Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create ...diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians.
A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis.
Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined.
Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.
The addition of bevacizumab to temozolomide and radiotherapy did not improve overall survival in patients with glioblastoma. Patients receiving bevacizumab had more symptoms, a worse quality of life, ...and more cognitive impairment than did those receiving placebo.
Glioblastoma is the most common primary malignant brain tumor in adults. After maximal surgical tumor resection, the current standard of care is based on a phase 3, randomized clinical trial conducted by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada, which showed that concurrent treatment with daily temozolomide and radiotherapy followed by maintenance temozolomide was superior to radiotherapy alone.
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Despite the improvement in outcomes with this combined chemoradiotherapy approach, few patients survive beyond 5 years; therefore, new therapeutic strategies are needed.
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Angiogenesis is a prominent feature of glioblastoma, most commonly attributed . . .
Patients with grade 2 glioma were randomly assigned to radiation therapy alone or radiation therapy plus six cycles of chemotherapy. The median overall survival with radiation therapy plus ...chemotherapy was 13.3 years, as compared with 7.8 years with radiation therapy alone.
Grade 2 gliomas are relatively uncommon, constituting 5 to 10% of all primary brain tumors in adults. Progressive neurologic symptoms eventually develop in nearly all patients, and nearly all patients die prematurely. At the time of the initiation of our trial, studies had shown that chemotherapy caused tumor regressions in patients with recurrent low-grade gliomas, with regimens that included procarbazine, lomustine (also called CCNU), and vincristine,
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carmustine (also called BCNU) plus interferon,
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and mechlorethamine, vincristine, and procarbazine.
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Similarly, the combination of procarbazine, CCNU, and vincristine, when administered as initial therapy, has been shown to result in tumor regressions.
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The . . .
The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in ...high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.
•Immunotherapy and radiosurgery are utilized for brain metastases but data are limited.•In this metaanalysis, concurrent therapy improved 1-year survival and brain control.•The overall rate of ...radionecrosis was 5.3%.•Prospective trials are needed to more accurately inform on this clinical scenario.
While the combination of stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is becoming more widely used in the treatment of brain metastases (BM), there is a paucity of prospective data to validate both the safety and efficacy, as well as the optimal timing of these two therapies relative to one another.
A PICOS/PRISMA/MOOSE selection protocol was used to identify 17 studies across 15 institutions in 3 countries. Inclusion criteria were patients: diagnosed with BM; treated with SRS/ICI, either concurrently or non-concurrently; with at least one of the primary or secondary outcome measures reported. Weighted random effects meta-analyses using the DerSimonian and Laird method were performed. The primary outcome was 1-year overall survival (OS). Secondary outcomes were 1-year local control (LC), 1-year regional brain control (RBC), and radionecrosis incidence.
A total of 534 patients with 1,570 BM were included. The 1-year OS was 64.6% and 51.6% for concurrent and non-concurrent therapy, respectively (p < 0.001). Local control at 1-year was 89.2% and 67.8% for concurrent and non-concurrent therapy, respectively (p = 0.09). The RBC at 1-year was 38.1% and 12.3% for concurrent and ICI administration prior to SRS, respectively (p = 0.049). The overall incidence of radionecrosis for all studies was 5.3%.
Concurrent administration of SRS/ICI may be associated with improved safety and efficacy versus sequential therapy. These findings, however, are hypothesis-generating and require further validation by ongoing and planned prospective trials.
Summary CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion ...is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
Atherosclerosis differs across major arteries. Although the biological basis is not fully understood, limited evidence of genetic differences has been documented. This study, therefore, was aimed to ...identify differentially expressed genes between clinically relevant major arteries and investigate their enrichment in endothelial dysfunction-related gene sets. A bioinformatic analysis of publicly available gene-level read counts for coronary, aortic, and tibial arteries was performed. Differential gene expression was conducted with
at a false discovery rate of 0.05. Differentially expressed genes were then subjected to over-representation analysis and active-subnetwork-oriented enrichment analysis, both at a false discovery rate of 0.005. Enriched terms common to both analyses were categorized for each contrast into immunity/inflammation-, membrane biology-, lipid metabolism-, and coagulation-related terms, and the top differentially expressed genes validated against Swiss Institute of Bioinformatics' Bgee database. There was mostly upregulation of differentially expressed genes for the coronary/tibial and aorta/tibial contrasts, but milder changes for the coronary/aorta contrast. Transcriptomic differences between coronary or aortic versus tibial samples largely involved immunity/inflammation-, membrane biology-, lipid metabolism-, and coagulation-related genes, suggesting potential to modulate endothelial dysfunction and atherosclerosis. These results imply atheroprone coronary and aortic environments compared with tibial artery tissue, which may explain observed relative inter-artery atherosclerosis risk.
Summary Background Traumatic brain injury (TBI) is the leading cause of long-term disability in children and young adults worldwide. However, accurate information about its incidence does not exist. ...We aimed to estimate the burden of TBI in rural and urban populations in New Zealand across all ages and TBI severities. Methods We did a population-based incidence study in an urban (Hamilton) and rural (Waikato District) population in New Zealand. We registered all cases of TBI (admitted to hospital or not, fatal or non-fatal) that occurred in the population between March 1, 2010, and Feb 28, 2011, using multiple overlapping sources of information. We calculated incidence per 100 000 person-years with 95% CIs using a Poisson distribution. We calculated rate ratios RRs to compare the age-standardised rates between sex, ethnicity, and residency (urban, rural) groups. We used direct standardisation to age-standardise the rates to the world population. Results The total incidence of TBI per 100 000 person-years was 790 cases (95% CI 749–832); incidence per 100 000 person-years of mild TBI was 749 cases (709–790) and of moderate to severe TBI was 41 cases (31–51). Children (aged 0–14 years) and adolescents and young adults (aged 15–34 years) constituted almost 70% of all TBI cases. TBI affected boys and men more than women and girls (RR 1·77, 95% CI 1·58–1·97). Most TBI cases were due to falls (38% 516 of 1369), mechanical forces (21% 288 of 1369), transport accidents (20% 277 of 1369), and assaults (17% 228 of 1369). Compared with people of European origin, Maori people had a greater risk of mild TBI (RR 1·23, 95% CI 1·08–1·39). Incidence of moderate to severe TBI in the rural population (73 per 100 000 person-years 95% CI 50–107) was almost 2·5 times greater than in the urban population (31 per 100 000 person-years 23–42). Interpretation Our findings suggest that the incidence of TBI, especially mild TBI, in New Zealand is far greater than would be estimated from the findings of previous studies done in other high-income countries. Our age-specific and residency-specific data for TBI incidence overall and by mechanism of injury should be considered when planning prevention and TBI care services. Funding Health Research Council of New Zealand.
Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous ...population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment DS-GPA).
A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment.
The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined.
The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.
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