Is young adult idiopathic scoliosis a distinct clinical entity from adolescent idiopathic scoliosis? a Systematic Review and Meta-analysis comparing pre-operative characteristics and operative outcomes.

PURPOSE: This study aims to conduct a systematic review of the literature comparing pre-operative, intraoperative, and post-operative characteristics between adolescent idiopathic scoliosis (AIS) and young adult idiopathic scoliosis (YAdIS) patients. METHODS: Following PRISMA guidelines, we conducted a search of the PubMed/Medline, EMBASE, and Cochrane Central databases to identify full-text articles in the English-language literature. Our inclusion criteria were studies that compared preoperative, intraoperative, and postoperative characteristics between AIS and YAdIS patients. We performed a meta-analysis reporting mean difference (MD) for continuous variables and Odds ratios (ORs) to assess differences in postoperative complications. RESULTS: Seven studies consisting of 1562 patients were included in the meta-analysis. The AIS group exhibited less intraoperative bleeding and shorter surgical procedures, with a mean difference between groups of 122.3 ml (95% CI 46.2-198.4, p = 0.002) and 28.7 min (95% CI 6.5-50.8, p = 0.01), respectively. Although the preoperative Cobb angle did not differ between groups (p = 0.65), patients with AIS achieved superior postoperative deformity correction, with a mean difference of 7.3% between groups, MD - 7.3 (95% CI - 9.7, - 4.8, p < 0.00001), and lower postoperative Cobb angles of the major curve, MD 4.2 (95% CI 3.1, 5.3, p < 0.00001). YAdIS patients were fused, on average, 0.2 more vertebral levels than AIS patients, MD 0.2 (95% CI 0.01, 0.5, p = 0.04). AIS patients experienced a significantly shorter length of stay after the surgical procedure, with an MD of 0.8 days (95% CI 0.1, 1.6, p = 0.02). No significant difference was found between groups in terms of complications (p = 0.19). CONCLUSIONS: YAdIS should be regarded as a distinct surgical entity, characterized by increased bleeding, longer surgical duration, greater deformity correction challenges, and the need for fusion of additional vertebral levels compared to AIS. Surgeons should be mindful of these differences and discuss them with patients and their families, especially in cases where the correction of the AIS deformity is delayed and there is a high risk of progression after skeletal maturity. Further research is needed to explore alternative surgical techniques and enhance outcomes for YAdIS patients.

Clinical Outcomes and Complication Profile of Spine Surgery in Septuagenarians and Octogenarians: Case Series.

OBJECTIVE: The aging global population presents an increasing challenge for spine surgeons. Advancements in spine surgery, including minimally invasive techniques, have broadened treatment options, potentially benefiting older patients. This study aims to explore the clinical outcomes of spine surgery in septuagenarians and octogenarians. METHODS: This retrospective analysis, conducted at a US tertiary center, included patients aged 70 and older who underwent elective spine surgery for degenerative conditions. Data included the Charlson Comorbidity Index (CCI), ASA classification, surgical procedures, intraoperative and postoperative complications, and reoperation rates. The objective of this study was to describe the outcomes of our cohort of older patients and discern whether differences existed between septuagenarians and octogenarians. RESULTS: Among the 120 patients meeting the inclusion criteria, there were no significant differences in preoperative factors between the age groups (P > 0.05). Notably, the septuagenarian group had a higher average number of fused levels (2.36 vs. 0.38, P = 0.001), while the octogenarian group underwent a higher proportion of minimally invasive procedures (P = 0.012), resulting in lower overall bleeding in the oldest group(P < 0.001). Mobility outcomes were more favorable in septuagenarians, whereas octogenarians tended to maintain or experience a decline in mobility(P = 0.012). A total of 6 (5%) intraoperative complications and 12 (10%) postoperative complications were documented, with no statistically significant differences observed between the groups. CONCLUSIONS: This case series demonstrates that septuagenarians and octogenarians can achieve favorable clinical outcomes with elective spine surgery. Spine surgeons should be well-versed in the clinical and surgical care of older adults, providing optimal management that considers their increased comorbidity burden and heightened fragility.

