Comparative Efficacy of Treatments for Brain Metastases from Non-Small Cell Lung Cancer without an EGFR-Mutation/ALK-Rearrangement: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: As many as 30% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases (BMs) over the course of their illness. Here, we quantitatively compare the efficacy of the various emerging regimens for NSCLC BMs without a definitive targetable epidermal growth factor receptor mutation/ALK rearrangement. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL, and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs that included ≥10 patients were included. We used a frequentist fixed or random-effects model for network meta-analysis. The outcomes of interest included intracranial progression-free survival (iPFS), overall survival (OS), and overall progression-free survival. RESULTS: In total, 18 studies representing 17 trials (n = 2726 patients) were identified. Immune checkpoint inhibitor regimens showed significant improvement in OS compared with chemotherapy alone, including pembrolizumab and chemotherapy (6 studies, hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.21-0.62), atezolizumab alone (HR 0.54, 95% CI 0.33-0.89), and nivolumab and ipilimumab (HR 0.64, 95% CI 0.42-0.97). An improvement in overall PFS was seen with use of pembrolizumab and chemotherapy compared with chemotherapy alone (3 studies, HR 0.42, 95% CI 0.26-0.68). Studies evaluating checkpoint inhibitors did not report iPFS data, and we did not find improvement in iPFS or OS with the addition of any chemotherapy regimen to whole-brain radiation therapy. CONCLUSIONS: In this network meta-analysis, we demonstrate the promising survival benefit with use of checkpoint inhibitor-based regimens in NSCLC BMs without a targetable epidermal growth factor receptor mutation/ALK rearrangement. Moving forward, large-scale BM-focused RCTs are necessary to establish the iPFS benefit of immune checkpoint inhibitor-based immunotherapy in this patient population.

Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS). RESULTS: We included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, with second-and third- generation TKIs showing the greatest benefit (HR=0.25, 95%CI 0.15-0.40). Overall PFS was also improved compared to conventional chemotherapy (HR=0.47, 95%CI 0.36-0.61). In EGFR-mutant patients, osimertinib showed the greatest benefit in iPFS (HR=0.32, 95%CI 0.15-0.69) compared to conventional chemotherapy, while gefitinib + chemotherapy showed the greatest overall PFS benefit (HR=0.26, 95%CI 0.10-0.70). All ALKi improved overall PFS compared to conventional chemotherapy, with alectinib having the greatest benefit (HR=0.13, 95%CI 0.07-0.24). CONCLUSIONS: In patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=179060.

Brainstem Associated Somatosensory Evoked Potentials and Response to Vagus Nerve Stimulation: An Investigation of the Vagus Afferent Network.

Despite decades of clinical usage, selection of patients with drug resistant epilepsy who are most likely to benefit from vagus nerve stimulation (VNS) remains a challenge. The mechanism of action of VNS is dependent upon afferent brainstem circuitry, which comprises a critical component of the Vagus Afferent Network (VagAN). To evaluate the association between brainstem afferent circuitry and seizure response, we retrospectively collected intraoperative data from sub-cortical recordings of somatosensory evoked potentials (SSEP) in 7 children with focal drug resistant epilepsy who had failed epilepsy surgery and subsequently underwent VNS. Using multivariate linear regression, we demonstrate a robust negative association between SSEP amplitude (p < 0.01), and seizure reduction. There was no association between SSEP latency and seizure outcomes. Our findings provide novel insights into the mechanism of VNS and inform our understanding of the importance of brainstem afferent circuitry within the VagAN for seizure responsiveness following VNS.

Management of Diffuse Low-Grade Glioma: The Renaissance of Robust Evidence.

