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Background: Given that the majority of suicide decedents visit primary care in the year preceding death, primary care has been identified as a key setting in which to engage patients at risk for suicide in mental health services. The objective of this research was to identify barriers and facilitators to engagement in mental health services among primary care patients at risk for suicide to inform the development of strategies to increase engagement., Methods: Seventy-four semi-structured qualitative interviews were conducted with primary care patients (n = 20), primary care (n = 18) and behavioral health (n = 12) clinicians, mental health intake coordinators (n = 4), and health system and clinic leaders (n = 20). Patients who had been referred for mental health services from primary care and reported an elevated score (≥ 1) on item 9 on the Patient Health Questionnaire at the time of referral were eligible to participate. Eligible clinicians and leaders were employed in a primary care or behavioral health setting in a single large health system with an integrated mental health program. Interviews typically lasted 30-60 min, were completed over video conference or phone, and were coded by members of the research team using a rapid qualitative analysis procedure., Results: Participants were primarily female (64.9%), white (70.3%) and non-Hispanic/Latine (91.9%). The most identified barriers to mental health care engagement were waitlists, capacity limits, insurance, patient characteristics, communication, collaboration, and/or difficulties surrounding travel. The most commonly cited facilitators of engagement included telehealth, integrated care models, reminders, case management support, psychoeducation, motivational enhancement, and scheduling flexibility. Concrete suggestions for improving engagement in mental health services included increasing communication between providers, streamlining referral and intake processes, providing reminders and follow ups, and advocacy for increased reimbursement for suicide risk assessment., Conclusions: Results underscore the myriad barriers patients at risk for suicide encounter when attempting to engage in mental health care in a primary care setting. Facilitators of engagement and suggestions for improving connections to care were also identified, which can inform the design of implementation strategies to improve engagement in mental health services among primary care patients at risk for suicide., Trial Registration: ClinicalTrials.gov Identifier: NCT05021224 (Registered August 19, 2021)., (© 2024. The Author(s).)

