Genetic modulation of longitudinal change in neurocognitive function among adult glioma patients.

PURPOSE: Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy. METHODS: Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). RESULTS: Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. CONCLUSION: Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.

A gene expression signature predicts recurrence-free survival in meningioma.

BACKGROUND: Meningioma is the most common primary brain tumor and has a variable risk of local recurrence. While World Health Organization (WHO) grade generally correlates with recurrence, there is substantial within-grade variation of recurrence risk. Current risk stratification does not accurately predict which patients are likely to benefit from adjuvant radiation therapy (RT). We hypothesized that tumors at risk for recurrence have unique gene expression profiles (GEP) that could better select patients for adjuvant RT. METHODS: We developed a recurrence predictor by machine learning modeling using a training/validation approach. RESULTS: Three publicly available AffymetrixU133 gene expression datasets (GSE9438, GSE16581, GSE43290) combining 127 primary, non-treated meningiomas of all grades served as the training set. Unsupervised variable selection was used to identify an 18-gene GEP model (18-GEP) that separated recurrences. This model was validated on 62 primary, non-treated cases with similar grade and clinical variable distribution as the training set. When applied to the validation set, 18-GEP separated recurrences with a misclassification error rate of 0.25 (log-rank p=0.0003). 18-GEP was predictive for tumor recurrence [p=0.0008, HR=4.61, 95%CI=1.89-11.23)] and was predictive after adjustment for WHO grade, mitotic index, sex, tumor location, and Simpson grade [p=0.0311, HR=9.28, 95%CI=(1.22-70.29)]. The expression signature included genes encoding proteins involved in normal embryonic development, cell proliferation, tumor growth and invasion (FGF9, SEMA3C, EDNRA), angiogenesis (angiopoietin-2), cell cycle regulation (CDKN1A), membrane signaling (tetraspanin-7, caveolin-2), WNT-pathway inhibitors (DKK3), complement system (C1QA) and neurotransmitter regulation (SLC1A3, Secretogranin-II). CONCLUSIONS: 18-GEP accurately stratifies patients with meningioma by recurrence risk having the potential to guide the use of adjuvant RT.

Melanoma brain metastases harboring BRAF V600K or NRAS mutations are associated with an increased local failure rate following conventional therapy.

Studies on melanoma brain metastases (MBM) with regard to mutational status are lacking. We investigated the outcomes of MBM in molecularly characterized patients for BRAF and NRAS mutations receiving conventional treatment. We investigated associations between outcomes [competing risk of local and distant brain failure (LF, DF) and overall survival (OS)] and clinical/pathological features of patients with known mutation status following initial treatment of MBM. Competing risk analysis was performed using the methods of Fine and Gray. We identified 235 patients with MBM diagnosed from 2005 to 2011. Mutation prevalence was BRAF non-V600K 98 (42%), BRAF V600K 34 (14%), NRAS 43 (18%), and wild-type for both genes (WT) 60 (26%) patients. Six month cumulative incidence LF rates were 3% for combined SRS or surgery with adjuvant radiation, 18% for surgery, 18% for SRS, 60% for WBRT, and 67% for systemic therapy. On multivariate analysis, only mutation status and initial treatment type were found to be independent predictors of local control. As compared to WT, NRAS (HR 2.58, 95% CI 1.18-5.67, p = 0.02) and BRAF V600K (HR 2.83, 95% CI 1.23-6.47, p = 0.01) mutational status were statistically significant while BRAF non-V600K status was not statistically significant (p = 0.23). Mutation status was not associated with DF or OS. BRAF V600K and NRAS mutation status predict increased LF following conventional treatments for MBM. These data can inform the design and interpretation of future MBM trials.

Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials.

