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Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local

A newly developed Gamma Knife relocatable eXtend frame system has enabled the delivery of multi-session Gamma Knife radiosurgery without the use of skull pin fixation frame system. In this study, we investigate and report for the first time the whole proce

OBJECTIVE: This study sought to describe a single institutions experience treating arteriovenous malformations (AVMs) of the basal ganglia, thalamus, and insula in a multimodal fashion.

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy., (© 2023. The Author(s).)

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background Primary central nervous system lymphoma (PCNSL) is rare, with a treatment backbone that typically includes high-dose methotrexate-based chemotherapy, with radiation often reserved for persistent or progressive disease. In this study, we report the outcomes of stereotactic radiosurgery (SRS) in patients with PCNSL to potentially defer whole brain radiotherapy (WBRT) or as salvage after WBRT. Methodology We performed a single-institution, retrospective review of 20 patients with PCNSL who received single-fraction or fractionated SRS to 32 lesions between September 1992 and July 2019. Results The median age at SRS was 67 years (interquartile range (IQR) = 56-74 years). The median Karnofsky Performance Status (KPS) at SRS was 80 (IQR = 50-80). In total, 18 (90%) patients received methotrexate-based chemotherapy prior to SRS, with a median of eight cycles (IQR = 5-10). A total of 10 patients received SRS for recurrent disease after chemotherapy and/or WBRT, nine patients received SRS for the persistent disease after chemotherapy alone, and one patient received up-front SRS. Overall, five patients received SRS following WBRT. The median SRS dose was 16 Gy (IQR = 14-22.5 Gy) in one fraction (IQR = 1-5 fractions). Eight patients (40%) were treated with consolidative pomalidomide or lenalidomide following SRS. The local control rate was 100% (32/32 lesions at a median follow-up of 15 months). In total, 13 of 16 (81%) patients with available follow-up experienced distant brain recurrence. The median time to distant failure following SRS was 10 months (IQR = 1-16 months). Three patients received salvage SRS, and three patients received salvage WBRT. The median overall survival from diagnosis was 39 months (95% confidence interval = 24-54 months). KPS at the time of SRS was significantly correlated with time to progression (p = 0.002). The use of lenalidomide or pomalidomide after SRS was associated with improved overall survival after SRS (three vs. 14 months, p = 0.035). Consolidative etoposide and cytarabine after initial methotrexate-based chemotherapy was also associated with improved survival following SRS (eight vs. 47 months, p = 0.028). Conclusions SRS offers effective local tumor control for patients with PCNSL; however, the majority of patients experience distant progression. SRS may have a role in the salvage setting for patients with recurrence after WBRT, or allow deferral of WBRT in select patients, although systemic therapy appears to strongly influence outcomes in this cohort., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wu et al.)

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.

Background: Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores., Methods: A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients., Results: Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively., Conclusions: Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.

