Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.

BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).

Cognitive Dysfunction in Non-CNS Metastatic Cancer: Comparing Brain Metastasis, Non-CNS Metastasis, and Healthy Controls.

Limited research has compared cognition of people with non-central nervous system metastatic cancer (NCM) vs. metastatic brain cancer (BM). This prospective cross-sectional study was comprised 37 healthy controls (HC), 40 NCM, and 61 BM completing 10 neuropsychological tests. The NCM performed below HCs on processing speed and executive functioning tasks, while the BM group demonstrated lower performance across tests. Tasks of processing speed, verbal fluency, and verbal memory differentiated the clinical groups (BM < NCM). Nearly 20% of the NCM group was impaired on at least three neuropsychological tests whereas approximately 40% of the BM group demonstrated the same level of impairment.

Racial and socioeconomic disparities in glioblastoma outcomes: A single-center, retrospective cohort study.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor. Emerging reports have suggested that racial and socioeconomic disparities influence the outcomes of patients with GBM. No studies to date have investigated these disparities controlling for isocitrate dehydrogenase (IDH) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) status. METHODS: Adult patients with GBM were retrospectively reviewed at a single institution from 2008 to 2019. Univariable and multivariable complete survival analyses were performed. A Cox proportional hazards model was used to assess the effect of race and socioeconomic status controlling for a priori selected variables with known relevance to survival. RESULTS: In total, 995 patients met inclusion criteria. Of these, 117 patients (11.7%) were African American (AA). The median overall survival for the entire cohort was 14.23 months. In the multivariable model, AA patients had better survival compared with White patients (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.2-0.69). The observed survival difference was significant in both a complete case analysis model and a multiple imputations model accounting for missing molecular data and controlling for treatment and socioeconomic status. AA patients with low income (HR, 2.17; 95% CI, 1.04-4.50), public insurance (HR, 2.25; 95% CI, 1.04-4.87), or no insurance (HR, 15.63; 95% CI, 2.72-89.67) had worse survival compared with White patients with low income, public insurance, or no insurance, respectively. CONCLUSIONS: Significant racial and socioeconomic disparities were identified after controlling for treatment, GBM genetic profile, and other variables associated with survival. Overall, AA patients demonstrated better survival. These findings may suggest the possibility of a protective genetic advantage in AA patients. PLAIN LANGUAGE SUMMARY: To best personalize treatment for and understand the causes of glioblastoma, racial and socioeconomic influences must be examined. The authors report their experience at the O'Neal Comprehensive Cancer Center in the deep south. In this report, contemporary molecular diagnostic data are included. The authors conclude that there are significant racial and socioeconomic disparities that influence glioblastoma outcome and that African American patients do better.

Commissioning and clinical evaluation of the IDENTIFYTM surface imaging system for frameless stereotactic radiosurgery.

PURPOSE: To commission and assess the clinical performance of a new commercial surface imaging (SI) system by analyzing intra-fraction motion from the initial cohort of patients treated with frameless stereotactic radiosurgery (fSRS). METHODS: The IDENTIFYTM SI system was commissioned for clinical use on an Edge (Varian Medical Systems, Palo Alto, CA) linear accelerator. All patients who received intracranial radiotherapy with HyperArcTM (Varian Medical Systems, Palo Alto, CA) were immobilized with the EncompassTM (Qfix, Avondale, PA) thermoplastic mask and monitored for intra-fraction motion with SI. IDENTIFYTM log files were correlated with trajectory log files to correlate treatment parameters with SI-reported offsets. IDENTIFYTM reported offsets were correlated with gantry and couch angles to assess system performance for obstructed and clear camera field of view. Data were stratified by race to evaluate performance differences due to skin tone. RESULTS: All commissioning data were found to meet recommended tolerances. IDENTIFYTM was used to monitor intra-fraction motion on 1164 fractions from 386 patients. The median magnitude of translational SI reported offsets at the end of treatment was 0.27 mm. SI reported offsets were shown to increase when camera pods are blocked by the gantry with larger increases seen at non-zero couch angles. With camera obstruction, the median magnitude of the SI reported offset was 0.50 and 0.80 mm for White and Black patients, respectively. CONCLUSIONS: IDENTIFYTM performance during fSRS is comparable to other commercially available SI systems where offsets are shown to increase at non-zero couch angles and during camera pod blockage.

A roadmap for implementation of kV-CBCT online adaptive radiation therapy and initial first year experiences.

