National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Patient Outcomes in Laparoscopic Appendectomy With Acute Surgical Care Model Compared to Traditional Call.

INTRODUCTION: Shift-based models for acute surgical care (ACS), where surgical emergencies are treated by a dedicated team of surgeons working shifts, without a concurrent elective practice, are becoming more common nationwide. We compared the outcomes for appendectomy, one of the most common emergency surgical procedures, between the traditional (TRAD) call and ACS model at the same institution during the same time frame. METHODS: A retrospective review of patients who underwent laparoscopic appendectomy for acute appendicitis during 2017-2018. ACS and TRAD-patient demographics, clinical presentation, operative details, and outcomes were compared using independent sample t-tests, Wilcoxon rank-sum tests and Fisher's exact or χ2 tests. Multiple exploratory regression models were constructed to examine the effects of confounding variables. RESULTS: Demographics, clinical presentation, and complication rates were similar between groups except for a longer duration of symptoms prior to arrival in the TRAD group (Δ = 0.5 d, P = 0.006). Time from admission to operating room (Δ = -1.85 h, P = 0.003), length of hospital stay (Δ = -2.0 d, P < 0.001), and total cost (Δ = $ -2477.02, P < 0.001) were significantly lower in the ACS group compared to the TRAD group. Furthermore, perforation rates were lower in ACS (8.3% versus 28.6%, P = 0.003). Differences for the outcomes remained significant even after controlling for duration of symptoms prior to arrival (P < 0.05). CONCLUSIONS: Acute appendicitis managed using the ACS shift-based model seems to be associated with reduced time to operation, hospital stay, and overall cost, with equivalent success rates, compared to TRAD.

Customizable landmark-based field aperture design for automated whole-brain radiotherapy treatment planning.

PURPOSE: To develop and evaluate an automated whole-brain radiotherapy (WBRT) treatment planning pipeline with a deep learning-based auto-contouring and customizable landmark-based field aperture design. METHODS: The pipeline consisted of the following steps: (1) Auto-contour normal structures on computed tomography scans and digitally reconstructed radiographs using deep learning techniques, (2) locate the landmark structures using the beam's-eye-view, (3) generate field apertures based on eight different landmark rules addressing different clinical purposes and physician preferences. Two parallel approaches for generating field apertures were developed for quality control. The performance of the generated field shapes and dose distributions were compared with the original clinical plans. The clinical acceptability of the plans was assessed by five radiation oncologists from four hospitals. RESULTS: The performance of the generated field apertures was evaluated by the Hausdorff distance (HD) and mean surface distance (MSD) from 182 patients' field apertures used in the clinic. The average HD and MSD for the generated field apertures were 16 ± 7 and 7 ± 3 mm for the first approach, respectively, and 17 ± 7 and 7 ± 3 mm, respectively, for the second approach. The differences regarding HD and MSD between the first and the second approaches were 1 ± 2 and 1 ± 3 mm, respectively. A clinical review of the field aperture design, conducted using 30 patients, achieved a 100% acceptance rate for both the first and second approaches, and the plan review achieved a 100% acceptance rate for the first approach and a 93% acceptance rate for the second approach. The average acceptance rate for meeting lens dosimetric recommendations was 80% (left lens) and 77% (right lens) for the first approach, and 70% (both left and right lenses) for the second approach, compared with 50% (left lens) and 53% (right lens) for the clinical plans. CONCLUSION: This study provided an automated pipeline with two field aperture generation approaches to automatically generate WBRT treatment plans. Both quantitative and qualitative evaluations demonstrated that our novel pipeline was comparable with the original clinical plans.

Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer.

PURPOSE: Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. METHODS: To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. RESULTS: Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response CONCLUSIONS: The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs.

Perioperative considerations in patients with chemotherapy-induced cognitive impairment: a narrative review.

Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

BACKGROUND: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. METHODS: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. FINDINGS: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). INTERPRETATION: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. FUNDING: Bristol Myers Squibb.

Systematic Reviews and Meta-Analyses of Portal Vein Embolization, Associated Liver Partition and Portal Vein Ligation, and Radiation Lobectomy Outcomes in Hepatocellular Carcinoma Patients.