Introduction: Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited., Methods: Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT)., Results: Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %., Conclusions: This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: Management paradigms now allow for systemic targeted drugs before central nervous system (CNS)-directed radiation therapy (RT) in selected asymptomatic patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). We aimed to quantify how novel targeted agents with improved CNS activity, such as second-generation anaplastic lymphoma kinase (ALK) inhibitors (eg, alectinib), might affect the role of CNS-directed RT., Methods and Materials: This retrospective, observational, real-world, patterns-of-care study used a nationwide, electronic, health record-derived, de-identified, longitudinal database. A random sample of patients with ALK+ advanced NSCLC and BM on first-line ALK-inhibitor monotherapy between January 1, 2014 and August 31, 2019 were included. Using an index date of the first instance of BM, the outcome was brain-directed local treatment within 4 months. Trends over time were reported and tested using multivariable modified Poisson regression with robust error variance, including an indicator during or after 2017 (when alectinib was approved)., Results: Of the 352 included patients, 146 had BM. In addition, 104 patients received CNS-directed local therapy, and 42 did not. The majority of patients (89.4%) were treated with RT alone. Of those receiving RT, stereotactic radiosurgery monotherapy was the most common (53%), followed by whole brain RT alone (39%). On multivariable analysis, patients who had their first BM during or after 2017 had a decreased rate of receiving local BM treatment versus those before 2017 with an adjusted incidence rate ratio of 0.63 (95% confidence interval [CI], 0.41-0.95; P = .026). We found no change in the proportion of BM treated with whole brain RT during or after 2017 versus before (adjusted incidence rate ratio: 0.70; 95% CI: 0.24-2.06; P = .517)., Conclusions: We found decreasing use of CNS-directed RT in patients with NSCLC with new BM on first-line ALK inhibitors. Clinical outcomes for these patients require continued investigation, because physicians may become increasingly comfortable deferring upfront local therapy for BM in lieu of novel targeted agents with improved CNS activity., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: This guideline provides evidence-based recommendations for adults with isocitrate dehydrogenase (IDH)-mutant grade 2 and grade 3 diffuse glioma, as classified in the 2021 World Health Organization (WHO) Classification of Tumours. It includes indications for radiation therapy (RT), advanced RT techniques, and clinical management of adverse effects., Methods: The American Society for Radiation Oncology convened a multidisciplinary task force to address 4 key questions focused on the RT management of patients with IDH-mutant grade 2 and grade 3 diffuse glioma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength., Results: A strong recommendation for close surveillance alone was made for patients with oligodendroglioma, IDH-mutant, 1p/19q codeleted, WHO grade 2 after gross total resection without high-risk features. For oligodendroglioma, WHO grade 2 with any high-risk features, adjuvant RT was conditionally recommended. However, adjuvant RT was strongly recommended for oligodendroglioma, WHO grade 3. A conditional recommendation for close surveillance alone was made for astrocytoma, IDH-mutant, WHO grade 2 after gross total resection without high-risk features. Adjuvant RT was conditionally recommended for astrocytoma, WHO grade 2, with any high-risk features and strongly recommended for astrocytoma, WHO grade 3. Dose recommendations varied based on histology and grade. Given known adverse long-term effects of RT, consideration for advanced techniques such as intensity modulated radiation therapy/volumetric modulated arc therapy or proton therapy were given as strong and conditional recommendations, respectively. Finally, based on expert opinion, the guideline recommends assessment, surveillance, and management for toxicity management., Conclusions: Based on published data, the American Society for Radiation Oncology task force has proposed recommendations to inform the management of adults with IDH-mutant grade 2 and grade 3 diffuse glioma as defined by WHO 2021 classification, based on the highest quality published data, and best translated by our task force of subject matter experts., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Application of linear-quadratic (LQ) model to large fractional dose treatments is inconsistent with observed cell survival curves having a straight portion at high doses. We have proposed a unified multi-activation (UMA) model to fit cell survival curves over the entire dose range that allows us to calculate EQD2 for hypofractionated SBRT, SRT, SRS, and HDRB., Methods: A unified formula of cell survival S = n / e D D o + n - 1 using only the extrapolation number of n and the dose slope of D o was derived. Coefficient of determination, R 2 , relative residuals, r, and relative experimental errors, e, normalized to survival fraction at each dose point, were calculated to quantify the goodness in modeling of a survival curve. Analytical solutions for α and β, the coefficients respectively describe the linear and quadratic parts of the survival curve, as well as the α/β ratio for the LQ model and EQD2 at any fractional doses were derived for tumor cells undertaking any fractionated radiation therapy., Results: Our proposed model fits survival curves of in-vivo and in-vitro tumor cells with R 2  > 0.97 and r < e. The predicted α, β, and α/β ratio are significantly different from their values in the LQ model. Average EQD2 of 20-Gy SRS of glioblastomas and melanomas metastatic to the brain, 10-Gy × 5 SBRT of the lung cancer, and 7-Gy × 5 HDRB of endometrial and cervical carcinomas are 36.7 (24.3-48.5), 114.1 (86.6-173.1),, and 45.5 (35-52.6) Gy, different from the LQ model estimates of 50.0, 90.0, and 49.6 Gy, respectively., Conclusion: Our UMA model validated through many tumor cell lines can fit cell survival curves over the entire dose range within their experimental errors. The unified formula theoretically indicates a common mechanism of cell inactivation and can estimate EQD2 at all dose levels., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Pulsed low-dose rate radiation therapy has been shown to reduce normal tissue damage while decreasing DNA damage repair in tumor cells. In a cohort of patients treated with palliative or definitive pelvic reirradiation using pulsed low-dose rate radiation therapy, we observed substantial local control and low rates of toxicity.

Aim/objectives/background: The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for image-guided radiation therapy (IGRT). IGRT is radiation therapy that employs imaging to maximize accuracy and precision throughout the entire process of treatment delivery with the goal of optimizing accuracy and reliability of radiation therapy to the target, while minimizing dose to normal tissues., Methods: The ACR-ASTRO Practice Parameter for IGRT was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document., Results: This practice parameter is developed to serve as a tool in the appropriate application of IGRT in the care of patients with conditions where radiation therapy is indicated. It addresses clinical implementation of IGRT including personnel qualifications, quality assurance standards, indications, and suggested documentation., Conclusions: This practice parameter is a tool to guide clinical use of IGRT and does not make recommendations on site-specific IGRT directives. It focuses on the best practices and principles to consider when using IGRT effectively, especially with the significant increase in imaging data that is now available with IGRT. The clinical benefit and medical necessity of the imaging modality and frequency of IGRT should be assessed for each patient.

