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Supplementary Figure 1 from Prognostic Significance of Growth Kinetics in Newly Diagnosed Glioblastomas Revealed by Combining Serial Imaging with a Novel Biomathematical Model

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Supplementary Methods, Figure and Table Legend from Prognostic Significance of Growth Kinetics in Newly Diagnosed Glioblastomas Revealed by Combining Serial Imaging with a Novel Biomathematical Model

Glioblastomas are the most aggressive primary brain tumors, characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with glioblastoma have been associated with a number of clinicopathologic factors including age and neurologic status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically based mathematical model for glioma growth and invasion, examination of serial pretreatment MRIs of 32 glioblastoma patients allowed quantification of these rates for each patient's tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age and Karnofsky performance status), these model-defined parameters quantifying biological aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were used to the duration of survival predicted (by the model) without any therapy would provide a therapeutic response index (TRI) of the overall effectiveness of the therapies. The TRI may provide important information, not otherwise available, about the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pretreatment imaging may be quantitatively useful in characterizing the survival of individual patients with glioblastoma. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for stratifying patients for clinical studies relative to their pretreatment biological aggressiveness. [Cancer Res 2009;69(23):9133–40]

Supplementary Table 1 from Prognostic Significance of Growth Kinetics in Newly Diagnosed Glioblastomas Revealed by Combining Serial Imaging with a Novel Biomathematical Model

Glioblastoma multiforme is the most aggressive type of primary brain tumor. Glioblastoma growth dynamics vary widely across patients, making it difficult to accurately gauge their response to treatment. We developed a model-based metric of therapy response called Days Gained that accounts for this heterogeneity. Here, we show in 63 newly diagnosed patients with glioblastoma that Days Gained scores from a simple glioblastoma growth model computed at the time of the first postradiotherapy MRI scan are prognostic for time to tumor recurrence and overall patient survival. After radiation treatment, Days Gained also distinguished patients with pseudoprogression from those with true progression. Because Days Gained scores can be easily computed with routinely available clinical imaging devices, this model offers immediate potential to be used in ongoing prospective studies. Cancer Res; 73(10); 2976–86. ©2013 AACR.

Radiation therapy is often used to treat meningioma with adverse features or when unresectable. Proton therapy has advantages over photon therapy in reducing integral dose to the brain. This study compared the incidence of radiological and clinical adverse events after photon versus proton therapy in the treatment of meningioma. A retrospective review was conducted on patients with meningioma treated with proton or photon therapy at two high-volume tertiary cancer centers. Patients with a history of prior radiation therapy (RT) or less than 3 months of follow-up were excluded. Post-RT imaging changes were categorized into abnormal T2 signal intensities (T2 changes) or abnormal T1 post-contrast and T2 signal intensities (T1c+T2 changes) on magnetic resonance imaging (MRI). Clinical outcomes of adverse events and survival were compared between the proton and photon therapies. Among the total of 77 patients, 38 patients received proton therapy and 39 patients received photon therapy. The median age at diagnosis was 55 years and median follow-up was 2.2 years. No significant differences in symptomatic adverse events were observed between the two groups: grade ≥ 2 adverse events were seen in 4 (10.5%) patients in the proton group and 3 (7.7%) patients in the photon group (p = 0.67). The 2-year cumulative incidences of T2 changes were 38.3% after proton therapy and 47.7% after photon therapy (p = 0.53) and the 2-year cumulative incidences of T1c+T2 changes were 26.8% after proton therapy and 5.3% after photon therapy (p = 0.02). One patient experienced grade ≥ 4 adverse event in each group (p = 0.99). Estimated 2-year progression-free survival was 79.5% (proton therapy 76.0% vs. photon therapy 81.3%, p = 0.66) and 2-year overall survival was 89.7% (proton therapy 86.6% vs. photon therapy 89.3%, p = 0.65). Following RT, high rates of T2 changes were seen in meningioma patients regardless of treatment modality. Proton therapy was associated with significantly higher rates of T1c+T2 changes compared with photon therapy, but severe adverse events were uncommon in both groups and survival outcomes were comparable between the two groups. Future studies will aim at correlating the MRI changes with models that can be incorporated into RT planning to avoid toxicity.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Introduction Clinical behavior, treatment parameters, and prognostic factors are less well defined in older adults with low-grade gliomas (LGG). We conducted a two-institution retrospective review of older patients with LGG to better understand disease characteristics and prognosis in this population. Methods Northwestern University (NU) and The University of Washington (UW) clinical research databases were queried for patients ≥ 50 years of age with a diagnosis of WHO grade II glioma between January 1, 2000 and December 2012 (UW). Medical records were reviewed and data relevant to diagnosis, treatment and outcomes were collected. PFS and OS with respect to prognostic factors were calculated. Log-rank test and multivariate proportional hazards models were calculated for multiple tumor characteristics. Results Thirty-five patients with a diagnosis of LGG (WHO grade II) were identified; 15 women and 20 men had a median age of 55 (range 50-78). Fourteen had astrocytomas, fourteen had oligodendrogliomas and seven had oligoastrocytomas. Eight patients had contrast enhancement on neuroimaging, 9 of 21 tested had 1p19q co-deletion and 5 of 14 tested had an IDH1 mutation. Five year PFS was 21% with median PFS of 17 months; 20 patients had died (5 year OS=43%, median OS=48 months). On univariate analysis There was a statistically significant improvement in OS for patients with mixed histology (p=0.001), no midline shift at diagnosis (p=0.002) and with IDH1 mutation (p=0.003). Conclusion LGG appear more aggressive in older patients. Treatment following surgical resection should be considered; ongoing studies may clarify the most appropriate treatments for this age group.