PURPOSE: Online Adaptive Radiation Therapy (oART) follows a different treatment paradigm than conventional radiotherapy, and because of this, the resources, implementation, and workflows needed are unique. The purpose of this report is to outline our institution's experience establishing, organizing, and implementing an oART program using the Ethos therapy system. METHODS: We include resources used, operational models utilized, program creation timelines, and our institutional experiences with the implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year's clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set-up, initial kV-CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2nd check and adaptive QA, 2nd kV-CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed. RESULTS: We retrospectively analyzed data from 97 patients treated from August 2021-August 2022. One thousand six hundred seventy seven individual fractions were treated and analyzed, 632(38%) were non-adaptive and 1045(62%) were adaptive. Seventy four of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52 ± 11.42 min from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84 ± 8.21 min. CONCLUSION: We present our institution's experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to the treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that the average overall treatment time was approximately 35 min and the average time for the adaptive component of treatment was approximately 20 min.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

PURPOSE: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. METHODS: In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. RESULTS: There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). CONCLUSION: Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Clinical correlates of the ability to consent to research participation in brain metastasis.

OBJECTIVE: Impairment in the ability to provide informed consent is common in persons with brain metastasis. However, little is known about what factors contribute to this impairment in the patient group. Our objective is to determine if the associations between demographic, cognitive, and clinical variables correlate with the ability to provide informed consent in persons with brain metastasis. METHODS: We administered a comprehensive neuropsychological battery to a group of 61 persons with brain metastasis. Demographic and clinical information was also collected. All diagnoses were made by board-certified oncologists and were verified histologically. Statistical analyses included Pearson's product-moment correlations, point biserial correlations, and linear regression. RESULTS: Results indicated that combinations of education, verbal memory, executive function, whole brain radiation therapy, and chemotherapy affected various aspects of the ability to provide informed consent. Subsequent regression models demonstrated that these variables contributed a significant amount of shared variance to the ability to provide informed consent. CONCLUSION: We found that the ability of persons with brain metastasis to provide informed consent is a cognitively complex ability that is also affected by education and treatment variables. This information can help clinical researchers in identifying persons with brain metastasis at risk of an impaired ability to provide informed consent and aid in the consenting process.

Using cognition to predict the ability to understand medical treatment in brain and metastatic cancer.

OBJECTIVE: To determine if cognition can be used to identify persons with cancer at high risk for the impaired ability to understand treatment decisions. METHODS: The association between understanding treatment decisions and cognition was examined using data from 181 participants across four groups: 67 with brain metastasis, 41 with metastatic cancer that has not spread to the brain, 27 with malignant glioma, and 46 healthy controls. All diagnoses were made by board-certified oncologists and were verified histologically. RESULTS: Results indicated that numerous cognitive functions were associated with the ability to understand treatment decisions in persons with cancer. The following proportion of participants demonstrated impaired understanding of treatment decisions in our three patient groups: approximately 51% malignant glioma, approximately 46% brain metastasis, and approximately 24% metastatic cancer. In a combined brain cancer group, we were able to use cognitive performance to predict the impaired ability to understand treatment decisions. CONCLUSIONS: An impaired ability to understand treatment decisions is prevalent in persons with brain cancer and persons with metastatic cancer. Performance on a brief cognitive battery can be used to help clinicians identify patients at particular risk for impaired medical decision making.

Treatment of pediatric high-grade central nervous system tumors with high-dose methotrexate in combination with multiagent chemotherapy: A single-institution experience.

BACKGROUND: Effective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described. PROCEDURE: We retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine. RESULTS: Six patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient.  Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial).  Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146).  Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%).  Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths. CONCLUSIONS: DIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors.

Surface guided imaging during stereotactic radiosurgery with automated delivery.

PURPOSE: To report on the use of surface guided imaging during frameless intracranial stereotactic radiotherapy with automated delivery via HyperArcTM (Varian Medical Systems, Palo Alto, CA). METHODS: All patients received intracranial radiotherapy with HyperArcTM and were monitored for intrafraction motion by the AlignRT® (VisionRT, London, UK) surface imaging (SI) system. Immobilization was with the EncompassTM (Qfix, Avondale, PA) aquaplast mask device. AlignRT® log files were correlated with trajectory log files to correlate treatment parameters with SI reported offsets. SI reported offsets were correlated with gantry angle and analyzed for performance issues at non-zero couch angles and during camera-pod blockage during gantry motion. Demographics in the treatment management system were used to identify race and determine if differences in SI reported offsets are due to skin tone settings. RESULTS: A total of 981 fractions were monitored over 14 months and 819 were analyzed. The median AlignRT® reported motion from beginning to the end of treatment was 0.24 mm. The median offset before beam on at non-zero couch angles was 0.55 mm. During gantry motion when camera pods are blocked, the median magnitude was below 1 mm. Median magnitude of offsets at non-zero couch angles was not found to be significantly different for patients stratified by race. CONCLUSIONS: Surface image guidance is a viable alternative to scheduled mid-treatment imaging for monitoring intrafraction motion during stereotactic radiosurgery with automated delivery.