Background: Because of the increased risk in cancer patients of developing complications caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), physicians have to balance the competing risks of the negative impact of the pandemic and the primary tumor. In this consensus statement, an international group of experts present mitigation strategies and treatment guidance for patients suffering from high grade gliomas (HGG) during the coronavirus disease 2019 (COVID-19) pandemic., Method / Results: 16 international experts in the treatment of HGG contributed to this consensus-based practice recommendation including neuro-oncologists, neurosurgeons, radiation -oncologists and a medical physicist. Generally, treatment of neuro-oncological patients cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19. We present detailed interdisciplinary treatment strategies for molecular subgroups in two pandemic scenarios, a scale-up phase and a crisis phase., Conclusion: This practice recommendation presents a pragmatic framework and consensus-based mitigation strategies for the treatment of HGG patients during the SARS-CoV-2 pandemic., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: For brain metastases, surgical resection with postoperative stereotactic radiosurgery is an emerging standard of care. Postoperative cavity stereotactic radiosurgery is associated with a specific, underrecognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease. We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve interrater reliability (IRR) and validity in diagnosing LMD., Methods and Materials: Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system expertise, completed a 2-phase survey that included magnetic resonance imaging and treatment information for 30 patients. In the "pretraining" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "posttraining" phase and relabeled the 30 cases using the 4 following labels: LR, DR, classical leptomeningeal disease, and nLMD., Results: IRR increased 34% after training (Fleiss' Kappa K = 0.41 to K = 0.55, P < .001). IRR increased most among non-central nervous system specialists (+58%, P < .001). Before training, IRR was lowest for LMD (K = 0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD., Conclusions: This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero gene modification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included.

Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS)., Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial., Design, Setting, and Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm., Interventions: Surgical resection or SRS., Main Outcomes and Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death., Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93)., Conclusions and Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time., Trial Registration: ClinicalTrials.gov Identifier: NCT00002899.

Purpose: Breast conservation therapy (BCT) is standard for T1-T2 tumors, but early trials excluded breast cancers > 5 cm. This study was performed to assess patterns and outcomes of BCT for T3 tumors., Methods: We reviewed the National Cancer Database (NCDB) for noninflammatory breast cancers > 5 cm, between 2004 and 2011 who underwent BCT or mastectomy (Mtx) with nodal evaluation. Patients with skin or chest wall involvement were excluded. Patients having clinical T3 tumors were analyzed to determine outcomes based upon presentation, with those having pathologic T3 tumors, subsequently assessed, irrespective of presentation. Overall survival (OS) was analyzed using multivariable Cox proportional hazards models, with adjusted survival curves estimated using inverse probability weighting., Results: After exclusions, 37,268 patients remained. Median age and tumor size for BCT versus Mtx were 53 versus 54 years (p < 0.001) and 6.0 versus 6.7 cm (p < 0.001), respectively. Predictors of BCT included age, race, location, facility type, year of diagnosis, tumor size, grade, histology, nodes examined and positive, and administration of chemotherapy and radiotherapy. OS was similar between Mtx and BCT (p = 0.36). This held true when neoadjuvant chemotherapy patients were excluded (p = 0.39). BCT percentages declined over time (p < 0.001), while tumor sizes remained the same (p = 0.77). Median follow-up was 51.4 months., Conclusions: OS for patients with T3 breast cancers is similar whether patients received Mtx or BCT, confirming that tumor size should not be an absolute BCT exclusion. Declining use of BCT for tumors > 5 cm in younger patients may be accounted for by recent trends toward mastectomy.

Purpose of Review: To summarize current approaches in the management of brain metastases from non-small cell lung cancer (NSCLC)., Recent Findings: Local treatment has evolved from whole-brain radiotherapy (WBRT) to increasing use of stereotactic radiosurgery (SRS) alone for patients with limited (1-4) brain metastases. Trials have established post-operative SRS as an alternative to adjuvant WBRT following resection of brain metastases. Second-generation TKIs for ALK rearranged NSCLC have demonstrated improved CNS penetration and activity. Current brain metastasis trials are focused on reducing cognitive toxicity: hippocampal sparing WBRT, SRS for 5-15 metastases, pre-operative SRS, and use of systemic targeted agents or immunotherapy. The role for radiotherapy in the management of brain metastases is becoming better defined with local treatment shifting from WBRT to SRS alone for limited brain metastases and post-operative SRS for resected metastases. Further trials are warranted to define the optimal integration of newer systemic agents with local therapies.