Objective: To determine whether a less-invasive approach to surgery for medically refractory temporal lobe epilepsy is associated with lower health care costs and costs of lost productivity over time, compared to open surgery., Methods: We compared direct medical costs and indirect productivity costs associated with treatment with stereotactic radiosurgery (SRS) or anterior temporal lobectomy (ATL) in the ROSE (Radiosurgery or Open Surgery for Epilepsy) trial. Health care use was abstracted from hospital bills, the study database, and diaries in which participants recorded health care use and time lost from work while seeking care. Costs of use were calculated using a Medicare costing approach used in a prior study of the costs of ATL. The power of many analyses was limited by the sample size and data skewing., Results: Combined treatment and follow-up costs (in thousands of US dollars) did not differ between SRS (n = 20, mean = $76.6, 95% confidence interval [CI] = 50.7-115.6) and ATL (n = 18, mean = $79.0, 95% CI = 60.09-103.8). Indirect costs also did not differ. More ATL than SRS participants were free of consciousness-impairing seizures in each year of follow-up (all P < 0.05). Costs declined following ATL (P = 0.005). Costs tended to increase over the first 18 months following SRS (P = 0.17) and declined thereafter (P = 0.06). This mostly reflected hospitalizations for SRS-related adverse events in the second year of follow-up., Significance: Lower initial costs of SRS for medial temporal lobe epilepsy were largely offset by hospitalization costs related to adverse events later in the course of follow-up. Future studies of less-invasive alternatives to ATL will need to assess adverse events and major costs systematically and prospectively to understand the economic implications of adopting these technologies., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: We investigated prognostic models based on clinical, radiologic, and radiomic feature to preoperatively identify meningiomas at risk for poor outcomes., Methods: Retrospective review was performed for 303 patients who underwent resection of 314 meningiomas (57% World Health Organization grade I, 35% grade II, and 8% grade III) at two independent institutions, which comprised primary and external datasets. For each patient in the primary dataset, 16 radiologic and 172 radiomic features were extracted from preoperative magnetic resonance images, and prognostic features for grade, local failure (LF) or overall survival (OS) were identified using the Kaplan-Meier method, log-rank tests and recursive partitioning analysis. Regressions and random forests were used to generate and test prognostic models, which were validated using the external dataset., Results: Multivariate analysis revealed that apparent diffusion coefficient hypointensity (HR 5.56, 95% CI 2.01-16.7, P = .002) was associated with high grade meningioma, and low sphericity was associated both with increased LF (HR 2.0, 95% CI 1.1-3.5, P = .02) and worse OS (HR 2.94, 95% CI 1.47-5.56, P = .002). Both radiologic and radiomic predictors of adverse meningioma outcomes were significantly associated with molecular markers of aggressive meningioma biology, such as somatic mutation burden, DNA methylation status, and FOXM1 expression. Integrated prognostic models combining clinical, radiologic, and radiomic features demonstrated improved accuracy for meningioma grade, LF, and OS (area under the curve 0.78, 0.75, and 0.78, respectively) compared to models based on clinical features alone., Conclusions: Preoperative radiologic and radiomic features such as apparent diffusion coefficient and sphericity can predict tumor grade, LF, and OS in patients with meningioma., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: The incidence of brain metastases is increasing as a result of more routine diagnostic imaging and improved extracranial systemic treatment strategies. As noted in recent consensus guidelines, postoperative stereotactic radiosurgery (SRS) to the resection cavity has lower rates of local control than whole brain radiation therapy but improved cognitive outcomes. Further analyses are needed to improve local control and minimize toxicity., Methods and Materials: Patients receiving SRS to a resection cavity between 2006 and 2016 were retrospectively analyzed. Presurgical variables, including tumor location, diameter, dural/meningeal contact, and histology, were collected, as were SRS treatment parameters. Patients had routine follow-up with magnetic resonance imaging, and those noted to have local failure were further assessed for the recurrence location, distance from the target volume, and dosimetric characteristics., Results: Overall, 82 patients and 85 resection cavities underwent postoperative SRS during the study period. Of these, 58 patients with 60 resection cavities with available follow-up magnetic resonance imaging scans were included in this analysis. With a median follow-up of 19.8 months, local recurrence occurred in 12 of the resection cavities for a 15% 1-year and 18% 2-year local recurrence rate. Pretreatment tumor volume contacted the dura/meninges in 100% of cavities with recurrence versus 67% of controlled cavities ( P  = .025). A total of 5 infield, 5 marginal, and 4 out-of-field recurrences were found, with a median distance to the centroid from the target volume of 3 mm. The addition of a 10-mm dural margin increased the target volume overlap with the recurrence contours for 10 of the 14 recurrences., Conclusions: Dural contact was associated with an increased rate of recurrence for patients who received SRS to a surgical cavity, and the median distance of marginal recurrences from the target volume was 3 mm. These results provide evidence in support of recent consensus guidelines suggesting that additional dural margin on SRS volumes may benefit local control.

Purpose: Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9-100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ., Methods: This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated., Results: No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status., Conclusion: The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20 + CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918., (© 2018 by The American Society of Hematology.)

Objective: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE)., Methods: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up., Results: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients., Significance: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma., (Published by Elsevier Inc.)