Laser Interstitial Thermal Therapy as a Treatment Option for Malignant Peripheral Nerve Sheath Tumor Metastases to the Brain: A Case Report.

We present the unique case of a 60-year-old female with neurofibromatosis type 1 (NF1) who underwent laser interstitial thermal therapy (LITT) for metastatic malignant peripheral nerve sheath tumor (MPNST) of the brain. She presented to the emergency room complaining of one week of dysarthria and facial droop. An MRI of the brain demonstrated a homogeneously enhancing left frontal mass; although rare, given her history of pulmonary MPNST, brain invasion was considered likely. No generally accepted guidelines for the treatment of MPNST with cerebral metastases exist; however, LITT was chosen due to tumor morphology and proximity to eloquent brain structures. She did not experience any new or worsening neurological deficits post-operatively. Post-ablation MRI showed white matter edema surrounding the lesion, which is consistent with previously reported cases. This case illustrates the use of LITT for cytoreduction for rare brain metastases located near eloquent brain structures.

Outcome differences between males and females undergoing deep brain stimulation for treatment-resistant depression: systematic review and individual patient data meta-analysis.

BACKGROUND: Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis. METHODS: A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses. RESULTS: Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %-51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %-25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification. LIMITATIONS: Studies included were open-label trials with small sample sizes. CONCLUSIONS: Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials.

C2 versus C3 or C4 as the upper instrumented vertebra for long-segment cervical fusions: a systematic review and meta-analysis.

OBJECTIVE: Selecting C2 versus C3 or C4 (i.e., C3/C4) as the rostral anchoring level in long-segment cervical fusions is a common clinical conundrum. The data regarding proximal failure in long constructs of the cervical spine is scarce. The objective of this study was to systematically review the published literature and perform a meta-analysis of the incidence for proximal adjacent-segment disease (ASD) in the context of long cervical fusions and cervicothoracic fusions ending in C2 versus those ending in the subaxial spine (C3 or C4). METHODS: Using the PRISMA guidelines, the authors performed a search of the PubMed/MEDLINE, Embase/Ovid, and Cochrane Central databases to identify all full-text articles in the English-language literature with the following inclusion criteria: 1) studies including patients with the upper instrumented vertebra (UIV) at C2 versus C3/C4; 2) patients undergoing ≥ 3-level posterior cervical fusion; and 3) indication for surgery of degenerative disc disease, cervical spondylotic myelopathy, or cervical deformity. Studies that were not published in the English language, case reports, review articles, letters to the editor, and meeting abstracts were excluded. A meta-analysis was conducted using a fixed-effects model when I2 values were below 70%. Conversely, when I2 values were equal to or greater than 70%, a random-effects model was used. A funnel plot was used to assess the presence of publication bias. RESULTS: Seven studies consisting of 1215 patients were included in the meta-analysis. There were 403 (32.8%) patients in the C2 UIV group and 812 (67.2%) patients in the C3/C4 UIV group. When the 7 studies were analyzed, the overall rate of reoperation was comparable between the C2 (9.2%) and C3/C4 (9.4%) UIV groups (p = 0.93) but the rate of surgical ASD due to proximal pathology was 1.2% and 3%, respectively (OR 0.36, 95% CI 0.15-0.86; p = 0.02). When comparing between groups, no statistical difference was found regarding the rate of reoperation due to distal pathology or surgical infection. CONCLUSIONS: Long-segment cervical or cervicothoracic constructs that anchor into C2 may have similar complication rates but lower revision rates for proximal ASD than constructs that anchor into the subaxial spine.

Trends in Spinal Orthosis Utilization Among Patients Insured through Medicare Part B.

