: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. METHODS AND MATERIALS: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests. RESULTS: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). CONCLUSIONS: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.


Assuntos
Neoplasias Encefálicas/radioterapia , Transtornos Cognitivos/prevenção & controle , Irradiação Craniana/normas , Melhoria de Qualidade , Radiocirurgia/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Intervalos de Confiança , Irradiação Craniana/efeitos adversos , Fracionamento da Dose de Radiação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/normas
10.
Neurosurgery ; 86(4): 557-564, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31140563

RESUMO

BACKGROUND: Patients with persistent or recurrent Cushing disease (CD) after prior transsphenoidal surgery require further treatment to reduce the disease's metabolic consequences. OBJECTIVE: To assess patient outcomes after stereotactic radiosurgery (SRS) for persistent or recurrent CD from adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas and propose a management algorithm. METHODS: Retrospective review of 38 patients without prior radiation treatment having SRS for ACTH-secreting pituitary adenomas from 1990 to 2015. Favorable outcome was defined as biochemical remission and tumor growth control. Patients were evaluated separately if they underwent bilateral adrenalectomy (Adx). RESULTS: Twenty patients (53%) were treated with Adx and SRS (median margin dose, 25 Gy) and 18 patients (47%) received SRS alone (median margin dose, 22.5 Gy). Median follow-up after SRS was 76 mo. Of patients undergoing Adx, 18/20 (90%) had a favorable outcome. Two patients (10%) had tumor growth requiring additional treatment. A favorable outcome was achieved in 13/18 patients (72%) having SRS alone (median, 14 mo; interquartile range, 8-23). Five patients (28%) required additional treatment due to persistent hypercortisolemia (n = 4) or hypercortisolemia and tumor growth (n = 1). Favorable outcomes were more frequent in the Adx and SRS group at 1 yr (100% vs 33%; P < .001) and 3 yr (100% vs 62%; P < .01), but no different at 5 yr (88% vs 77%; P = .63). CONCLUSION: SRS was effective for patients with persistent or recurrent CD. Patients with mild to moderate CD can be safely managed with SRS alone; patients with severe CD should be considered for Adx with either concurrent SRS or SRS performed at a later date if tumor growth occurs.

11.
Radiother Oncol ; 142: 36-42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31431375

RESUMO

BACKGROUND: Pseudoprogression (PsP) following radiation therapy (RT) for low grade glioma (LGG, WHO grade I and II), including both photon-based intensity-modulated RT (IMRT) and proton beam therapy (PBT), has been described. However, its incidence has yet to be consolidated. The aim of this systematic review and meta-analysis was to pool the current literature and establish the incidence of PsP in these groups to better inform surveillance protocols in the future. METHODS: Searches of 4 electronic databases from inception to April 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of outcomes was then extracted and pooled by random-effects meta-analysis of proportions. RESULTS: A total of 5 pediatric and 4 adult cohort studies describing 517 and 424 LGG subjects respectively satisfied all selection criteria. The estimated incidences of PsP in pediatric subjects following IMRT and PBT were 33% (95% CI, 20-47%) and 34% (95% CI, 23-45%) respectively, with no difference between modalities. The estimated incidences of PsP in adult subjects following IMRT and PBT were 18% (95% CI, 12-25%) and 30% (95% CI, 21-39%) respectively, with PsP significantly less common following IMRT than PBT (P-heterogeneity = 0.04). Median time from radiation initiation to first detection of PsP ranged from 6 to 12 months across all modalities and age groups. CONCLUSIONS: The incidence of PsP following both IMRT and PBT in the management of pediatric and adult LGG is not negligible, and should therefore be recognized as a pertinent sequala within the first year at least following treatment. However, a lack of accountability in the current literature for the differences in PsP interpretation, radiation modality, radiobiology and molecular biology of LGGs precludes any firm surveillance recommendations at this time.

12.
Br J Radiol ; 93(1107): 20190673, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31600082

RESUMO

OBJECTIVE: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed. METHODS AND MATERIALS: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites. RESULTS: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma (n = 349), ependymoma (n = 309), and glial/astrocytoma tumors (n = 279). The most common non-CNS diagnoses are rhabdomyosarcoma (n = 284), Ewing's sarcoma (n = 153), and neuroblastoma (n = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study. CONCLUSIONS: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research. ADVANCES IN KNOWLEDGE: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.


Assuntos
Coleta de Dados/normas , Neoplasias/radioterapia , Fótons/uso terapêutico , Terapia com Prótons/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Adolescente , Astrocitoma/radioterapia , Neoplasias do Sistema Nervoso Central/radioterapia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Computação em Nuvem , Ependimoma/radioterapia , Feminino , Glioma/radioterapia , Humanos , Lactente , Cooperação Internacional , Masculino , Meduloblastoma/radioterapia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Autorrelato , Adulto Jovem
13.
Pract Radiat Oncol ; 10(2): 104-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31783172