Background and Objectives Intra-parenchymal brain surgical resection cavities usually contract in volume following low dose rate (LDR) brachytherapy implants. In this study, we systematically modeled and assessed dose variability resulting from such changes for I-125 versus Cs-131 radioactive sources. Methods Resection cavity contraction was modeled based on 95 consecutive patient cases, using surveillance magnetic resonance (MR) images. The model was derived for single point source geometry and then fully simulated in 3D where I-125 or Cs-131 seeds were placed on the surface of an ellipsoidal resection cavity. Dose distribution estimated via TG-43 calculations and biological effective dose (BED) calculations were compared for both I-125 and Cs-131, accounting for resection cavity contractions. Results Resection cavity volumes were found to contract with an effective half-life of approximately 3.4 months (time to reach 50% of maximum volume contraction). As a result, significant differences in dose distributions were noted between I-125 and Cs-131 radioactive sources. For example, when comparing with static volume, assuming no contraction effect, I-125 exhibited a 31.8% and 30.5% increase in D90 and D10 values (i.e., the minimal dose to 90% and 10% of the volume respectively) in the peripheral target areas over the follow-up period of 20.5 months. In contrast, Cs-131 seeds only exhibited a 1.44% and 0.64% increase in D90 and D10 values respectively. Such discrepancy is likewise similar for BED calculations. Conclusion Resection cavity contractions affects Cs-131 dose distribution significantly less than that of I-125 for permanent brain implants. Care must be taken to account for cavity contractions when prescribing accumulative doses of a radioactive source in performing the brain implant procedures., Competing Interests: The authors have declared that no competing interests exist.

A 42-year-old woman at 29 weeks gestation via in vitro fertilization who presented with eight metastatic brain lesions received Gamma Knife stereotactic radiosurgery (GKSRS) at our institution. In this study, we report our clinical experience and a general procedure of determining the fetal dose from patient-specific treatment plans and we describe quality assurance measurements to guide the safe practice of multi-target GKSRS of pregnant patients. To estimate fetal dose pre-treatment, peripheral dose-to-focal dose ratios (PFRs) were measured in a phantom at the distance approximating the fundus of uterus. Post-treatment, fetal dose was calculated from the actual patient treatment plan. Quality assurance measurements were carried out via the extrapolation dosimetry method in a head phantom at increasing distances along the longitudinal axis. The measurements were then empirically fitted and the fetal dose was extracted from the curve. The computed and measured fetal dose values were compared with each other and associated radiation risk was estimated. Based on low estimated fetal dose from preliminary phantom measurements, the patient was accepted for GKSRS. Eight brain metastases were treated with prescription doses of 15-19 Gy over 143 min involving all collimator sizes as well as composite sector mixed shots. Direct fetal dose computation based on the actual patient's treatment plan estimated a maximum fetal dose of 0.253 cGy, which was in agreement with surface dose measurements at the level of the patient's uterine fundus during the actual treatment. Later phantom measurements also estimated fetal dose to be in the range of 0.21-0.28 cGy (dose extrapolation curve R 2 = 0.998). Using the National Council on Radiation Protection and Measurements (NCRP) population-based model, we estimate the fetal risk of secondary malignancy, which is the primary toxicity after 25 weeks gestation, to be less than 0.01%. Of note, the patient delivered the baby via scheduled cesarean section at 36 weeks without complications attributable to the GKSRS procedure. GKSRS of multiple brain metastases was demonstrated to be safe and feasible during pregnancy. The applicability of a general patient-specific fetal dose determination method was also demonstrated for the first time for such a treatment., Competing Interests: The authors have declared financial relationships, which are detailed in the next section.

Background: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions., Methods: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests., Results: Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification., Classification: Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes., Conclusions: PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local progression in the interval between surgery and SRS are likely important factors in deciding when to proceed with adjuvant SRS. We conducted a retrospective review of patients with a brain metastasis treated with surgical resection followed by SRS to the resection cavity. Post-operative and pre-radiosurgery magnetic resonance imaging (MRI) was reviewed for evidence of cavity volume changes, amount of edema, and local tumor progression. Resection cavity volume and edema volume were measured using volumetric analysis. We identified 21 consecutive patients with a brain metastasis treated with surgical resection and radiosurgery to the resection cavity. Mean age was 57 yrs. The most common site of metastasis was the frontal lobe (38%), and the most common primary neoplasms were lung adenocarcinoma and melanoma (24% each). The mean postoperative resection cavity volume was 7.8 cm(3) and shrank to a mean of 4.5 cm(3) at the time of repeat imaging for radiosurgical planning (median 41 days after initial post-operative MRI), resulting in a mean reduction in cavity volume of 43%. Patients who underwent pre-SRS imaging within 1 month of their initial post-operative MRI had a mean volume reduction of 13% compared to 61% in those whose pre-SRS imaging was ≥1 month (p=0.0003). Post-resection edema volume was not related to volume reduction (p=0.59). During the interval between MRIs, 52% of patients showed evidence of tumor progression within the resection cavity wall. There was no significant difference in local recurrence if the interval between resection and radiosurgery was <1 month (n=8) versus ≥1 month (n=13, p=0.46). These data suggest that the surgical cavity after brain metastasis resection constricts over time with greater constriction seen in patients whose pre-SRS imaging is ≥1 month after initial post-operative imaging. Given that there was no difference in local recurrence rate, the data suggest there is benefit in waiting in order to treat a smaller resection cavity.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.