STUDY DESIGN: Retrospective population-based database analysis from the Physician/Supplier Procedure Summary Medicare/Medicaid Dataset. OBJECTIVE: To provide a comprehensive analysis of trends in spinal orthosis utilization over a 12-year period. SUMMARY OF BACKGROUND DATA: Widespread prescription of spinal orthosis persists, despite evidence suggesting equivocal efficacy in many spinal conditions. The utilization of spinal orthosis on a national level, including prescribing specialty data, has not been previously analyzed. METHODS: Healthcare common procedure coding system (HCPCS) codes for cervical (CO), thoracic-lumbar-sacral (TLSO), lumbar (LO), lumbar-sacral (LSO), and cervical-thoracic-lumbar-sacral (CTLSO) orthosis were used to determine spinal orthosis utilization from 2010 to 2021. Provider specialty codes were utilized to compare trends between select specialties. Additionally, a neurosurgical CO analysis, based on subclassifications of cervical bracing, was performed. Linear trendlines were implemented to elucidate and present trends by slope (ß). RESULTS: Among 332,241 claims, decreases in CO (ß=-0.3387), TLSO (ß=-0.0942), LO (ß=-0.3485), and LSO (ß=-0.1545) per 100,000 Medicare Part B enrollees and CTLSO (ß=-0.052) per 1,000,000 Medicare Part B enrollees were observed. Decreases among neurosurgery (ß=-7.9208), family medicine (ß=-1.0097), emergency medicine (ß=-2.1958), internal medicine (ß=-1.1151), interventional pain management (ß=-5.0945), and chiropractic medicine (ß=-49.012), and increases among orthopedic surgery (ß=5.5891), pain management (ß=30.416), physical medicine and rehabilitation (ß=4.6524), general practice (ß=79.111), and osteopathic manipulative medicine (ß=45.303) in total spinal orthosis use per 100,000 specialty claims were observed. Analysis on subclassifications of cervical orthosis among neurosurgeons revealed decreases in flexible (ß=-1.7641), semi-rigid (ß=-0.6157), and collar bracing (ß=-2.7603), and an increase in multi-post collar bracing (ß=2.2032) per 100 neurosurgical cervical orthosis claims. CONCLUSIONS: While utilization of spinal orthosis decreased between 2010-2021, increased utilization was observed among a subset of specialties. Identifying these specialties allows for focused research and educational efforts to minimize unnecessary durable medical equipment use for effective healthcare spending.

Indications for Fusion With Intradural Spine Tumor Resection in Adults: A Systematic Review and Meta-analysis.

BACKGROUND: The evidence for instrumented fusion in the setting of degenerative, traumatic, or congenital deformity is well established. Data on fusion indications in intradural spinal tumors (IDST) are scarce and reduced to retrospective studies. The objective of this work is to systematically review the published literature since 2015 and analyze the change of practice patterns for stabilization and fusion after intradural tumor resection in adults. METHODS: A systematic literature review was performed via PubMed with the terms: "intradural spinal tumors", "intramedullary spinal tumors", and "intraspinal tumors". The analysis was limited to adult patients with IDST and studies with more than 10 patients. Data on the proportion of patients who underwent instrumentation and had postoperative deformity was pooled in a meta-analysis. RESULTS: A total of 1073 articles were identified and 47 papers were selected. All the studies were retrospective series and a total of 2473 patients were included. The follow-up ranged from 1 to 96 months, the pooled spinal fixation rate was 6% (95% CI 4.5%-7.6%), the pooled laminoplasty rate was 14.4% (95% CI 5.9%-23%), the pooled rate of postoperative deformity or malalignment in patients with a follow up of at least 6 months was 2.1% (95% CI 1.2%-3%) and just 7 patients were reoperated due to progressive deformity. CONCLUSIONS: Based on existing evidence, the rate of fusion during resection of intradural spinal tumors is low. Prophylactic fixation is often unnecessary and only indicated in unique cases that require extensive bony resection.

History of Ablation Therapies in Neurosurgery.

Laser interstitial thermal therapy (LITT) and high-intensity focused ultrasound thermal ablation are treatment options with great potential to treat glioblastoma, metastasis, epilepsy, essential tremor, and chronic pain. Results from recent studies show that LITT is a viable alternative to conventional surgical techniques in select patient populations. Although many of the bases for these treatments have existed since the 1930s, the most important advancement in these techniques has occurred in the last 15 years and the coming years hold much promise for these treatments.