Purpose: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique., Methods and Materials: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the χ 2 and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression., Results: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade ≥2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade ≥4 acute or subacute toxicity. The only grade ≥2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief., Conclusion: Reirradiation with PLDR is effective and well-tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases., Materials/methods: We identified 149 patients with adenocarcinoma of the lung and newly diagnosed brain metastases without a targetable mutation receiving stereotactic radiation. Kaplan-Meier plots and Cox regression were employed to assess whether use of pemetrexed was associated with intracranial disease control and radiation necrosis., Results: Among the entire cohort, 105 patients received pemetrexed while 44 did not. Among patients who were chemotherapy-naïve, use of pemetrexed (n = 43) versus alternative regimens after stereotactic radiation (n = 24) was associated with a reduced likelihood of developing new brain metastases (HR 0.42, 95% CI 0.22-0.79, p = 0.006) and a reduced need for salvage brain-directed radiation therapy (HR 0.36, 95% CI 0.18-0.73, p = 0.005). Pemetrexed use was associated with increased radiographic necrosis. (HR 2.70, 95% CI 1.09-6.70, p = 0.03)., Conclusions: Patients receiving pemetrexed after brain-directed stereotactic radiation appear to benefit from improved intracranial disease control at the possible expense of radiation-related radiographic necrosis. Whether symptomatic radiation injury occurs more frequently in patients receiving pemetrexed requires further study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To compare the dosimetric parameters of a novel rotating gamma ray system (RGS) with well-established CyberKnife system (CK) for treating malignant brain lesions. RGS has a treatment head of 16 cobalt-60 sources focused to the isocenter, which can rotate 360° on the ring gantry and swing 35° in the superior direction. We compared several dosimetric parameters in 10 patients undergoing brain stereotactic radiosurgery including plan normalization, number of beams and nodes for CK and shots for RGS, collimators used, estimated treatment time, D 2 cm and conformity index (CI) among two modalities. The median plan normalization for RGS was 56.7% versus 68.5% (p  =  0.002) for CK plans. The median number of shots from RGS was 7.5 whereas the median number of beams and nodes for CK was 79.5 and 46. The median collimator's diameter used was 3.5 mm for RGS as compared to 5 mm for CK (p  =  0.26). Mean D 2 cm was 5.57 Gy for CyberKnife whereas it was 3.11 Gy for RGS (p  =  0.99). For RGS plans, the median CI was 1.4 compared to 1.3 for the CK treatment plans (p  =  0.98). The average minimum and maximum doses to optic chiasm were 21 and 93 cGy for RGS as compared to 32 and 209 cGy for CK whereas these were 0.5 and 364 cGy by RGS and 18 and 399 cGy by CK to brainstem. The mean V12 Gy for brain predicting for radionecrosis with RGS was 3.75 cm 3 as compared to 4.09 cm 3 with the CK (p  =  0.41). The dosimetric parameters of a novel RGS with a ring type gantry are comparable with CyberKnife, allowing its use for intracranial lesions and is worth exploring in a clinical setting.

Purpose: To evaluate the impact of rheumatoid arthritis (RA) on toxicity and cosmesis in women undergoing radiotherapy for breast cancer., Methods: We queried an institutional database for women with RA treated with external beam radiotherapy for breast cancer between 1981 and 2016. Matching each patient to three controls without RA was attempted. Radiation toxicity was graded using CTCAE 4.0. Cosmesis was graded using the Global Harris Scoring System of Excellent, Good, Fair, or Poor. Grade 2+ (G2+) acute and late toxicities were compared between women with RA and their matched pairs using a generalized estimating equation (GEE). Wilcoxon test and mixed effects model were used to compare the cosmesis between two groups., Results: Forty women with RA at time of radiation were matched to 117 controls. The median radiation dose was 60 Gy (50-66 Gy) and the median follow-up was 94 months (1-354 months). When comparing the women with RA to their matched pairs, there was no significant difference in the rates of G2+ acute toxicity (25.0 vs. 13.7%, O 2.1, CI 0.91-4.9) or G2+ late toxicity (7.5 vs. 4.3%, OR 1.8, CI 0.48-6.8). Mean cosmesis was between Good and Excellent for both groups of patients, although women with RA were less likely to get Excellent cosmesis compared to their matched pairs (OR 0.35, CI 0.15-0.84)., Conclusions: Among women with RA, radiation for breast cancer was well tolerated without significantly increased toxicity. Their cosmesis was generally Good to Excellent, although they might be less likely to get Excellent cosmesis compared to their matched pairs.