RESUMO

PURPOSE: (1) Demonstrate feasibility of electrocardiogram-gated computed tomography with coronary angiography (E-CTA) in treatment planning for mediastinal lymphoma and (2) assess whether inclusion of cardiac substructures in the radiation plan optimization (CSS optimization) results in increased cardiac substructure sparing. METHODS AND MATERIALS: Patients with mediastinal lymphomas requiring radiation therapy were prospectively enrolled in an observational study. Patients completed a treatment planning computed tomography scan and E-CTA in the deep inspiration breath hold position. Avoidance structures (eg, coronary arteries and cardiac valves) were created in systole and diastole and then merged into a single planning organ-at-risk volume based on a cardiac substructure contouring atlas. In the photon cohort, 2 volumetric modulated arc therapy plans were created per patient with and without CSS optimization. Dosimetric endpoints were compared. RESULTS: In the photon cohort, 7 patients were enrolled. For all 7 patients, the treating physician elected to use the CSS optimization plan. At the individual level, 2 patients had reductions of 10.8% and 16.2% of the right coronary artery receiving at least 15 Gy, and 1 had a reduction of 9.6% of the left anterior descending artery receiving 30 Gy. No other differences for coronary arteries were detected between 15 and 30 Gy. Conversely, 5 of 7 patients had >10% reductions in dose between 15 to 30 Gy to at least 1 cardiac valve. The greatest reduction was 22.8% of the aortic valve receiving at least 30 Gy for 1 patient. At the cohort level, the maximum, mean, and 5-Gy increment analyses were nominally similar between planning techniques for all cardiac substructures and the lungs. CONCLUSIONS: Cardiac substructure delineation using E-CTA was feasible, and inclusion in optimization led to modest improvements in sparing of radiosensitive cardiac substructures for some patients.

14.
Adv Radiat Oncol ; 4(4): 579-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673651

RESUMO

Purpose: NRG Oncology's RTOG 0933 demonstrated benefits to memory preservation after hippocampal avoidant whole-brain radiation therapy (HA-WBRT), the avoidance of radiation dose to the hippocampus (using intensity modulated radiation planning and delivery techniques) during WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity play a role. White matter injury (WMI) has been implicated in radiation therapy-induced neurocognitive decline. This secondary analysis explored the relationship between pretreatment WMI and memory after HA-WBRT. Methods and Materials: Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pretreatment magnetic resonance image. Correlational analyses were performed examining the relationship between pretreatment WMI and Hopkins Verbal Learning Test-Revised (HVLT-R) outcomes at baseline and 4 months after HA-WBRT. Results: In the study, 113 patients received HA-WBRT. Of 113 patients, 33 underwent pretreatment and 4-month posttreatment HVLT testing and pretreatment postcontrast volumetric T1 and axial T2/fluid-attenuated inversion recovery magnetic resonance imaging. Correlation was found between larger volumes of pretreatment WMI and decline in HVLT-R recognition (r = 0.54, P < .05), and a correlational trend was observed between larger volume of pretreatment WMI and decline in HVLT-R delayed recall (r = 0.31, P = .08). Patients with higher pretreatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-R recall and delayed recall after HA-WBRT (r = -0.36 and r = -0.36, P < .05), compared to the magnitude of stability or positive shift in those with lesser disease burden. Conclusions: In patients receiving HA-WBRT for brain metastases, extent of pretreatment WMI predicts posttreatment memory decline, suggesting a mechanism for radiation therapy-induced neurocognitive toxicity independent of hippocampal stem cell radiosensitivity. Stability or improvement in HVLT after HA-WBRT for patients with higher pretreatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on neurocognition.

16.
J Neuropathol Exp Neurol ; 78(11): 1011-1021, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562743

RESUMO

MAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600_W604delinsDQTDG, at 8%-27% variant allele frequency) and 1 showed a TPM3-NRTK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19-139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.

17.
Neurooncol Pract ; 6(4): 274-282, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31386073

RESUMO

Background: This study evaluated the association between health-related quality of life (HRQOL) and cognition in patients receiving memantine for prevention of cognitive dysfunction during whole-brain radiotherapy (WBRT). Methods: Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine, 20 mg per day, within 3 days of initiating radiotherapy, for 24 weeks. The Functional Assessment of Cancer Therapy-Brain module (FACT-Br) and Medical Outcomes Scale-Cognitive Functioning Scale (MOS-C) were completed in coordination with serial standardized tests of cognitive function. Results: Of the 508 eligible patients, 442 (87%) consented to participate in the HRQOL portion and contributed to baseline analyses. Evaluable patients at 24 weeks (n = 246) included surviving patients completing FACT-Br, MOS-C, and objective cognitive assessments (n = 146, 59%) and patients alive at time of missed assessment (n = 100, 41%). Baseline cognitive function correlated significantly with FACT-Br and MOS-C self-reports. All domains of objective cognitive function showed declines over time. Neither FACT-Br nor MOS-C differed between the treatment arms. Emotional and functional well-being subscales of the FACT improved over time while the remainder of the FACT-Br domains remained stable. MOS-C scores declined over time. Conclusion: Baseline cognitive function correlated significantly with FACT-Br and MOS-C scores. No by-arm differences in HRQOL were observed despite differences in objective cognitive function. Patient attrition and poor testing compliance remain significant problems in studies of cognitive function of brain metastases patients and further effort is needed to improve compliance with testing and sensitivity of patient-reported measures.

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