Background Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit. Objective To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas. Methods We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line. Results Most patients with recurrent HGG developed "in-field" treatment failure following SRS (n = 40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio = 0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P = .016). There was a statistically significant increase in distant versus in-field failure among older patients (P = .035). This effect was independent of bevacizumab use (odds ratio = 0.54, P = 1.0). Conclusion Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Multisession stereotactic radiation therapy is increasingly being seen as a preferred option for intracranial diseases in close proximity to critical structures and for larger target volumes. The objective of this study is to investigate the reproducibility of the Extend system from Elekta. A retrospective review was conducted for all patients treated with multisession Gamma Knife between July 2010 and June 2015, including both malignant and benign lesions. Eighty-four patients were treated in this 5-year span. The average residual daily setup uncertainty was 0.48 (0.19) mm. We compare measurements of setup uncertainty from the Extend system to measurements performed with a linac-based approach previously used in our center. The Extend system has significantly reduced setup uncertainty for fractionated intracranial treatments at our institution. Positive results were observed in a small population of edentulous patients. The Extend system compares favorably with other approaches to delivering intracranial stereotactic radiotherapy and is a robust, simple-to-use, and precise method for treating multisession intracranial lesions.

OBJECTIVE Brain arteriovenous malformations (bAVMs) are rare in pediatric patients but represent the most common cause of hemorrhagic stroke in this population. Pediatric patients demonstrate superior outcomes in comparison with adult patients with similar lesions and presentations. Most studies of clinical outcomes of pediatric bAVMs use the modified Rankin Scale (mRS), despite a lack of validation in pediatric patients. METHODS The authors interviewed the parents of 26 pediatric patients who underwent multimodality bAVM treatment and administered the Pediatric Quality of Life Inventory (PedsQL)—a well-validated tool for pediatric outcomes that quantifies performance in a physical, emotional, social, and school domains. They also reviewed clinical information from the patients' medical charts. Statistical analysis was performed using a log-transformed t-test, the Mann-Whitney exact test, the Kruskal-Wallis test, and Spearman correlation. In addition, the literature was reviewed for prior reports of clinical outcome of pediatric cases of bAVM. RESULTS The average PedsQL health-related quality of life score was 71 ± 24, with an average age at diagnosis of 12.5 years and an average follow-up period of 6.8 years. Seventeen patients (65%) presented with hemorrhage and 4 (15%) with seizures. PedsQL scores correlated strongly and at a statistically significant level (p < 0.001) with mRS, Pediatric Overall Performance Category (POPC), Pediatric Cerebral Performance Category (PCPC), and Glasgow Outcome Scale scores. Multivariate modeling validated special education, corrective devices, and cure status as significant predictors of PedsQL scores. Statistically significant risk factors for undergoing placement of a ventriculoperitoneal shunt included lower Glasgow Coma Scale motor scores on admission (p = 0.042), cerebellar location (p = 0.046), and nidus volume (p = 0.017). Neither treatment modality nor location statistically affected clinical outcomes at follow-up. CONCLUSIONS There have been few studies of long-term clinical outcomes of bAVM in pediatric patients, and previously published studies have used conventional metrics that have been validated in the adult population, such as the mRS. Although these metrics can serve as reasonable surrogates, an accurate understanding of overall health-related quality of life is contingent on utilizing validated toolsets, such as the PedsQL.