PURPOSE OF REVIEW: To understand portal vein embolization (PVE), associated liver partition and portal vein ligation (ALPPS) and radiation lobectomy (RL) outcomes in hepatocellular carcinoma (HCC) patients. Systematic reviews of future liver remnant (FLR) percent hypertrophy, proportion undergoing hepatectomy and proportion with major complications following PVE, ALPPS, and RL were performed by searching Ovid MEDLINE, Ovid EMBASE, The Cochrane Library, and Web of Science. Separate meta-analyses using random-effects models with assessment of study heterogeneity and publication bias were performed whenever allowable by available data. RECENT FINDINGS: Of the 10,616 articles screened, 21 articles with 636 subjects, 4 articles with 65 subjects, and 4 articles with 195 subjects met the inclusion criteria for systematic reviews and meta-analyses for PVE, ALPPS, and RL, respectively. The pooled estimate of mean percent FLR hypertrophy was 30.9% (95%CI: 22-39%, Q = 4034.8, p < 0.0001) over 40.3 +/- 26.3 days for PVE, 54.9% (95%CI: 36-74%, Q = 73.8, p < 0.0001) over 11.1 +/- 3.1 days for ALPPS, and 29.0% (95%CI: 23-35%, Q = 56.2, p < 0.0001) over 138.5 +/- 56.5 days for RL. The pooled proportion undergoing hepatectomy was 91% (95%CI: 83-95%, Q = 43.9, p = 0.002) following PVE and 98% (95%CI: 50-100%, Q = 0.0, p = 1.0) following ALPPS. The pooled proportion with major complications was 5% (95%CI: 2-10%, Q = 7.3, p = 0.887) following PVE and 38% (95%CI: 18-63%, Q = 10.0, p = 0.019) following ALPPS. Though liver hypertrophy occurs following all three treatments in HCC patients, PVE balances effective hypertrophy with a short time frame and low major complication rate.

Glioma consensus contouring recommendations from a MR-Linac International Consortium Research Group and evaluation of a CT-MRI and MRI-only workflow.

INTRODUCTION: This study proposes contouring recommendations for radiation treatment planning target volumes and organs-at-risk (OARs) for both low grade and high grade gliomas. METHODS: Ten cases consisting of 5 glioblastomas and 5 grade II or III gliomas, including their respective gross tumor volume (GTV), clinical target volume (CTV), and OARs were each contoured by 6 experienced neuro-radiation oncologists from 5 international institutions. Each case was first contoured using only MRI sequences (MRI-only), and then re-contoured with the addition of a fused planning CT (CT-MRI). The level of agreement among all contours was assessed using simultaneous truth and performance level estimation (STAPLE) with the kappa statistic and Dice similarity coefficient. RESULTS: A high level of agreement was observed between the GTV and CTV contours in the MRI-only workflow with a mean kappa of 0.88 and 0.89, respectively, with no statistically significant differences compared to the CT-MRI workflow (p = 0.88 and p = 0.82 for GTV and CTV, respectively). Agreement in cochlea contours improved from a mean kappa of 0.39 to 0.41, to 0.69 to 0.71 with the addition of CT information (p < 0.0001 for both cochleae). Substantial to near perfect level of agreement was observed in all other contoured OARs with a mean kappa range of 0.60 to 0.90 in both MRI-only and CT-MRI workflows. CONCLUSIONS: Consensus contouring recommendations for low grade and high grade gliomas were established using the results from the consensus STAPLE contours, which will serve as a basis for further study and clinical trials by the MR-Linac Consortium.

The joint effect of aging and HIV infection on microstructure of white matter bundles.

Recent evidence suggests the aging process is accelerated by HIV. Degradation of white matter (WM) has been independently associated with HIV and healthy aging. Thus, WM may be vulnerable to joint effects of HIV and aging. Diffusion-weighted imaging (DWI) was conducted with HIV-seropositive (n = 72) and HIV-seronegative (n = 34) adults. DWI data underwent tractography, which was parcellated into 18 WM tracts of interest (TOIs). Functional Analysis of Diffusion Tensor Tract Statistics (FADTTS) regression was conducted assessing the joint effect of advanced age and HIV on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along TOI fibers. In addition to main effects of age and HIV on WM microstructure, the interactive effect of age and HIV was significantly related to lower FA and higher MD, AD, and RD across all TOIs. The location of findings was consistent with the clinical presentation of HIV-associated neurocognitive disorders. While older age is related to poorer WM microstructure, its detrimental effect on WM is stronger among HIV+ relative to HIV- individuals. Loss of WM integrity in the context of advancing age may place HIV+ individuals at increased risk for brain and cognitive compromise.