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 µM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

Diagnosing growth in low-grade gliomas with and without longitudinal volume measurements: A retrospective observational study.

BACKGROUND: Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas. METHODS AND FINDINGS: We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation (p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods (p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients (n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials. CONCLUSIONS: The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting growth of low-grade gliomas. Our findings support the idea that physicians aided by CAD detect growth at significantly smaller volumes than physicians using visual comparison alone. This study does not answer the questions whether to treat or not and which treatment modality is optimal. Nonetheless, early growth detection sets the stage for future clinical studies that address these questions and whether early therapeutic interventions prolong survival and improve quality of life.

LINAC based stereotactic radiosurgery for multiple brain metastases: guidance for clinical implementation.

Introduction: Stereotactic radiosurgery (SRS) is a promising treatment option for patients with multiple brain metastases (BM). Recent technical advances have made LINAC based SRS a patient friendly technique, allowing for accurate patient positioning and a short treatment time. Since SRS is increasingly being used for patients with multiple BM, it remains essential that SRS be performed with the highest achievable quality in order to prevent unnecessary complications such as radionecrosis. The purpose of this article is to provide guidance for high-quality LINAC based SRS for patients with BM, with a focus on single isocenter non-coplanar volumetric modulated arc therapy (VMAT). Methods: The article is based on a consensus statement by the study coordinators and medical physicists of four trials which investigated whether patients with multiple BM are better palliated with SRS instead of whole brain radiotherapy (WBRT): A European trial (NCT02353000), two American trials and a Canadian CCTG lead intergroup trial (CE.7). This manuscript summarizes the quality assurance measures concerning imaging, planning and delivery. Results: To optimize the treatment, the interval between the planning-MRI (gadolinium contrast-enhanced, maximum slice thickness of 1.5 mm) and treatment should be kept as short as possible (< two weeks). The BM are contoured based on the planning-MRI, fused with the planning-CT. GTV-PTV margins are minimized or even avoided when possible. To maximize efficiency, the preferable technique is single isocenter (non-)coplanar VMAT, which delivers high doses to the target with maximal sparing of the organs at risk. The use of flattening filter free photon beams ensures a lower peripheral dose and shortens the treatment time. To bench mark SRS treatment plan quality, it is advisable to compare treatment plans between hospitals. Conclusion: This paper provides guidance for quality assurance and optimization of treatment delivery for LINAC-based radiosurgery for patients with multiple BM.

Stereotactic radiosurgery with MLC-defined arcs: Verification of dosimetry, spatial accuracy, and end-to-end tests.

PURPOSE: To measure dosimetric and spatial accuracy of stereotactic radiosurgery (SRS) delivered to targets as small as the trigeminal nerve (TN) using a standard external beam treatment planning system (TPS) and multileaf collimator-(MLC) equipped linear accelerator without cones or other special attachments or modifications. METHODS: Dosimetric performance was assessed by comparing computed dose distributions to film measurements. Comparisons included the γ-index, beam profiles, isodose lines, maximum dose, and spatial accuracy. Initially, single static 360° arcs of MLC-shaped fields ranging from 1.6 × 5 to 30 × 30 mm2 were planned and delivered to an in-house built block phantom having approximate dimensions of a human head. The phantom was equipped with markings that allowed accurate setup using planar kV images. Couch walkout during multiple-arc treatments was investigated by tracking a ball pointer, initially positioned at cone beam computed tomography (CBCT) isocenter, as the couch was rotated. Tracks were mapped with no load and a 90 kg stack of plastic plates simulating patient treatment. The dosimetric effect of walkout was assessed computationally by comparing test plans that corrected for walkout to plans that neglected walkout. The plans involved nine 160° arcs of 2.4 × 5 mm2 fields applied at six different couch angles. For end-to-end tests that included CT simulation, target contouring, planning, and delivery, a cylindrical phantom mimicking a 3 mm lesion was constructed and irradiated with the nine-arc regimen. The phantom, lacking markings as setup aids was positioned under CBCT guidance by registering its surface and internal structures with CTs from simulation. Radiochromic film passing through the target center was inserted parallel to the coronal and the sagittal plane for assessment of spatial and dosimetric accuracy. RESULTS: In the single-arc block phantom tests computed maximum doses of all field sizes agreed with measurements within 2.4 ± 2.0%. Profile widths at 50% maximum agreed within 0.2 mm. The largest targeting error was 0.33 mm. The γ-index (3%, 1 mm) averaged over 10 experiments was >1 in only 1% of pixels for field sizes up to 10 × 10 mm2 and rose to 4.4% as field size increased to 20 × 20 mm2 . Table walkout was not affected by load. Walkout shifted the target up to 0.6 mm from CBCT isocenter but, according to computations shifted the dose cloud of the nine-arc plan by only 0.16 mm. Film measurements verified the small dosimetric effect of walkout, allowing walkout to be neglected during planning and treatment. In the end-to-end tests average and maximum targeting errors were 0.30 ± 0.10 and 0.43 mm, respectively. Gamma analysis of coronal and sagittal dose distributions based on a 3%/0.3 mm agreement remained <1 at all pixels. To date, more than 50 functional SRS treatments using MLC-shaped static field arcs have been delivered. CONCLUSION: Stereotactic radiosurgery (SRS) can be planned and delivered on a standard linac without cones or other modifications with better than 0.5 mm spatial and 5% dosimetric accuracy.