Background: Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program., Methods: We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases., Results: We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively)., Conclusions: In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses., Patients and Methods: We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC)., Results: A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]., Conclusions: Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance., Clinical Trials Number: NCT00002899., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Geriatric glioblastoma (GBM) patients have a poorer prognosis than younger patients, but IDH1/2 mutations (more common in younger patients) confer a favorable prognosis. We compared key GBM molecular alterations between an elderly (age ≥ 70) and younger (18 < = age < = 45) cohort to explore potential therapeutic opportunities., Results: Alterations more prevalent in the young GBM cohort compared to the older cohort (P < 0.05) were: overexpression of ALK, RRM1, TUBB3 and mutation of ATRX, BRAF, IDH1, and TP53. However, PTEN mutation was significantly more frequent in older patients. Among patients with wild-type IDH1/2 status, TOPO1 expression was higher in younger patients, whereas MGMT methylation was more frequent in older patients. Within the molecularly-defined IDH wild-type GBM cohort, younger patients had significantly more mutations in PDGFRA, PTPN11, SMARCA4, BRAF and TP53., Methods: GBMs from 178 elderly patients and 197 young patients were analyzed using DNA sequencing, immunohistochemistry, in situ hybridization, and MGMT-methylation assay to ascertain mutational and amplification/expressional status., Conclusions: Significant molecular differences occurred in GBMs from elderly and young patients. Except for the older cohort's more frequent PTEN mutation and MGMT methylation, younger patients had a higher frequency of potential therapeutic targets.

Purpose/objective(s): The risk of developing symptomatic edema or seizure following stereotactic radiosurgery (SRS) is poorly defined, and many practitioners prescribe prophylactic corticosteroids and/or anticonvulsants. Because there are no clear guidelines regarding appropriate use, we sought to characterize prescribing practices and factors associated with these recommendations., Methods and Materials: We conducted a 1-time, internet-based survey among 500 randomly selected radiation oncologists self-described as specializing in central nervous system diseases who were registered in the American Society for Radiation Oncology directory. Physicians were contacted by e-mail and invited to complete the 22-question survey., Results: The response rate was 32% (n = 161). Sixty-six percent of respondents had been in practice for >10 years, and 45% of respondents practiced at an academic medical center. During/after SRS, 53% of respondents "always" or "usually" recommended corticosteroids, whereas 47% "never," "rarely," or "sometimes" recommended them. When prescribing corticosteroids, the recommended duration of use was <1 week, 1-2 weeks, or >2 weeks among 49%, 33%, and 18% of respondents, respectively. Respondents who worked in an academic medical center were less likely to prescribe corticosteroids, although this did not reach significance (P = .09). Seizure prophylaxis was less common overall, as 79% of respondents "rarely" or "never" prescribed anticonvulsants for SRS. Respondents who prescribed anticonvulsants more frequently had higher estimations of the risk of seizure within 2 weeks of SRS (P < .001), and their recommended duration of anticonvulsant use was <1 week, 1-2 weeks, and >2 weeks among 35%, 25%, and 41% of respondents, respectively., Conclusions: There is extreme variation in physician recommendations regarding prophylactic corticosteroid and anticonvulsant use for patients undergoing SRS. Further investigation of the risks and benefits of these medications for SRS is warranted, which may promote guideline development and more patient-centered, rational prescribing practices., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Randomized data examining adjuvant radiation therapy (RT) alone in elderly women with low-risk, hormone receptor-positive (HR(+)) breast cancer is lacking. We investigated the outcomes for elderly women treated with adjuvant RT alone versus RT plus endocrine therapy (ET) after breast-conserving surgery., Patients and Methods: We queried our institutional breast cancer database for the following patients: age > 65 years, stage T1-T2N0, HR(+), and treatment with breast-conserving surgery, including adjuvant RT. The χ(2) analysis identified significant baseline differences between the groups. Cox proportional hazard methods identified predictors of endpoints on multivariate analysis. Kaplan-Meier estimates of survival were compared using the log-rank test., Results: A total of 504 patients were identified, 311 had undergone RT plus ET (62%) and 193, RT alone (38%). The median follow-up time was 88 months. The RT-alone group versus RT plus ET group had different median age (72 vs.71 years, P < .001), different median tumor size (1 vs. 1.3 cm, P < .001), lower grade (40% vs. 29%, P = .05), and fewer close or positive margins (11% vs. 19%, P = .01). The adherence rate to prescribed ET was 70%. Tumor size predicted an increased risk of distant metastasis (DM) (hazard ratio, 1.96; 95% confidence interval [CI], 1.23-3.13) and worse disease-free survival (DFS) (hazard ratio, 1.86; 95% CI, 1.22-2.86). ET nonadherence versus adherence predicted for risk of DM (hazard ratio, 5.03; 95% CI, 1.98-12.66) and DFS (HR, 4.24; 95% CI, 1.9-10.3). Of the women with DM, 83.8% had tumors > 1 cm in size., Conclusion: ET nonadherence and tumor size > 1 cm predicted an increased risk of DM and worse DFS, favoring the addition of ET in this group. However, RT alone for women with tumors less than or equal to 1 cm may be appropriate., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM)., Experimental Design: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis., Results: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75)., Conclusions: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study., (©2015 American Association for Cancer Research.)