Quantitative imaging biomarkers alliance (QIBA) recommendations for improved precision of DWI and DCE-MRI derived biomarkers in multicenter oncology trials.

Physiological properties of tumors can be measured both in vivo and noninvasively by diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging. Although these techniques have been used for more than two decades to study tumor diffusion, perfusion, and/or permeability, the methods and studies on how to reduce measurement error and bias in the derived imaging metrics is still lacking in the literature. This is of paramount importance because the objective is to translate these quantitative imaging biomarkers (QIBs) into clinical trials, and ultimately in clinical practice. Standardization of the image acquisition using appropriate phantoms is the first step from a technical performance standpoint. The next step is to assess whether the imaging metrics have clinical value and meet the requirements for being a QIB as defined by the Radiological Society of North America's Quantitative Imaging Biomarkers Alliance (QIBA). The goal and mission of QIBA and the National Cancer Institute Quantitative Imaging Network (QIN) initiatives are to provide technical performance standards (QIBA profiles) and QIN tools for producing reliable QIBs for use in the clinical imaging community. Some of QIBA's development of quantitative diffusion-weighted imaging and dynamic contrast-enhanced QIB profiles has been hampered by the lack of literature for repeatability and reproducibility of the derived QIBs. The available research on this topic is scant and is not in sync with improvements or upgrades in MRI technology over the years. This review focuses on the need for QIBs in oncology applications and emphasizes the importance of the assessment of their reproducibility and repeatability. Level of Evidence: 5 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;49:e101-e121.

Specialty Classifications of Physicians Who Provide Neurocritical Care in the United States.

BACKGROUND: We sought to characterize the specialty classification of US physicians who provide critical care for neurological/neurosurgical disease. METHODS: Using inpatient claims between 2009 and 2015 from a nationally representative 5% sample of Medicare beneficiaries, we selected hospitalizations for neurological/neurosurgical diseases with potential to result in life-threatening manifestations requiring critical care. Using Current Procedural Terminology® codes, we determined the medical specialty of providers submitting critical care claims, and, using National Provider Identifier numbers, we merged in data from the United Council for Neurologic Subspecialties (UCNS) to determine whether the provider was a UCNS diplomate in neurocritical care. We defined providers with a clinical neuroscience background as neurologists, neurosurgeons, and/or UCNS diplomates in neurocritical care. We defined neurocritical care service as a critical care claim with a qualifying neurological/neurosurgical diagnosis in patients with a relevant primary hospital discharge diagnosis and ≥ 3 total critical care claims, excluding claims from the first day of hospitalization since these were mostly emergency-department claims. Our findings were reported using descriptive statistics with exact confidence intervals (CI). RESULTS: Among 1,952,305 Medicare beneficiaries, we identified 99,937 hospitalizations with at least one claim for neurocritical care. In our primary analysis, neurologists accounted for 28.0% (95% CI, 27.5-28.5%) of claims, neurosurgeons for 3.7% (95% CI, 3.5-3.9%), UCNS-certified neurointensivists for 25.8% (95% CI, 25.3-26.3%), and providers with any clinical neuroscience background for 42.8% (95% CI, 42.2-43.3%). The likelihood of management by physicians with a clinical neuroscience background increased proportionally with patients' county-level socioeconomic status and such providers were 3 times more likely to be based at an academic medical center than other physicians who billed for critical care in our sample (odds ratio, 2.9; 95% CI, 1.1-8.1). CONCLUSIONS: Physicians with a dedicated clinical neuroscience background accounted for less than half of neurocritical care service in US Medicare beneficiaries.

Multi-institutional study of the variability in target delineation for six targets commonly treated with radiosurgery.