BACKGROUND Brain arteriovenous malformations (BAVMs) are a frequent cause of pediatric hemorrhagic stroke, which frequently results in significant morbidity and mortality. OBJECTIVE To analyze the results of multimodality treatment for a consecutive series of pediatric patients with ruptured and unruptured BAVMs at a single institution. METHODS Forty patients

Background The design and conclusions of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial are controversial, and its structure limits analysis of patients who could potentially benefit from treatment. Objective To analyze the results of a consecutive series of patients with unruptured brain arteriovenous malformations (BAVMs), including a subgroup analysis of ARUBA-eligible patients. Methods One hundred five patients with unruptured BAVMs were treated over an 8-year period. From this series, 90 adult patients and a subgroup of 61 patients determined to be ARUBA eligible were retrospectively reviewed. A subgroup analysis for Spetzler-Martin grades I/II, III, and IV/V was performed. The modified Rankin Scale was used to assess functional outcome. Results Persistent deficits, modified Rankin Scale score deterioration, and impaired functional outcome occurred less frequently in ARUBA-eligible grade I/II patients compared with grade III to V patients combined (P = .04, P = .04, P = .03, respectively). Twenty-two of 39 patients (56%) unruptured grade I and II BAVMs were treated with surgery without and with preoperative embolization, and all had a modified Rankin Scale score of 0 to 1 at the last follow-up. All patients treated with surgery without and with preoperative embolization had radiographic cure at the last follow-up. Conclusion The results of ARUBA-eligible and unruptured grade I/II patients overall show that excellent outcomes can be obtained in this subgroup of patients, especially with surgical management. Functional outcomes for ARUBA-eligible patients were similar to those of patients who were randomized to medical management in ARUBA. On the basis of these data, in appropriately selected patients, we recommend treatment for low-grade BAVMs.

BackgroundEmbolization before stereotactic radiosurgery (SRS) for brain arteriovenous malformations (BAVMs) is controversial.ObjectiveTo compare clinical and radiographic outcomes in patients undergoing pre-SRS embolization with ethylene copolymer (Onyx) with outcomes in patients undergoing SRS alone.MethodsSeventy consecutive patients with BAVMs who underwent SRS were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the factors associated with radiographic obliteration and complication.ResultsForty-one (59%) patients presented without BAVM rupture and 29 (41%) patients presented with rupture. Pre-SRS embolization was used in 20 patients (28.6%; 7 unruptured and 13 ruptured). Twenty-five of 70 (36%) patients sustained a complication from treatment, including 6 (9%) patients with a post-SRS latency period hemorrhage. Ten (14%) patients had persistent neurological deficits after treatment. Functional outcome (as modified Rankin Scale), complication rate, and radiographic obliteration at last follow-up were not significantly different between embolized and non-embolized groups in both unruptured and ruptured BAVMs. For unruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 23% and 73% for non-embolized patients and 20% and 60% for embolized patients, respectively. For ruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 45% and 72% for non-embolized patients and 53% and 82% for embolized patients, respectively.ConclusionPre-SRS embolization with Onyx was not associated with worse clinical or radiographic outcomes than SRS treatment without embolization. Pre-SRS embolization has a low complication rate and can safely be used to target high-risk BAVM features in carefully selected patients destined for SRS.

Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.We enrolled 7 newly diagnosed glioblastoma patients with MGMT(hi) tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5-57+) months and OS of 20 (range 13-57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG.These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.Clinicaltrials.gov NCT00669669.R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

See the editorial by Lathia, on pages 763–764. Since the 2008 discovery of a mutation in the isocitrate dehydrogenase 1 (IDH1) gene in a subset of glioma patients, more than 2 dozen manuscripts have been published about the role of this IDH1 mutation in the natural history of glioma.1–6 This unique mutation in IDH1, which changes arginine at position 132 to histidine, is disproportionately represented in lower-grade gliomas; it is present in >75% of grade II and III gliomas but only ∼10% of grade IV glioblastomas (GBMs).1,7 Furthermore, this mutation in IDH1 is more prevalent in younger patients. Glioma patients with the mutation show significantly longer survival times than those with the wild-type copy of the gene, having a median survival of 3.8 years versus 1.1 years.1,8 Additionally, secondary GBMs are predominantly mutant in IDH1 (83%), while very few primary GBMs (5%) harbor the mutation.7 Since IDH1mut GBMs (and perhaps more contrast-enhancing gliomas) have a significantly better prognosis than IDH1wt GBMs, it is clinically important to have pretreatment (presurgical) predictors of IDH1mut status. Our laboratory has developed a patient-specific mathematical model of glioma growth that is based on diagnostic and pretreatment MRI scans obtained in the course of normal clinical treatment.9–15 By combining our model formalism with tumor volume measures extracted from these routinely obtained pretreatment MRIs, we are able to estimate patient-specific parameters that quantify the net proliferation rate (ρ) of the glioma cells and their net dispersal or diffusion rate (D). These parameters can be used to characterize the differential role of proliferation versus diffusion in driving the overall tumor growth pattern seen in each patient. The variation in the parameters across patients is consistent with the wide heterogeneity in imaging results and invasive capacity typical of the disease.12 These 2 kinetic parameters can be combined to produce a biological aggressiveness ratio (ρ/D) that quantifies the relative proliferative to invasive nature of each tumor. This measure of biological aggressiveness is predictive of worse prognosis14 and increasing degrees of hypoxia,15 a known feature of tumor aggressiveness. Also, we have previously shown that a high ρ/D (characteristic of more nodular, less diffuse tumors) is more likely to represent a rapidly developing primary GBM that is relatively less invasive, whereas a low ρ/D (characteristic of a more diffuse, less nodular tumor) is associated with a slower developing but more invasive secondary GBM.16 This novel discovery suggests the possibility of predicting primary versus secondary GBM natural histories and, by extension, likely IDH1mutation status based on a single measure quantifiable from routinely obtained MR images alone. Further, a recent game theory-based consideration of the evolutionary role of IDH1 mutation in cellular populations suggested that such a mutation would select for a more invasive overall tumor phenotype.17 Combining these 2 insights suggests the following question: can we predict IDH1 mutation status from image-based analysis of tumor invasion using patient-specific mathematical models of glioma proliferation and invasion kinetics? One of our main hypotheses was that the most diffuse contrast-enhancing gliomas (low ρ/D) would be mutant in IDH1. To test this hypothesis, we examined the mutational status of IDH1 by mutation-specific immunohistochemistry in a cohort of 172 newly diagnosed, contrast-enhancing glioma patients, 91% of whom were ultimately found to have grade IV tumors. The concept was to distinguish IDH1 mutant tumors (with their associated favorable prognosis) within a cohort of contrast-enhancing gliomas by mapping a favorable molecular feature to patient-specific disease kinetics (ie, net proliferation and invasion rates).