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastases, but concerns over potential toxicity limit applications for larger lesions or those in eloquent areas. Fractionated stereotactic radiation therapy (SRT) is often substituted for SRS in these cases. We retrospectively analyzed the efficacy and toxicity outcomes of patients who received SRT at our institution. Seventy patients with brain metastases treated with SRT from 2006-2012 were analyzed. The rates of local and distant intracranial progression, overall survival, acute toxicity, and radionecrosis were determined. The SRT regimen was 25 Gy in 5 fractions among 87 % of patients. The most common tumor histologies were non-small cell lung cancer (37 %), breast cancer (20 %) and melanoma (20 %), and the median tumor diameter was 1.7 cm (range 0.4-6.4 cm). Median survival after SRT was 10.7 months. Median time to local progression was 17 months, with a local control rate of 68 % at 6 months and 56 % at 1 year. Acute toxicity was seen in 11 patients (16 %), mostly grade 1 or 2 with the most common symptom being mild headache. Symptomatic radiation-induced treatment change was seen on follow-up MRIs in three patients (4.3 %). SRT appears to be a safe and reasonably effective technique to treat brain metastases deemed less suitable for SRS, though dose intensification strategies may further improve local control.

Background: The impact of adjuvant radiation in patients with atypical meningioma remains poorly defined. We sought to determine the impact of adjuvant radiation therapy in this population., Methods: We identified 91 patients with World Health Organization grade II (atypical) meningioma managed at Dana-Farber/Brigham and Women's Cancer Center between 1997 and 2011. A propensity score model incorporating age at diagnosis, gender, Karnofsky performance status, tumor location, tumor size, reason for diagnosis, and era of treatment was constructed using logistic regression for the outcome of receipt versus nonreceipt of radiation therapy. Propensity scores were then used as continuous covariates in a Cox proportional hazards model to determine the adjusted impact of adjuvant radiation therapy on both local recurrence and the combined endpoint of use of salvage therapy and death due to progressive meningioma., Results: The median follow-up in patients without recurrent disease was 4.9 years. After adjustment for pertinent confounding variables, radiation therapy was associated with decreased local recurrence in those undergoing gross total resection (hazard ratio, 0.25; 95% CI, 0.07-0.96; P = .04). No differences in overall survival were seen in patients who did and did not receive radiation therapy., Conclusion: Patients who have had a gross total resection of an atypical meningioma should be considered for adjuvant radiation therapy given the improvement in local control. Multicenter, prospective trials are required to definitively evaluate the potential impact of radiation therapy on survival in patients with atypical meningioma., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as "radioresistant," the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT)., Methods: We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model., Results: WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08)., Conclusions: Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials.