Unlike scheduled radiotherapy treatments, treatment planning time and resources are limited for emergency treatments. Consequently, plans are often simple 2D image-based treatments that lag behind technical capabilities available for nonurgent radiotherapy. We have developed a novel integrated urgent workflow that uses onboard MV CBCT imaging for patient simulation to improve planning accuracy and reduce the total time for urgent treatments. This study evaluates both MV CBCT dose planning accuracy and novel urgent workflow feasibility for a variety of anatomic sites. We sought to limit local mean dose differences to less than 5% compared to conventional CT simulation. To improve dose calculation accuracy, we created separate Hounsfield unit-to-density calibration curves for regular and extended field-of-view (FOV) MV CBCTs. We evaluated dose calculation accuracy on phantoms and four clinical anatomical sites (brain, thorax/spine, pelvis, and extremities). Plans were created for each case and dose was calculated on both the CT and MV CBCT. All steps (simulation, planning, setup verification, QA, and dose delivery) were performed in one 30 min session using phantoms. The monitor units (MU) for each plan were compared and dose distribution agreement was evaluated using mean dose difference over the entire volume and gamma index on the central 2D axial plane. All whole-brain dose distributions gave gamma passing rates higher than 95% for 2%/2 mm criteria, and pelvic sites ranged between 90% and 98% for 3%/3 mm criteria. However, thoracic spine treatments produced gamma passing rates as low as 47% for 3%/3 mm criteria. Our novel MV CBCT-based dose planning and delivery approach was feasible and time-efficient for the majority of cases. Limited MV CBCT FOV precluded workflow use for pelvic sites of larger patients and resulted in image clearance issues when tumor position was far off midline. The agreement of calculated MU on CT and MV CBCT was acceptable for all treatment sites.

A technique for delivering high-precision volume-staged stereotactic radiosurgery has been developed with Leksell Gamma Knife Perfexion for treating large arteriorvenous malformations (AVMs). The technique employs a hybrid method of combining landmark registration and voxel-based 3D image registration to enable multiple staged partial-volume treatments that accommodate repeated stereotactic frame placements. The technique was clinically implemented at our institution and the results were analyzed for a series (n=14) of large AVM cases treated since 2007. Overall, an averaged 0.34±0.09 mm in matching procedural accuracy versus standard single-fraction radiosurgery was found for these treatments. Such a result is a factor of 3-4 times lower than those previously reported, and it approaches the physical accuracy of the latest Leksell Gamma Knife Perfexion system. In conclusion, volume-staged radiosurgery has been demonstrated to be deliverable with the same level of accuracy as standard single-fraction radiosurgery.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Background and Purpose: MR image-guided gamma knife radiosurgery is often used to treat intra-axial metastatic neoplasms. Following treatment, it is often difficult to determine whether a progressively enhancing lesion is due to metastatic tumor recurrence or radiation necrosis. The purpose of our study was to determine whether relative cerebral blood volume (rCBV), relative peak height (rPH), and percentage of signal-intensity recovery (PSR) derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can distinguish recurrent metastatic tumor from radiation necrosis., Materials and Methods: Twenty-seven patients with systemic cancer underwent gamma knife radiosurgery for metastatic lesions of the brain and subsequently developed enlarging regions of enhancement within the radiation field. Subsequent surgical resection or clinicoradiologic follow-up established a diagnosis of recurrent metastatic tumor or radiation necrosis. Perfusion MR imaging datasets were retrospectively reprocessed, and regions of interest were drawn around the entire contrast-enhancing region. The resulting T2* signal-intensity time curves produced rCBV, rPH, and PSR values for each examination. A Welch t test was used to compare imaging values between groups., Results: The mean, minimum, and maximum PSR values were significantly lower (P < .01) in cases of recurrent metastatic tumor. The mean and maximum rCBV and rPH values were significantly higher (P < .02) in the recurrent metastatic tumor group., Conclusions: The findings of our study suggest that perfusion MR imaging may be used to differentiate recurrent intra-axial metastatic tumor from gamma knife-induced radiation necrosis.