BACKGROUND: Although accurate delineation of the target is a key factor of success in radiosurgery there are no consensus guidelines for target contouring. AIM: The aim of the present study was therefore to quantify the variability in target delineation and discuss the potential clinical implications, for six targets regarded as common in stereotactic radiosurgery. MATERIAL AND METHODS: Twelve Gamma Knife centers participated in the study by contouring the targets and organs at risks and performing the treatment plans. Analysis of target delineation variability was based on metrics defined based on agreement volumes derived from overlapping structures following a previously developed method. The 50% agreement volume (AV50), the common and the encompassing volumes as well as the Agreement Volume Index (AVI) were determined. RESULTS: Results showed that the lowest AVI (0.16) was found for one of the analyzed metastases (range of delineated volumes 1.27-3.33 cm3). AVI for the other two metastases was 0.62 and 0.37, respectively. Corresponding AVIs for the cavernous sinus meningioma, pituitary adenoma and vestibular schwannoma were 0.22, 0.37 and 0.50. CONCLUSIONS: This study showed that the variability in the contouring was much higher than expected and therefore further work in standardizing the contouring practice in radiosurgery is warranted.

Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery.

BACKGROUND: Brain radionecrosis (tissue death caused by radiation) can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QoL) and function. The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging. OBJECTIVES: To assess the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old. SEARCH METHODS: In October 2017, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies. We also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and handsearched relevant conference material. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain. We anticipated a limited number of RCTs, so we also planned to include all comparative prospective intervention trials and quasi-randomised trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e. placebo or corticosteroids). Selection bias was likely to be an issue in all the included non-randomised studies therefore results are interpreted with caution. DATA COLLECTION AND ANALYSIS: Two review authors (CC, PB) independently extracted data from selected studies and completed a 'Risk of bias' assessment. For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported. For continuous outcomes, treatment effect was reported as mean difference (MD) between treatment arms with 95% confidence intervals (CIs). MAIN RESULTS: Two RCTs and one prospective non-randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta-analysis was not possible. There were no trials of non-pharmacological interventions that met the inclusion criteria.A very small randomised, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed.An open-label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95% CI - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low-certainty evidence due to open-label design). No differences in treatment toxicities were observed between arms.One included prospective non-randomised study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double-blinded randomised controlled trial, the other studies were prone to selection and detection biases.None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements.A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints. AUTHORS' CONCLUSIONS: There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open-label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified.

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape.

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies.

Neutrophil-lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival.

Elevated neutrophil-lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan-Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18-70), 369 patients were included. Median follow up was 15.1 month (range 1.6-134.6). The OS was 66.1% (95% CI 61.2-70.6) and 31.4 (95% CI 26.8-36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p < 0.0001) and baseline NLR < 7.5 (HR 0.628, p < 0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578-0.915), age (HR 1.025, 95% CI 1.012-1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532-0.891), total TMZ cycles (HR 0.89, 95% CI 0.867-0.913) and PS (HR 0.476, 95% CI 0.332-0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.

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

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

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas.

BACKGROUND: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. METHODS: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. RESULTS: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. CONCLUSIONS: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

Informational and Supportive Care Needs of Brain Metastases Patients and Caregivers: a Systematic Review.

While brain metastases (BM) are associated with significant morbidity and mortality, the needs of BM patients and their caregivers (CGs) remain largely unknown. The purpose of this systematic review was to summarize (a) the informational needs of BM patients and CGs, (b) their supportive care needs, and (c) studies evaluating existing programs and resources addressing one or more of informational needs. A systematic search was conducted in four databases to identify studies, published from 2000 to April 2015, discussing informational or supportive care needs of BM patients and/or their CGs. Duplicate screening, data abstraction, and risk of bias assessments were conducted. Results were qualitatively summarized. From 973 references, seven studies fulfilled inclusion criteria. While physical and medical informational needs concerning prognosis, symptom management, treatment options, and side effects were reported, no studies exploring patient or CG social, emotional, or spiritual informational needs were identified. Discordance was observed between patient, CG, and health care professional perspectives on patient supportive care needs. One study evaluated an intervention addressing informational needs. Patients required information on prognosis, managing symptoms, and available treatment options and associated side effects. They needed support managing housework, pain, and fatigue. The findings of this study suggest an ongoing need to elicit psychosocial informational needs, supportive care needs, and a need for patient- and CG-centered resource development. Since ascertaining these needs is vital to the delivery of patient-centered care, efforts must be undertaken to explore these in the context of BM patients and CGs.

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial.

IMPORTANCE: Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE: To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS: At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS: The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES: The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS: There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04). CONCLUSIONS AND RELEVANCE: Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00377156.