Optical surface guidance for submillimeter monitoring of patient position during frameless stereotactic radiotherapy.

PURPOSE: To evaluate the accuracy of monitoring intrafraction motion during stereotactic radiotherapy with the optical surface monitoring system. Prior studies showing a false increase in the magnitude of translational offsets at non-coplanar couch positions prompted the vendor to implement software changes. This study evaluated two software improvements intended to address false offsets. METHODS: The vendor implemented two software improvements: a volumetric (ACO) rather than planar calibration and, approximately 6 months later, an improved calibration workflow (CIB) designed to better compensate for thermal drift. Offsets relative to the reference position, obtained at table angle 0 following image-guided setup, were recorded before beam-on at each table position and at the end of treatment the table returned to 0° for patients receiving SRT. RESULTS: Prior to ACO, between ACO and CIB, and after CIB, 223, 155, and 436 fractions were observed respectively. The median magnitude of translational offsets at the end of treatment was similar for all three intervals: 0.29, 0.33, and 0.27 mm. Prior to ACO, the offset magnitude for non-zero table positions had a median of 0.79 mm and was found to increase with increasing distance from isocenter to the anterior patient surface. After ACO, the median magnitude was 0.74 mm, but the dependence on surface-to-isocenter distance was eliminated. After CIB, the median magnitude for non-zero table positions was reduced to 0.57 mm. CONCLUSION: Ongoing improvements in software and calibration procedures have decreased reporting of false offsets at non-zero table angles. However, the median magnitude for non-zero table angles is larger than that observed at the end of treatment, indicating that accuracy remains better when the table is not rotated.

CT Measures of Bone Mineral Density and Muscle Mass Can Be Used to Predict Noncancer Death in Men with Prostate Cancer.

Purpose To determine if computed tomographic (CT) metrics of bone mineral density and muscle mass can improve the prediction of noncancer death in men with localized prostate cancer. Materials and Methods Institutional review board approval was obtained, with waiver of informed consent. All patients who underwent radiation therapy for localized prostate cancer between 2001 and 2012 with height, weight, and past medical history documented and who underwent CT that included the L4-5 vertebral interspace were included. On a single axial CT section obtained at the mid-L5 level, the mean CT attenuation of the trabecular bone of the L5 vertebral body (L5HU) was measured. The height-normalized psoas cross-sectional area (PsoasL4-5) was measured on a single CT section obtained at the L4-5 vertebral interface. Multivariable Cox proportional hazards models were used to assess effects on noncancer death. By using parameter estimates from an adjusted model, a prognostic index for prediction of noncancer death was generated and compared with age-adjusted Charlson Comorbidity Index (CCI) by using the Harrell c statistic. Results Six hundred fifty-three men met the inclusion criteria. Prostate cancer risk grouping, androgen deprivation, race, age-adjusted CCI, L5HU, and PsoasL4-5 were included in a multivariable model. Age-adjusted CCI (hazard ratio [HR] = 1.36, P < .001), L5HU (HR = 2.88 for L5HU < 105 HU, HR = 1.42 for 105 HU ≤ L5HU ≤ 150 HU, P < .001), PsoasL4-5 (HR = 1.95 for PsoasL4-5 < 7.5 cm2/m2, P = .003), and race (HR = 1.68 for African American race, HR = 1.77 for other nonwhite race, P = .019) were independent predictors of noncancer death. The prognostic index yielded a c value of 0.747 for the prediction of noncancer death versus 0.718 for age-adjusted CCI alone. Conclusion L5HU and PsoasL4-5, which are surrogates for bone mineral density and muscle mass, respectively, were independent predictors of noncancer death. The prognostic index that incorporated these measures with the CCI was associated with improved accuracy for prediction of noncancer death. © RSNA, 2016 Online supplemental material is available for this article.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Combining Computed Tomography-Based Bone Density Assessment with FRAX Screening in Men with Prostate Cancer.