Moderate and severe TBI in children and adolescents: The effects of age, sex, and injury severity on patient outcome 6 months after injury.

The interaction of age, sex, and outcomes of children with head injury remains incompletely understood and these factors need rigorous evaluation in prognostic models for pediatric head injury. We leveraged our large institutional pediatric TBI population to evaluate age and sex along with a series of predictive factors used in the acute care of injury to describe the response and outcome of children and adolescents with moderate to severe injury. We hypothesized that younger age at injury and male sex would be associated with adverse outcomes and that a novel GCS-based scale incorporating pupillary response (GCS-P) would have superior performance in predicting 6-month outcome. GCS and GCS-P along with established CT scan variables associated with neurologic outcomes were retrospectively reviewed in children (age birth to 18 years) with moderate or severe head injury. GOS-E was prospectively collected 6 months after injury; 570 patients were enrolled in the study, 520 with TBI and 50 with abusive head trauma, each analyzed separately. In the TBI cohort, the median age of patients was 8 years and 42.7% had a severe head injury. Multiple predictors of outcome were identified in univariate analysis; however, based on a multivariate analysis, the GCS was identified as most reliable, outperforming GCS-P, pupil score, and other clinical and CT scan predictors. After stratifying patients for severity of injury by GCS, no age- or sex-related effects were observed in our patient population, except for a trend toward worse outcomes in the neonatal group. Patients with abusive head trauma were more likely to have severe injury on presentation, increased mortality rate, and unfavorable outcome. Additionally, there was clear evidence that secondary injuries, including hypoxia, hypotension, and hypothermia were significantly associated with lower GCS and higher mortality in both AHT and TBI populations. Our findings support the use of GCS to guide clinical decision-making and prognostication in addition to emphasizing the need to stratify head injuries for severity when undertaking outcome studies. Finally, secondary injuries are a clear predictor of poor outcome and how we record and manage these events need to be considered moving forward.

Predictors of treatment delay in aneurysmal subarachnoid hemorrhage patients.

BACKGROUND AND PURPOSE: Expeditious treatment is critical in patients with aneurysmal subarachnoid hemorrhage (aSAH) due to the risk of rebleeding. This study aimed to define predictors of treatment delay among aSAH patients. METHODS: A retrospective study of the Nationwide Inpatient Sample database identified patients diagnosed with SAH between 2002 and 2007. Patient's characteristics such as age, gender, race, insurance, SAH severity, treatment (coil versus clip), and other factors were studied. The Cochrane-Armitage test was used to assess delayed care trends by procedure, time of treatment, and hospital volume. Multivariate logistic regression evaluated factors associated with treatment delays. RESULTS: A total of 38,827 patients were admitted between 2002 and 2007; 69.0% were women and 61% were white. The overall median age was 52 years. More patients underwent treatment with surgical clipping than with endovascular coiling (60.4% versus 39.6%, respectively). Overall, 74% of hospital admissions occurred on weekdays; the remaining 26% occurred on weekends. Multivariate analysis revealed that older age (odds ratio [OR]: 1.1; p = 0.0004) and surgical clipping versus endovascular coiling (OR: 1.3; p = 0.02) were independent predictors of delayed treatment (i.e., >2 days from admission). Nonwhite patients experienced greater treatment delays on weekdays compared with white patients (OR: 1.4; p = 0.01). Furthermore, patients treated in low-volume hospitals were significantly more likely to experience delays than those treated in higher volume hospitals (OR: 2.0; p = 0.007). CONCLUSIONS: Risk factors associated with treatment delay in aSAH patients include older age, nonwhite race, surgical clipping, and admission to low surgical volume hospitals.

Spinal surgery: variations in health care costs and implications for episode-based bundled payments.