Object: Whole-brain radiotherapy (WBRT) after resection of a single brain metastasis can cause long-term radiation toxicity. The authors evaluated the efficacy of resection and placement of 125I seeds (without concomitant WBRT) for newly diagnosed single brain metastases., Methods: In a retrospective review from two institutions (1997-2003), 15 women and 11 men (mean age 55 years) with single brain metastasis underwent gross-total resection and placement of permanent low-activity 125I seeds. Primary systemic cancer sites varied. Patients were monitored clinically and radiographically. With neuroimaging evidence of local recurrence or new distant metastasis, further treatment was administered at the physician's discretion. By the median follow-up evaluation (12 months), the local tumor control rate was 96%. Distant metastases occurred in three patients within 3 months, suggesting synchronous metastasis, and in six patients more than 3 months after treatment, indicating metachronous metastasis. Treatment in these cases included radiosurgery in seven patients, WBRT in two, and resection together with 125I seed placement in one. Two patients who suffered radiation necrosis required operative intervention (lesion diameter > 3 cm, total activity > 40 mCi). All 26 patients who had been treated using resection and placement of 125I seeds had a stable or an improved Karnofsky Performance Scale score. At the last review, nine of 16 living patients showed no evidence of treatment failure. The median actuarial survival rate was 17.8 months (Kaplan-Meier method)., Conclusions: Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumor control. Local control and patient survival rates were at least as good as those reported for resection combined with WBRT. Although the authors noted a higher incidence of distant metastases compared with that reported in other studies of initial WBRT, these metastases were generally well controlled with a combination of surgery, stereotactic radiosurgery, and, less often, WBRT. Twenty-four patients (92%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirty-eight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score > or =60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150-500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy.

Interstitial techniques for hyperthermia therapy of cancer continue to evolve in response to requirements for better localization and control over heating of deep seated tissues. Magnetic induction heating of ferromagnetic implants is one of several available techniques for producing interstitial hyperthermia, using thermal conduction to redistribute heat within an array of controlled temperature "hot sources." This report describes seven induction heating coil designs that can be used for producing strong magnetic fields around ferromagnetic seed implants located in different sites in the body. The effect of coil design on the extent and uniformity of the magnetic field is characterized, and appropriate electrostatic shield designs for minimizing electric field coupling to the patient are described. Advantages and disadvantages of each coil type are discussed in terms of the radiated fields, coil efficiency, and ease of use, and appropriate applications are given for each design. This armamentarium of induction coils provides the ability to customize magnetic field distributions for improved coupling of energy into ferromagnetic implant arrays located at any depth or orientation in the body. Proper selection of heating coil configuration should simplify patient setup, improve the safety of patient treatments, and pave the way for future applications of interstitial heating in sites that were previously untreatable.

Radiation has provided excellent local control rates in choroidal melanoma, but significant impairment in visual acuity has occurred in 30-60% of patients due in part to the development of radiation vasculopathy in the fovea and optic disc. Hyperthermia has been shown to have a synergistic effect when added to radiation therapy in human malignancies. The use of hyperthermia in ocular melanoma may allow a reduction in the total radiation dose necessary to achieve local control. A 2450-MHz microwave plaque applicator with integral surface cooling was used to deliver hyperthermia treatments to rabbit eyes containing choroidal melanomas. Extensive thermal mapping was done in acute eyes. In 18 survival animals, a single 23-G needle thermocouple probe with three sensors was inserted into the tumor. Target temperatures of 41.0-46.0 degrees C were maintained for 1 hour. All tumor-bearing eyes were followed for 1 month after treatment, or until tumor growth was noted, with serial ultrasound measurements and visual examinations. A 92% response rate was obtained in tumors treated at temperatures greater than 43.0 degrees C for 1 hour with no significant toxicity. Heat alone has significant tumoricidal properties in this animal model.