Purpose: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases., Methods and Materials: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model., Results: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) ≤ 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS ≤ 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes., Conclusions: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Whole-brain radiation therapy (WBRT) is the standard of care after resection of a brain metastasis. However, concern regarding possible neurocognitive effects and the lack of survival benefit with this approach has led to the use of stereotactic radiosurgery (SRS) to the resection cavity in place of WBRT. We report our initial experience using an image-guided linear accelerator-based frameless stereotactic system and review the technical issues in applying this technique., Methods and Materials: We retrospectively reviewed the setup accuracy, treatment outcome, and patterns of failure of the first 18 consecutive cases treated at Brigham and Women's Hospital. The target volume was the resection cavity without a margin excluding the surgical track., Results: The median number of brain metastases per patient was 1 (range, 1-3). The median planning target volume was 3.49 mL. The median prescribed dose was 18 Gy (range, 15-18 Gy) with normalization ranging from 68% to 85%. In all cases, 99% of the planning target volume was covered by the prescribed dose. The median conformity index was 1.6 (range, 1.41-1.92). The SRS was delivered with submillimeter accuracy. At a median follow-up of 12.7 months, local control was achieved in 16/18 cavities treated. True local recurrence occurred in 2 patients. No marginal failures occurred. Distant recurrence occurred in 6/17 patients. Median time to any failure was 7.4 months. No Grade 3 or higher toxicity was recorded. A long interval between initial cancer diagnosis and the development of brain metastasis was the only factor that trended toward a significant association with the absence of recurrence (local or distant) (log-rank p = 0.097)., Conclusions: Frameless stereotactic irradiation of the resection cavity after surgery for a brain metastasis is a safe and accurate technique that offers durable local control and defers the use of WBRT in select patients. This technique should be tested in larger prospective studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Shimmering is a collective defence behaviour in Giant honeybees (Apis dorsata) whereby individual bees flip their abdomen upwards, producing Mexican wave-like patterns on the nest surface. Bucket bridging has been used to explain the spread of information in a chain of members including three testable concepts: first, linearity assumes that individual "agent bees" that participate in the wave will be affected preferentially from the side of wave origin. The directed-trigger hypothesis addresses the coincidence of the individual property of trigger direction with the collective property of wave direction. Second, continuity describes the transfer of information without being stopped, delayed or re-routed. The active-neighbours hypothesis assumes coincidence between the direction of the majority of shimmering-active neighbours and the trigger direction of the agents. Third, the graduality hypothesis refers to the interaction between an agent and her active neighbours, assuming a proportional relationship in the strength of abdomen flipping of the agent and her previously active neighbours. Shimmering waves provoked by dummy wasps were recorded with high-resolution video cameras. Individual bees were identified by 3D-image analysis, and their strength of abdominal flipping was assessed by pixel-based luminance changes in sequential frames. For each agent, the directedness of wave propagation was based on wave direction, trigger direction, and the direction of the majority of shimmering-active neighbours. The data supported the bucket bridging hypothesis, but only for a small proportion of agents: linearity was confirmed for 2.5%, continuity for 11.3% and graduality for 0.4% of surface bees (but in 2.6% of those agents with high wave-strength levels). The complimentary part of 90% of surface bees did not conform to bucket bridging. This fuzziness is discussed in terms of self-organisation and evolutionary adaptedness in Giant honeybee colonies to respond to rapidly changing threats such as predatory wasps scanning in front of the nest.

To review the safety and efficacy of linear accelerator-based stereotactic radiosurgery (SRS) for brainstem metastases. We reviewed all patients with brain metastases treated with SRS at DF/BWCC from 2001 to 2009 to identify patients who had SRS to a single brainstem metastasis. Overall survival and freedom-from-local failure rates were calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model. A total of 24 consecutive patients with brainstem metastases had SRS. At the time of SRS, 21/24 had metastatic lesions elsewhere within the brain. 23/24 had undergone prior WBRT. Primary diagnoses included eight NSCLC, eight breast cancer, three melanoma, three renal cell carcinoma and two others. Median dose was 13 Gy (range, 8-16). One patient had fractionated SRS 5 Gy ×5. Median target volume was 0.2 cc (range, 0.02-2.39). The median age was 57 years (range, 42-92). Follow-up information was available in 22/24 cases. At the time of analysis, 18/22 patients (82%) had died. The median overall survival time was 5.3 months (range, 0.8-21.1 months). The only prognostic factor that trended toward statistical significance for overall survival was the absence of synchronous brain metastasis at the time of SRS; 1-year overall survival was 31% with versus 67% without synchronous brain metastasis (log rank P = 0.11). Non-significant factors included primary tumor histology and status of extracranial disease (progressing vs. stable/absent). Local failure occurred in 4/22 cases (18%). Actuarial freedom from local failure for all cases was 78.6% at 1 year. RTOG grade 3 toxicities were recorded in two patients (ataxia, confusion). Linac-based SRS for small volume brainstem metastases using a median dose of 13 Gy is associated with acceptable local control and low morbidity.