To investigate the addition of a computed tomography (CT)-based method of osteoporosis screening to FRAX without bone mineral density (BMD) fracture risk assessment in men undergoing radiotherapy for prostate cancer, we reviewed the records of all patients with localized prostate cancer treated with external beam radiotherapy at our institution between 2001 and 2012. The 10-yr probability of hip fracture was calculated using the FRAX algorithm without BMD. The CT attenuation of the L5 trabecular bone (L5CT) was assessed by contouring the trabecular bone on a single CT slice at the level of the midvertebral body and by averaging the Hounsfield units (HU) of all included voxels. L5CT values of 105 and 130 HU were used as screening thresholds. The clinical characteristics of additional patients identified by each L5CT screening threshold value were compared to patients whose estimated 10-yr risk of hip fracture was 3% or greater by FRAX without BMD. A total of 609 patients treated between 2001 and 2012 had CT scans available for review and complete clinical information allowing for FRAX without BMD risk calculation. Seventy-four (12.2%) patients had an estimated 10-yr risk of hip fracture of 3% or greater. An additional 22 (3.6%) and 71 (11.6%) patients were identified by CT screening when thresholds L5CT = 105 HU and L5CT = 130 HU were used, respectively. Compared to the group of patients identified by FRAX without BMD, the additional patients identified by CT screening at each L5CT threshold level tended to be younger and heavier, and were more likely to be African-American or treated without androgen deprivation therapy. These results suggest that the addition of CT-based screening to FRAX without BMD risk assessment identifies additional men with different underlying clinical characteristics who may be at risk for osteoporosis and may benefit from pharmacological therapy to increase BMD and reduce fracture risk.

Cognitive predictors of understanding treatment decisions in patients with newly diagnosed brain metastasis.

BACKGROUND: Medical decision-making capacity is a higher-order functional skill that refers to a patient's ability to make informed, sound decisions related to care and treatment. In a medical context, understanding is the most cognitively demanding consent standard and refers to a patient's ability to comprehend information to the extent that informed decisions can be made. METHODS: The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board-certified radiation oncologist and were verified histologically. In total, 41 demographically matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (ie, intact or impaired). RESULTS: Results indicate that measures of simple attention, verbal fluency, verbal memory, processing speed, and executive functioning were all associated with understanding, and that verbal memory and phonemic fluency were the primary cognitive predictors. Using these two primary predictors, equations can be constructed to predict the ability to understand treatment decisions in patients with brain metastasis. CONCLUSIONS: Although preliminary, these data demonstrate how cognitive measures can estimate understanding as it relates to medical decision-making capacities in these patients. Clinically, these findings suggest that poor verbal memory and expressive language function could serve as "red flags" for reduced consent capacity in this patient population, thus signaling that a more comprehensive medical decision-making capacity evaluation is warranted.

Prolonged treatment with bevacizumab is associated with brain atrophy: a pilot study in patients with high-grade gliomas.

Bevacizumab is widely used for treatment of high-grade gliomas and other malignancies. Because bevacizumab has been shown to be associated with neurocognitive decline, this study is designed to investigate whether prolonged treatment with bevacizumab is also associated with brain atrophy. We identified 12 high-grade glioma patients who received bevacizumab for 12 months at the first recurrence and 13 matched controls and blindly compared the volumes of the contralateral hemispheres and contralateral ventricle in these two groups at baseline and after 12 ± 2 months of the baseline scan by two independent analyses. The volumes of the contralateral hemispheres and ventricles did not differ significantly between the two groups at baseline. Whereas, in the control group the volumes of the contralateral hemisphere changed subtly from baseline to follow-up (p = 0.23), in the bevacizumab-treated group the volumes significantly decreased from baseline to follow-up (p = 0.03). There was significant increase in the contralateral ventricle volume from base line to follow-up scans in both the control group (p = 0.01) and in the bevacizumab group (p = 0.005). Both the absolute and the percentage changes of contralateral hemisphere volumes and contralateral ventricular volumes between the two patient groups were statistically significant (p < 0.05). Results of this study demonstrate prolonged treatment with bevacizumab is associated with atrophy of the contralateral brain hemisphere.