OBJECTIVE The objective of this study was to compare fractionation schemes and outcomes of patients with renal cell carcinoma (RCC) treated in institutional prospective spinal stereotactic radiosurgery (SSRS) trials who did not previously undergo radiation treatment at the site of the SSRS. METHODS Patients enrolled in 2 separate institutional prospective protocols and treated with SSRS between 2002 and 2011 were included. A secondary analysis was performed on patients with previously nonirradiated RCC spinal metastases treated with either single-fraction (SF) or multifraction (MF) SSRS. RESULTS SSRS was performed in 47 spinal sites on 43 patients. The median age of the patients was 62 years (range 38-75 years). The most common histological subtype was clear cell (n = 30). Fifteen sites underwent surgery prior to the SSRS, with laminectomy the most common procedure performed (n = 10). All SF SSRS was delivered to a dose of 24 Gy (n = 21) while MF regiments were either 27 Gy in 3 fractions (n = 20) or 30 Gy in 5 fractions (n = 6). The median overall survival duration for the entire cohort was 22.8 months. The median local control (LC) for the entire cohort was 80.6 months with 1-year and 2-year actuarial LC rates of 82% and 68%, respectively. Single-fraction SSRS correlated with improved 1- and 2-year actuarial LC relative to MF SSRS (95% vs 71% and 86% vs 55%, respectively; p = 0.009). On competing risk analysis, SF SSRS showed superior LC to MF SSRS (subhazard ratio [SHR] 6.57, p = 0.014). On multivariate analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), gross tumor volume (GTV) coverage (p = 0.225), and GTV minimum point dose (p = 0.97) as covariates, MF SSRS remained inferior to SF SSRS (SHR 5.26, p = 0.033) CONCLUSIONS SSRS offers durable LC for spinal metastases from RCC. Single-fraction SSRS is associated with improved LC over MF SSRS for previously nonirradiated RCC spinal metastases.

Imaging Changes in Pediatric Intracranial Ependymoma Patients Treated With Proton Beam Radiation Therapy Compared to Intensity Modulated Radiation Therapy.

PURPOSE: The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT). METHODS AND MATERIALS: Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists. RESULTS: Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P = .06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio [OR]: 0.35, P = .048; OR: 0.36, P = .05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P = .019) and multivariate (OR: 3.89, P = .024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis. CONCLUSIONS: Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.

Prospective randomized double-blind study of atlas-based organ-at-risk autosegmentation-assisted radiation planning in head and neck cancer.

BACKGROUND AND PURPOSE: Target volumes and organs-at-risk (OARs) for radiotherapy (RT) planning are manually defined, which is a tedious and inaccurate process. We sought to assess the feasibility, time reduction, and acceptability of an atlas-based autosegmentation (AS) compared to manual segmentation (MS) of OARs. MATERIALS AND METHODS: A commercial platform generated 16 OARs. Resident physicians were randomly assigned to modify AS OAR (AS+R) or to draw MS OAR followed by attending physician correction. Dice similarity coefficient (DSC) was used to measure overlap between groups compared with attending approved OARs (DSC=1 means perfect overlap). 40 cases were segmented. RESULTS: Mean ± SD segmentation time in the AS+R group was 19.7 ± 8.0 min, compared to 28.5 ± 8.0 min in the MS cohort, amounting to a 30.9% time reduction (Wilcoxon p<0.01). For each OAR, AS DSC was statistically different from both AS+R and MS ROIs (all Steel-Dwass p<0.01) except the spinal cord and the mandible, suggesting oversight of AS/MS processes is required; AS+R and MS DSCs were non-different. AS compared to attending approved OAR DSCs varied considerably, with a chiasm mean ± SD DSC of 0.37 ± 0.32 and brainstem of 0.97 ± 0.03. CONCLUSIONS: Autosegmentation provides a time savings in head and neck regions of interest generation. However, attending physician approval remains vital.

Establishing high-quality prostate brachytherapy using a phantom simulator training program.

PURPOSE: To design and implement a unique training program that uses a phantom-based simulator to teach the process of prostate brachytherapy (PB) quality assurance and improve the quality of education. METHODS AND MATERIALS: Trainees in our simulator program were practicing radiation oncologists, radiation oncology residents, and fellows of the American Brachytherapy Society. The program emphasized 6 core areas of quality assurance: patient selection, simulation, treatment planning, implant technique, treatment evaluation, and outcome assessment. Using the Iodine 125 ((125)I) preoperative treatment planning technique, trainees implanted their ultrasound phantoms with dummy seeds (ie, seeds with no activity). Pre- and postimplant dosimetric parameters were compared and correlated using regression analysis. RESULTS: Thirty-one trainees successfully completed the simulator program during the period under study. The mean phantom prostate size, number of seeds used, and total activity were generally consistent between trainees. All trainees met the V100 >95% objective both before and after implantation. Regardless of the initial volume of the prostate phantom, trainees' ability to cover the target volume with at least 100% of the dose (V100) was not compromised (R=0.99 pre- and postimplant). However, the V150 had lower concordance (R=0.37) and may better reflect heterogeneity control of the implant process. CONCLUSIONS: Analysis of implants from this phantom-based simulator shows a high degree of consistency between trainees and uniformly high-quality implants with respect to parameters used in clinical practice. This training program provides a valuable educational opportunity that improves the quality of PB training and likely accelerates the learning curve inherent in PB. Prostate phantom implantation can be a valuable first step in the acquisition of the required skills to safely perform PB.