Hemangiopericytomas (HPC) are mesenchymal tumors with a propensity towards chronicity and metastasis. This study aimed to reflect a single institution experience with both World Health Organization (WHO) grade II and III HPC. Pathology records from the years 1990-2013 at the University of Washington were searched to identify tumors unequivocally classified as HPC. Electronic chart review was then utilized to collect pertinent patient data. Of the WHO grade II HPC, there were four men and two women (average age 52 years) while the grade III HPC group had eight men and two women (average age 51 years). Sixty-six percent of WHO grade II tumors were located in the middle or posterior fossa as compared to none of the grade III tumors. Survival analysis revealed a significant survival benefit for patients who underwent complete resection (223 months) versus those with subtotal resection (138 months, p0.05). Factors such as age, sex, the use of up-front radiation, and whether the patient had a recurrence did not show statistical significance related to overall survival or progression free survival. Radiation in the form of external beam radiotherapy given at the time of the first recurrence did trend towards improved progression free survival (56 months) compared to those patients who were not radiated (22 months, p=0.09) All patients with radical resection went on to never have a recurrence. Our results indicate that HPC are tumors with limited response to radiation and best treated with aggressive resection. Future studies will determine whether molecular-based therapies may provide added adjuvant benefit.

Pseudoprogression is defined as the appearance of false progression on MR imaging following radiation therapy. Proton therapy is thought to have increased relative biological effectiveness-the ratio of the doses required by two types of radiation to cause the same level of effect-near the edges of the high dose volume. This could lead to different rates of pseudoprogression for protons compared to photons. In our IRB approved study, a board-certified neuroradiologist reviewed serial imaging of 74 patients (photons: n=37, protons: n=37) treated from 2013–2018 with either proton or photon radiotherapy to 59.4–60 Gy in 30–33 fractions and temozolomide for high grade glioma. MR imaging was performed 1 month after completion of treatment and then every 3 months. True progression was scored based on updated RANO criteria. Pseudoprogression was determined if imaging improved without change in therapy. Cumulative incidences of these outcomes and survival were calculated utilizing Kaplan-Meier analyses. Patient and treatment factors were analyzed for their association with incidence of pseudoprogression. Median follow-up for alive patients in the proton and photon groups were 15 and 29 months, respectively. Median age was 49 years in the proton group and 54 years in the photon group (p=0.17). Among proton patients, 14 had grade III glioma and 23 had grade IV glioblastoma. Among photon patients, 1 had grade III glioma. Median survival was 23 and 35 months for the proton and photon groups, respectively (p=0.57). The cumulative incidence of pseudoprogression was 14.4% and 10.4% at 12 months for the proton and photon groups, respectively (p=0.53). Grade, extent of resection, age, and IDH status, were not significantly associated with development of pseudoprogression. MGMT methylated tumors showed a trend toward association with pseudoprogression compared to unmethylated tumors (p=0.058). We concluded that the incidence of pseudoprogression is similar regardless of whether proton or photon therapy was utilized.

A complex therapeutic challenge for Alzheimer's disease (AD) is minimizing deleterious aspects of microglial activation while maximizing beneficial actions, including phagocytosis/clearance of amyloid beta (Abeta) peptides. One potential target is selective suppression of microglial prostaglandin E(2) receptor subtype 2 (EP2) function, which influences microglial phagocytosis and elaboration of neurotoxic cytokines. To test this hypothesis, we transplanted bone marrow cells derived from wild-type mice or mice homozygous deficient for EP2 (EP2(-/-)) into lethally irradiated 5-month-old wild-type or APPswe-PS1DeltaE9 double transgenic AD mouse model recipients. We found that cerebral engraftment by bone marrow transplant (BMT)-derived wild-type or EP2(-/-) microglia was more efficient in APPswe-PS1DeltaE9 than in wild-type mice, and APPswe-PS1DeltaE9 mice that received EP2(-/-) BMT had increased cortical microglia compared with APPswe-PS1DeltaE9 mice that received wild-type BMT. We found that myeloablative irradiation followed by bone marrow transplant-derived microglia engraftment, rather than cranial irradiation or BMT alone, was responsible for the approximate one-third reduction in both Abeta plaques and potentially more neurotoxic soluble Abeta species. An additional 25% reduction in cerebral cortical Abeta burden was achieved in mice that received EP2(-/-) BMT compared with mice that received wild-type BMT. Our results provide a foundation for an adult stem cell-based therapy to suppress soluble Abeta peptide and plaque accumulation in the cerebrum of patients with AD.