To study the ability of dual phase FDG-PET/CT imaging to accurately distinguish tumor versus necrosis in patients treated for brain metastases. 32 (22 female, 10 male) consecutive patients with treated brain metastases, lesion size greater than 0.5 cm(3) and suspected recurrence on MRI underwent dual-phase FDG-PET/CT. Clinical outcome was assessed by biopsy or by MRI. SUVmax and SUVmean values of the lesion (L) and gray matter (GM) at the level of the thalamus were measured on early (1) and delayed (2) imaging. L1/GM1 and L2/GM2 and the change of L/GM ratios as a function of time were calculated [(L2/GM2 - L1/GM1)/(L1/GM1)]. Cut-off values were obtained by ROC analysis. P < 0.05 defined statistical significance. Seven patients were excluded due to indeterminate outcomes. 25 patients (16 female, 9 male; 27 lesions; 28 scan sessions) had clear outcomes, proven by either biopsy (n = 16 patients) or serial follow-up MRI (n = 9 patients). Primary subtypes included breast (n = 9), lung (n = 7), melanoma (n = 3), squamous cell cancer of the head and neck (n = 2) and other (n = 4). Twenty-two patients underwent prior radiation (2-113 months) and three received only prior chemotherapy (5 months to 3 years). A change >0.19 of L/GM ratios as a function of time was 95% sensitive, 100% specific, and 96.4% accurate (P = 0.0001; AUC = 0.97) for distinguishing tumor versus radiation necrosis. The ratio of the change of the lesion to WM ratios over time was the second best indicator of outcome when compared to all indices used (ROC cut-off = 0.25, sensitivity 89.5% and specificity 90.9%, and accuracy 89.2%; P = 0.0001; AUC = 0.95), Early or late SUVs of the lesion alone did not differentiate between tumor and necrosis. Regardless of histological type, differentiation of necrosis from metastatic brain lesions was improved by using the change of lesion to gray matter SUVmax ratios as a function of time.

The purpose of this case series is to report the unexpected occurrence of four cases of late radiation-induced neurotoxicity with bevacizumab use following radiotherapy to the CNS. We retrospectively reviewed the case records of four patients, three with glioblastoma and one with bone metastases secondary to metastatic breast cancer, who were treated with radiotherapy and developed late radiation-induced neurotoxicity following bevacizumab use. Three cases of optic neuropathy in glioblastoma patients and a single case of Brown-Séquard syndrome in the thoracic spine of a patient with metastatic breast cancer are reported. We hypothesize that bevacizumab use following radiotherapy to the CNS may inhibit vascular endothelial growth factor-dependent repair of normal neural tissue, and thus may increase the risk of late radiation neurotoxicity. Phase III data on the safety and efficacy of bevacizumab use with radiation in the setting of glioblastoma is awaited.

Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ)., Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs., Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT., Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33-74 years), and median KPS was 70 (range, 60-100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted.

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, IIIA, and IIIB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.

Background: Poor survival among African American patients with breast cancer has been attributed to low socioeconomic status and lack of access to health care. However, Hispanics of equivalent socioeconomic status and health care access exhibit much higher survival rates, almost comparable to whites. This suggests that biologic differences play a role in differences in breast cancer survival in addition to socioeconomic and health care access factors., Methods: The authors studied clinical and molecular differences between patients with breast cancer of different ethnicity to determine biologic explanations for the observed differences in survival. Consecutive patients scheduled for breast biopsies were identified preoperatively and were interviewed. Blood was withdrawn for serum marker measurements, and tumor specimens collected at frozen section diagnosis were analyzed by flow cytometry, hormone receptor concentration, tumor grade, and Ki-67 nuclear antigen, HER-2/neu, and epidermal growth factor oncoprotein expression., Results: Age, age at menarche, number of lymph nodes with metastasis, estrogen and progesterone receptor levels, ploidy status, S-phase, Ki-67, HER-2/neu expression, tumor grade, epidermal growth factor receptor expression, lipid-associated sialic acid (LASA), and carcinoembryonic antigen level were not significantly related to ethnicity. African Americans presented at a significantly more advanced stage and with significantly larger tumors. They were significantly heavier and had a significantly higher mean Quetelet's index and a significantly higher number of pregnancies and number of live births. Whites and Hispanics were significantly older at menopause., Conclusions: The molecular indices associated with breast cancer prognosis do not differ significantly among whites, African Americans, and Hispanics, suggesting that the reported differences in survival among these groups are not due to biologic differences in breast cancer among ethnic groups.