STUDY DESIGN: Retrospective, observational. OBJECTIVE: To simulate what episodes of care in spinal surgery might look like in a bundled payment system and to evaluate the associated costs and characteristics. SUMMARY OF BACKGROUND DATA: Episode-based payment bundling has received considerable attention as a potential method to help curb the rise in health care spending and is being investigated as a new payment model as part of the Affordable Care Act. Although earlier studies investigated bundled payments in a number of surgical settings, very few focused on spine surgery, specifically. METHODS: We analyzed data from MarketScan. Patients were included in the study if they underwent cervical or lumbar spinal surgery during 2000-2009, had at least 2-year preoperative and 90-day postoperative follow-up data. Patients were grouped on the basis of their diagnosis-related group (DRG) and then tracked in simulated episodes-of-care/payment bundles that lasted for the duration of 30, 60, and 90 days after the discharge from the index-surgical hospitalization. The total cost associated with each episode-of-care duration was measured and characterized. RESULTS: A total of 196,918 patients met our inclusion criteria. Significant variation existed between DRGs, ranging from $11,180 (30-day bundle, DRG 491) to $107,642 (30-day bundle, DRG 456). There were significant cost variations within each individual DRG. Postdischarge care accounted for a relatively small portion of overall bundle costs (range, 4%-8% in 90-day bundles). Total bundle costs remained relatively flat as bundle-length increased (total average cost of 30-day bundle: $33,522 vs. $35,165 for 90-day bundle). Payments to hospitals accounted for the largest portion of bundle costs (76%). CONCLUSION: There exists significant variation in total health care costs for patients who undergo spinal surgery, even within a given DRG. Better characterization of impacts of a bundled payment system in spine surgery is important for understanding the costs of index procedure hospital, physician services, and postoperative care on potential future health care policy decision making. LEVEL OF EVIDENCE: N/A.

Effectiveness of radiotherapy for elderly patients with anaplastic gliomas.

Postoperative radiotherapy (RT) is utilized routinely in the management of anaplastic World Health Organization Grade III gliomas (AG), including anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO). However, the optimal role of RT in elderly AG patients remains controversial. We evaluated the effectiveness of RT in elderly AG patients using a national cancer registry. The USA Surveillance, Epidemiology, and End Results database (1990-2008) was used to query patients over 70 years of age with AA or AO. Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Among 390 elderly patients with AG, 333 (85%) had AA and 57 (15%) had AO. Approximately two-thirds of AA patients (64%) and AO patients (65%) received RT. Most AO patients (58%) and many AA patients (41%) underwent surgical resection; the remainder had biopsy. The median overall survival for all patients who underwent RT was 6 months (95% confidence interval [CI], 5-7 months) versus 2 months (95% CI 1-6) in patients who did not have RT. Patients who had gross total resection (GTR) plus RT had a median overall survival of 11 months (95% CI 7-14). Multivariate analysis for all patients showed that undergoing RT was significantly associated with improved survival (hazard ratio [HR] 0.52, p<.0001). AA tumor type (HR 1.37, p=.03) was associated with worse survival than AO tumor type; female sex (HR 0.59, p<.0001) and being married (HR 0.66, p=.002) significantly improved survival. Patients that underwent GTR had a significant reduction in the hazards of mortality compared to biopsy (HR 0.72, p=.04). Elderly AG patients undergoing RT had better overall survival compared to patients who did not receive RT. Treatment strategies involving maximal safe resection plus RT should be considered in the optimal management of AG in elderly patients.

The effect of weight in the outcomes of meningioma patients.

BACKGROUND: Meningiomas are more prevalent in women and mostly benign in nature. Our aim was to evaluate the association of weight and outcomes of meningioma patients undergoing craniotomy. METHODS: A retrospective analysis of meningioma patients discharged postcraniotomy between 1998 and 2007 was conducted. Univariate and multivariate analysis evaluated in-hospital mortality, complications, length of stay (LOS), and cost. RESULTS: According to the nationwide inpatient sample (NIS) database, an estimated 72,257 adult meningioma patients underwent a craniotomy in US hospitals during the study period. Female and male weight loss rates were 0.7% and 1.2%, respectively; obesity rates were 5.2% and 3.7%. Males had higher rates of malignant tumors than females (6.2% vs. 3.5%, P < 0.0001), and malignant tumors were more common in patients with weight loss (6.4% vs. 4.3%, P = 0.03). Weight loss was associated with higher mortality in men (OR 6.66, P < 0.0001) and women (OR 3.92, P = 0.04) as well as higher rates of postoperative complications in both men (OR 6.13, P < 0.0001) and women (OR 8.37, P < 0.0001). Furthermore, patients suffering weight loss had longer LOS and higher overall hospital cost when compared with all patients. In contrast, obesity seemed to reduce mortality (OR 0.47, P = 0.0006) and complications (OR 0.8, P = 0.0007) among women. CONCLUSIONS: In summary, weight loss seems to be the single most critical factor present in patients experiencing higher mortality, complications, hospital charges, and longer LOS. However, further studies aimed to assess the inter-relation of potential preexisting comorbidities and weight loss are needed to establish causation.