Stereotactic radiosurgery has become a more frequently used treatment modality for vestibular schwannomas; a few reports of malignant transformation and/or radiation-associated tumors have surfaced. The majority of these reported cases were in patients with underlying neurofibromatosis. The authors report a case of a 74-year-old man with rapid progression of a cerebellar-pontine angle tumor 14 years after surgical resection of a vestibular schwannoma (VS) from the same site, and 6 years after stereotactic radiosurgery. A pathological study of the recent tumor showed a high-grade spindle cell neoplasm that bore no resemblance to the initial schwannoma. The patient had no diagnosis of neurofibromatosis. Secondary malignancy occurred in a non-neurofibromatosis patient 6 years after stereotactic radiosurgery. It is our belief that documentation of such cases will provide important evidence that helps evaluate the long-term effect of radiosurgery for VS. Such observations can influence clinical decisions regarding the choice of treatment modalities.

Patients with cancer are concerned about their ability to interact with friends and family and to perform activities associated with daily living. The combined effects of the disease process, its treatment with surgery, radiation, and chemotherapy, and the medications used to manage symptoms may all impact cognitive function. Minimizing the effect of each treatment modality on cognitive processing requires an understanding of how these treatment modalities may impact cognition.

Purpose: Hypoxia is associated with resistance to radiotherapy and chemotherapy and activates transcription factors that support cell survival and migration. We measured the volume of hypoxic tumor and the maximum level of hypoxia in glioblastoma multiforme before radiotherapy with [18F]fluoromisonidazole positron emission tomography to assess their impact on time to progression (TTP) or survival. Experimental Design: Twenty-two patients were studied before biopsy or between resection and starting radiotherapy. Each had a 20-minute emission scan 2 hours after i.v. injection of 7 mCi of [18F]fluoromisonidazole. Venous blood samples taken during imaging were used to create tissue to blood concentration (T/B) ratios. The volume of tumor with T/B values above 1.2 defined the hypoxic volume (HV). Maximum T/B values (T/Bmax) were determined from the pixel with the highest uptake. Results: Kaplan-Meier plots showed shorter TTP and survival in patients whose tumors contained HVs or tumor T/Bmax ratios greater than the median (P ≤ 0.001). In univariate analyses, greater HV or tumor T/Bmax were associated with shorter TTP or survival (P < 0.002). Multivariate analyses for survival and TTP against the covariates HV (or T/Bmax), magnetic resonance imaging (MRI) T1Gd volume, age, and Karnovsky performance score reached significance only for HV (or T/Bmax; P < 0.03). Conclusions: The volume and intensity of hypoxia in glioblastoma multiforme before radiotherapy are strongly associated with poorer TTP and survival. This type of imaging could be integrated into new treatment strategies to target hypoxia more aggressively in glioblastoma multiforme and could be applied to assess the treatment outcomes.

Pain is a feared component of cancer for a patient. The patient's prior experience with cancer pain will affect how he or she deals with ongoing and acute onset new pain. Radiation therapy has been and continues to be a major component in the management of cancer pain. New technologies are rapidly becoming available that will allow more specific and accurate targeting, while limiting the dose that is received by normal tissues and thus minimizing the potential for tissue toxicity. How new techniques and technologies are incorporated into the management of cancer pain will require a better understanding of the disease process being treated.

High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF-A, has been used in the treatment of recurrent or progressive meningiomas resistant to standard therapy. We report a patient with a recurrent left frontotemporal meningioma and associated-vision loss who experienced substantial visual field recovery after 3 cycles of bevacizumab. In addition, we provide a review of the literature regarding the efficacy of bevacizumab in the treatment of recurrent meningiomas.