Implications of acute left ventricular remodeling during squatting stress echocardiography.

BACKGROUND: We previously demonstrated that squatting induces left ventricular (LV) wall motion abnormalities (WMA) in areas subtended by stenotic coronary arteries. In addition, it was observed that some subjects developed acute changes in LV shape (acute left ventricular remodeling [ALVRM]) during squatting. OBJECTIVE: This study tested the hypothesis that patients with ALVRM during squatting echocardiography have higher incidences of severe coronary artery disease (CAD). METHODS: Echocardiography was performed in all standard views during standing and squatting. End-systolic frames in the apical four-chamber view were analyzed. RESULTS: The subjects were divided into three groups. Group 1 consisted of 12 subjects who developed squatting-induced ALVRM with apical and distal posterior septal akinesis, dilation of the apex and marked LV shape change at end-systole. Group 2 consisted of 20 subjects with distal posterior septal and apical akinesis without ALVRM, during squatting. Group 3 consisted of 64 subjects who developed WMA in areas other than the apex (n = 49), or normal wall motion (n = 15) during squatting. Coronary angiography in group 1 revealed that 6 subjects had left main coronary artery stenosis (LMCAS ≥ 50%), two had severe three vessel disease (≥ 90% stenosis), and one had 100% left anterior descending coronary artery occlusion. Severe CAD was defined for purpose of this study as the presence of LMCAS, or severe three vessel disease (≥ 90% stenosis). Six subjects in group 2 had LMCAS and none had severe three vessel disease (P < 0.05 vs. group 1 for LMCAS and/or three vessel disease). In group 3, eight had LMCAS and none had severe three vessel disease (P < 0.0001 vs. group 1). CONCLUSION: Patients with ALVRM have severe CAD. Therefore, patients who develop ALVRM during squatting require urgent evaluation for revascularization therapy.

Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases.

OBJECT: The aim of this study was to identify potential risk factors for and determine the rate of vertebral compression fracture (VCF) after intensity-modulated, near-simultaneous, CT image-guided stereotactic body radiotherapy (SBRT) for spinal metastases. METHODS: The study group consisted of 123 vertebral bodies (VBs) in 93 patients enrolled in prospective protocols for metastatic disease. Data from these patients were retrospectively analyzed. Stereotactic body radiotherapy consisted of 1, 3, or 5 fractions for overall median doses of 18, 27, and 30 Gy, respectively. Magnetic resonance imaging studies, obtained at baseline and at each follow-up, were evaluated for VCFs, tumor involvement, and radiographic progression. Self-reported average pain levels were scored based on the 11-point (0-10) Brief Pain Inventory both at baseline and at follow-up. Obesity was defined as a body mass index ≥ 30. RESULTS: The median imaging follow-up was 14.9 months (range 1-71 months). Twenty-five new or progressing fractures (20%) were identified, and the median time to progression was 3 months after SBRT. The most common histologies included renal cancer (36 VBs, 10 fractures, 10 tumor progressions), breast cancer (20 VBs, 0 fractures, 5 tumor progressions), thyroid cancer (14 VBs, 1 fracture, 2 tumor progressions), non-small cell lung cancer (13 VBs, 3 fractures, 3 tumor progressions), and sarcoma (9 VBs, 2 fractures, 2 tumor progressions). Fifteen VBs were treated with kyphoplasty or vertebroplasty after SBRT, with 5 procedures done for preexisting VCFs. Tumor progression was noted in 32 locations (26%) with 5 months' median time to progression. At the time of noted fracture progression there was a trend toward higher average pain scores but no significant change in the median value. Univariate logistic regression showed that an age > 55 years (HR 6.05, 95% CI 2.1-17.47), a preexisting fracture (HR 5.05, 95% CI 1.94-13.16), baseline pain and narcotic use before SBRT (pain: HR 1.31, 95% CI 1.06-1.62; narcotic: HR 2.98, 95% CI 1.17-7.56) and after SBRT (pain: HR 1.34, 95% CI 1.06-1.70; narcotic: HR 3.63, 95% CI 1.41-9.29) were statistically significant predictors of fracture progression. On multivariate analysis an age > 55 years (HR 10.66, 95% CI 2.81-40.36), a preexisting fracture (HR 9.17, 95% CI 2.31-36.43), and baseline pain (HR 1.41, 95% CI 1.05-1.9) were found to be significant risks, whereas obesity (HR 0.02, 95% CI 0-0.2) was protective. CONCLUSIONS: Stereotactic body radiotherapy is associated with a significant risk (20%) of VCF. Risk factors for VCF include an age > 55 years, a preexisting fracture, and baseline pain. These risk factors may aid in the selection of which spinal SBRT patients should be considered for prophylactic vertebral stabilization or augmentation procedures. Clinical trial registration no.: NCT00508443.

Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas.

PURPOSE: Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. METHODS AND MATERIALS: IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose-volume histograms. RESULTS: The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3%*), dentate gyrus (27.3, 75.0%*), and subventricular zone (4.5, 57.8%*). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3*, 100.0%*; middle cerebral arteries, 25.9%*, 100%*; anterior communicating arteries, 30.8*, 41.7%*; and carotid arteries, 51.5*, 77.6*). Relative reduction of integral dose to the infratentorial brain (190.7*, 109.7%*), supratentorial brain without PTV (9.6, 26.8%*), brainstem (45.6, 22.4%*), and whole brain without PTV (19.4*, 34.4%*) were recorded with the use of proton therapy. (*Differences were significant based on Friedman's test with Bonferroni-Dunn correction, α = 0.05) CONCLUSIONS: The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Improving cardiac dosimetry: Alternative beam arrangements for intensity modulated radiation therapy planning in patients with carcinoma of the distal esophagus.

PURPOSE: Radiation for carcinoma of the distal esophagus is associated with cardiac perfusion deficits and pericardial effusion. We performed a dosimetric analysis of alternative beam arrangements for use in intensity modulated radiation therapy (IMRT) planning, seeking to lower radiation dose to the heart. METHODS AND MATERIALS: Treatment plans using 4 separate beam arrangements were generated and optimized for 12 patients. Hemispheric and butterfly beam arrangements were compared with plans with posterior and lateral beam entries. Radiotherapy was planned to 50.4 Gy in 28 fractions, using step and shoot IMRT with 6 MV photons. Mean heart dose and volumes of heart and lung receiving up to specified doses (V5-V40) were recorded. Isodose distributions were evaluated for target coverage and normal tissue exposure. RESULTS: IMRT plans utilizing posterior-lateral beam arrangements significantly reduced mean cardiac doses (32.5 ± 3.9 Gy, 33.3 ± 3.2 Gy vs 24.3 ± 3.7 Gy, and 23.4 ± 4.2 Gy, P < .05, paired Student t test with post hoc Bonferroni correction) as well as the total heart volumes receiving at least 20 and 30 Gy. IMRT allowed the maximum cord dose to be limited to less than 40 Gy. While both posterior-lateral beam arrangements lead to improved cardiac dosimetry, mean lung doses as well as V5 and V20 were slightly higher, although within accepted limits. Target coverage, homogeneity, and conformality were similar or improved with the use of alternative beam configurations. CONCLUSIONS: The use of IMRT with posterior-lateral beams can significantly reduce radiation dose to cardiac structures with minimal increased dose to the lung. Future studies will assess the physiologic and clinical impact of cardiac sparing.

Coordinate down-regulation of adenylyl cyclase isoforms and the stimulatory G protein (G(s)) in intestinal epithelial cell differentiation.

The intestinal epithelium is dynamic, with proliferation of undifferentiated crypt cells balanced by terminal differentiation and cell death at the colon surface or small intestinal villus tips. Cyclic AMP, induced by agonists such as prostaglandin E(2) and vasoactive intestinal polypeptide, promotes proliferation and ion secretion and suppresses apoptosis in intestinal epithelial cells. Here, we show that cell differentiation in a model intestinal epithelium leads to attenuation of cAMP production in response to G protein-coupled receptor and receptor-independent agonists. Concomitantly, key components of the cAMP cascade, the alpha subunit of the stimulatory G protein, G(s), and adenylyl cyclase (AC) isoforms 3, 4, 6, and 7 are down-regulated. By contrast, AC1, AC2, AC8, and AC9, and the receptors for prostaglandin E(2) and vasoactive intestinal polypeptide, are not expressed or not affected by differentiation. We confirmed key findings in normal murine colon epithelium, in which the major AC isoforms and G(s)alpha are markedly down-regulated in differentiated surface cells. Suppression of AC isoforms and G(s)alpha is functionally important, because their constitutive expression completely reverses differentiation-induced cAMP attenuation. Thus, down-regulation of AC isoforms and G(s)alpha is an integral part of the intestinal epithelial differentiation program, perhaps serving to release cells from cAMP-promoted anti-apoptosis as a prerequisite for cell death upon terminal differentiation.