Trends in surgical use and associated patient outcomes in the treatment of acoustic neuroma.

OBJECTIVE: To investigate recent trends in surgical volume and associated patient outcomes in the treatment of acoustic neuromas. METHODS: A retrospective analysis was performed using the Nationwide Inpatient Sample database from 2000-2007; cases from 2005 were excluded because of coding inconsistencies. Univariate and multivariate analyses were used to describe surgical trends and analyze inpatient outcomes. RESULTS: Among 14,928 patients studied, 87.1% were treated at large (based on number of beds) hospitals. Cases at these hospitals declined progressively from 2054 to 1467 cases (a 28.6% decrease) from 2000-2007; a 40.8% (178 cases per year, R(2) = 0.73) reduction in surgeries was observed from 2001-2007. Although mortality remained steady at 0.3%, nonroutine discharge (increase from 10.9% to 19.1%) and complication rates (increase from 21.5% to 23.3%) increased in recent years. Patients without private insurance had an increased risk of nonroutine discharge (odds ratio [OR] 1.7, P = 0.0033; OR 1.5, P = 0.0382), and patients with more comorbidities had an increased risk of complications (OR 1.8, P < 0.0001; OR 1.5, P < 0.0001). High surgical caseload reduced nonroutine discharge by 30% (OR 0.7, P < 0.0001) and complications by 10% (OR 0.9, P < 0.0281). CONCLUSIONS: A 41%, or 178 cases per year, reduction in surgical excision of acoustic neuroma cases was observed during the period 2001-2007. A possible explanation for this trend includes increased use of stereotactic radiosurgery. Nonroutine discharge and complications after surgical excision have increased perhaps because of surgery being used for larger tumors.

Racial and gender disparities and the role of primary tumor type on inpatient outcomes following craniotomy for brain metastases.

BACKGROUND: Race and gender disparities in outcomes have been documented in many cancers. Our study evaluated the role of race, gender, and tumor primary site in predicting in-hospital mortality, discharge disposition, and complications among patients with brain metastases. METHODS: Using Nationwide Inpatient Sample (NIS) data from 1998 to 2007, we evaluated in-patient outcomes of brain metastases patients who underwent a craniotomy in U.S. hospitals. Univariate and multivariate analyses were used to assess the effect of patient/tumor characteristics in predicting the proposed outcomes. RESULTS: NIS estimated 78,170 patients with metastatic brain tumors underwent craniotomy between 1998 and 2007 in the United States. Median age was 59.2 years, 52.1 % were women, and 6.4 % were black. In-hospital mortality rate was 2.2 % with an average length of stay of 7.6 days. Black patients had significantly higher morbidity and nonroutine discharges than whites/others (p < .0001). Black women had almost twice the mortality (3.4 vs 1.8 %, p < .0001), a higher complication rate (24.6 vs 18.8 %, p < .0001), longer hospital stays (10.0 vs 7.3 days, p < .0001), and more nonroutine discharges (45.1 vs 36.8 %, p < .0001), compared with white/other women. Tumor histology was a significant predictor of outcomes, with female lung cancer patients having the highest odds of mortality and primary gastrointestinal tumors having the highest number of complications. CONCLUSIONS: Evidence of race and gender disparities in outcomes were found in black patients, especially in black females who underwent surgical resection for brain metastases. These findings highlight an opportunity to reduce the gap of outcome disparities in brain metastasis patients.