Purpose The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Methods and Materials Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. Results In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control ( P =.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Conclusions Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Brain metastases (BM) from primary breast cancer can arise despite use of systemic therapies that provide excellent extracranial disease control. Local modalities for treating BM include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). We sought to determine the benefits of SRS for management of BM arising from different biologic breast cancer subtypes. We reviewed records of 131 patients who received SRS for breast cancer BM between 2001 and 2013. Survival was estimated by the Kaplan-Meier method. Effects of tumor biology, number and location of lesions, and number of SRS sessions on survival were evaluated by Cox proportional hazards regression. Of the 122 patients with subtypes available, 41 patients (31%) were classified as estrogen receptor positive/HER2 negative (ER(+)HER2(-)); 30 patients (23%), ER(+)HER2(+); 23 patients (18%), ER(-)HER2(+); and 28 patients (21%), ER(-)HER2(-) (or triple negative breast cancer, TNBC). Median age at first SRS was 50 years. Median overall survival for ER(+)HER2(-), ER(+)HER2(+), ER(-)HER2(+), and TNBC was 16, 26, 23, and 7 months, respectively (p0.001 for difference between groups). Patients with TNBC had the shortest time to retreatment with WBRT or SRS or death with hazard ratio of 3.12 (p0.001) compared to ER(+)HER2(-). In all subtypes other than TNBC, SRS can provide meaningful control of BM even in the setting of multiple lesions and may be worth repeating for new lesions that develop metachronously. For patients with TNBC, prognosis is guarded following SRS, and there is an urgent need to develop more effective treatment strategies.

Purpose: To identify and illustrate the potential problems with brachytherapy in obese patients. Methods and Materials: Three patients with body mass index greater than 30 were treated with prostate brachytherapy. Transrectal ultrasound (TRUS) was performed using a 6.0-MHz Siemens Sonoline Prima ultrasound machine and a Barzell-Whitmore stepper unit. The patients' weight required use of an accessory table support. Results: Once set up, there was ample room to maneuver, providing that the patient's legs were abducted fully. TRUS imaging of the prostate was unaffected by patients' obesity. The amount of periprostate adipose tissue visualized on TRUS appeared to be no different than that noted in nonobese patients. Similarly, there was no increased distance between the prostate and rectal surface, either on preimplant CT or transverse TRUS. To date, our experience is that the perineal skin to prostate distance was not so great that standard 20-cm applicator needles could not be used. For the 2 sub–350-pound patients who could be imaged on our CT scanner, postimplant target coverage (V100) was 88% and 95%. Conclusions: Standard TRUS and brachytherapy needles are sufficient to implant even the largest patients.

Purpose: This study investigates the feasibility of personalizing radiotherapy prescription schemes (treatment margins and fractional doses) for glioblastoma (GBM) patients and their potential benefits using a proliferation and invasion (PI) glioma model on phantoms. Methods and Materials: We propose a strategy to personalize radiotherapy prescription schemes by simulating the proliferation and invasion of the tumor in 2D according to the PI glioma model. We demonstrate the strategy and its potential benefits by presenting virtual cases, where the standard and personalized prescriptions were applied to the tumor. Standard prescription was assumed to deliver 46 Gy in 23 fractions to the initial, gross tumor volume (GTV1) plus a 2 cm margin and an additional 14 Gy in 7 fractions to the boost GTV2 plus a 2 cm margin. The virtual cases include the tumors with a moving velocity of 0.029 (slow-move), 0.079 (average-move), and 0.13 (fast-move) mm/day for the gross tumor volume (GTV) with a radius of 1 (small) and 2 (large) cm. For each tumor size and velocity, the margin around GTV1 and GTV2 was varied between 0–6 cm and 1–3 cm, respectively. Equivalent uniform dose (EUD) to normal brain was constrained to the EUD value obtained by using the standard prescription. Various linear dose policies, where the fractional dose is linearly decreasing, constant, or increasing, were investigated to estimate the temporal effect of the radiation dose on tumor cell-kills. The goal was to find the combination of margins for GTV1 and GTV2 and a linear dose policy, which minimize the tumor cell-surviving fraction (SF) under a normal tissue constraint. The efficacy of a personalized prescription was evaluated by tumor EUD and the estimated survival time. Results: The personalized prescription for the slow-move tumors was to use 3.0–3.5 cm margins for GTV1, and a 1.5 cm margin for GTV2. For the average- and fast-move tumors, it was optimal to use a 6.0 cm margin for GTV1 and then 1.5–3.0 cm margins for GTV2, suggesting a course of whole brain therapy followed by a boost to a smaller volume. It was more effective to deliver the boost sequentially using a linearly decreasing fractional dose for all tumors. Personalized prescriptions led to surviving fractions of 0.001–0.465% compared to the standard prescription, and increased the tumor EUDs by 25.3–49.3% and estimated survival times by 7.6–22.2 months. Conclusions: Personalizing treatment margins based on the measured proliferative capacity of GBM tumor cells can potentially lead to significant improvements in tumor cell kill and related clinical outcomes.

BACKGROUND: Glioblastoma is the most aggressive adult primary malignant brain tumor. It is associated with poor prognosis (median survival of 12-15 months) despite treatment. Combination chemotherapy with carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used but it has been associated with dose limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed GBM patients in an attempt to chemoprotect bone marrow during combination O6BG/TMZ therapy. METHODS: Seven patients have been enrolled in the first cohort of the study. Following tumor resection, patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, aphaeresis and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Post transplant, patients were treated with 28-day cycles of single dose TMZ (472mg/m2) with 48-hour intravenous O6BG (120mg/m2 bolus, followed by 30mg/m2/24h). RESULTS: The BCNU dose was nonmyeloablative. Gene marking in pre-infusion colony forming units (CFUs) was robust in most patients. Similarly, following engraftment, gene marking in white blood cells and sorted granulocytes assessed by real-time PCR was high. Patients have received up to nine cycles of O6BG/TMZ with evidence for selection of gene-modified cells and tolerable hematologic toxicity. This is significantly more cycles compared to recurrent patients receiving O6BG/TMZ in the absence of gene modified, chemoprotected cells (Quinn et al., 2005) (p < 0.05). No extra-hematopoietic toxicity has been observed thus far and all seven patients exhibited improved survival over historical controls. The longest surviving patient is 56+ months from the diagnosis without evidence of disease progression. CONCLUSIONS: These data demonstrate feasibility of achieving significant engraftment of MGMTP140K- modified cells with a well-tolerated dose of BCNU. Combination of TMZ and O6BG is well tolerated in this setting and patients with newly diagnosed GBM exhibiting unmethylated MGMT promoter achieve prolonged survivals.

Glioblastoma multiforme is the most aggressive type of primary brain tumor. Glioblastoma growth dynamics vary widely across patients, making it difficult to accurately gauge their response to treatment. We developed a model-based metric of therapy response called Days Gained that accounts for this heterogeneity. Here, we show in 63 newly diagnosed patients with glioblastoma that Days Gained scores from a simple glioblastoma growth model computed at the time of the first postradiotherapy MRI scan are prognostic for time to tumor recurrence and overall patient survival. After radiation treatment, Days Gained also distinguished patients with pseudoprogression from those with true progression. Because Days Gained scores can be easily computed with routinely available clinical imaging devices, this model offers immediate potential to be used in ongoing prospective studies. Cancer Res; 73(10); 2976–86. ©2013 AACR.

A novel deoxynucleoside, 2‘-deoxy-7-(hydroxymethyl)-7-deazaadenosine, was synthesized with the intent of using the analogue to mimic the role of “structural” waters in the major groove of DNA. The target compound was synthesized in four steps starting from 2-((ethoxymethylene)amino)-5-bromo-1-(2‘-deoxy-3‘,5‘-di-O-p-toluoyl-β-d-erythro-pentofuranosyl)pyrrole-3,4-dicarbonitrile. The structure was characterized by X-ray diffraction and proton NMR spectroscopic analyses. The crystal structure shows an intramolecular hydrogen bond between an amino proton on N6 and the oxygen of the hydroxymethyl group. When superimposed onto particular adenines in the structure of the tryptophan (trp) repressor/operator complex, the analogue places the oxygen of the hydroxymethyl group very near the oxygen contributed by the water in the protein/DNA complex. This analogue may be useful for probing the role of structural waters in other specific protein/DNA complexes and in DNA bending.

Stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HFSRT) have become important treatment modalities for brain metastases. While effective, there are still areas of extensive debate on its appropriate use in patients with life-limiting diseases. This review provides an overview of the indications and challenges of SRS and HFSRT in the management of brain metastases.