The surgical management of diffuse low-grade gliomas (DLGGs) has undergone a paradigm shift toward striving for maximal safe resection when feasible. While extensive observational data supports this transition, unbiased evidence in the form of high quality randomized-controlled trials (RCTs) is lacking. Furthermore, despite a high volume of molecular, genetic, and imaging data, the field of neuro-oncology lacks personalized care algorithms for individuals with DLGGs based on a robust foundation of evidence. In this manuscript, we (1) discuss the logistical and philosophical challenges hindering the development of surgical RCTs for DLGGs, (2) highlight the potential impact of well-designed international prospective observational registries, (3) discuss ways in which cutting-edge computational techniques can be harnessed to generate maximal insight from high volumes of multi-faceted data, and (4) outline a comprehensive plan of action that will enable a multi-disciplinary approach to future DLGG management, integrating advances in clinical medicine, basic molecular research and large-scale data mining.

Comparison of endoscopic third ventriculostomy with or without choroid plexus cauterization in pediatric hydrocephalus: a systematic review and meta-analysis.

OBJECTIVE: Pediatric hydrocephalus is a significant contributor to infant morbidity and mortality, particularly in developing countries. The mainstay of treatment has long been shunt placement for CSF diversion, but recent years have seen the rise of alternative procedures such as endoscopic third ventriculostomy (ETV), which provides similar efficacy in selected patients. The addition of choroid plexus cauterization (CPC) to ETV has been proposed to increase efficacy, but the evidence of its utility is limited. This systematic review and meta-analysis aimed to determine the efficacy and safety of ETV+CPC in comparison to ETV alone for the treatment of pediatric all-cause hydrocephalus. METHODS: MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and ICRCTN databases were searched from conception through to October 2018 for comparative studies including both ETV+CPC and ETV in a pediatric population. The primary outcome was success rate, defined as no secondary procedure required for CSF diversion; secondary outcomes included time to failure, mortality, and complications. Data were pooled using random-effects models of meta-analysis, and relative risk (RR) was calculated. RESULTS: Five studies were included for final qualitative and quantitative analysis, including 2 prospective and 3 retrospective studies representing a total of 963 patients. Overall, there was no significant difference in success rates between ETV and ETV+CPC (RR 1.24, 95% CI 0.88-1.75, p = 0.21). However, a subgroup analysis including the 4 studies focusing on African cohorts demonstrated a significant benefit of ETV+CPC (RR 1.38, 95% CI 1.08-1.78, p = 0.01). There were no notable differences in complication rates among studies. CONCLUSIONS: This systematic review and meta-analysis failed to find an overall benefit to the addition of CPC to ETV; however, a subgroup analysis showed efficacy in sub-Saharan African populations. This points to the need for future randomized clinical trials investigating the efficacy of ETV+CPC versus ETV in varied patient populations and geographic locales.

Considerations for a surgical RCT for diffuse low-grade glioma: a survey.

BACKGROUND: Diffuse low-grade gliomas (DLGGs) are heterogeneous tumors that inevitably differentiate into malignant entities, leading to disability and death. Recently, a shift toward up-front maximal safe resection of DLGGs has been favored. However, this transition is not supported by randomized controlled trial (RCT) data. Here, we sought to survey the neuro-oncology community on considerations for a surgical RCT for DLGGs. METHODS: A 21-question survey focusing on a surgical RCT for DLGGs was developed and validated by 2 neurosurgeons. A sample case of a patient for whom management might be debatable was presented to gather additional insight. The survey was disseminated to members of the Society for Neuro-Oncology (SNO) and responses were collected from March 16 to July 10, 2018. RESULTS: A total of 131 responses were collected. Sixty-three of 117 (54%) respondents thought an RCT would not be ethical, 39 of 117 (33%) would consider participating, and 56 of 117 (48%) believed an RCT would be valuable for determining the differing roles of biopsy, surgery, and observation. This was exemplified by an evenly distributed selection of the latter management options for our sample case. Eighty-three of 120 (69.2%) respondents did not believe in equipoise for DLGG patients. Quality of life and overall survival were deemed equally important end points for a putative RCT. CONCLUSIONS: Based on our survey, it is evident that management of certain DLGG patients is not well defined and an RCT may be justified. As with any surgical RCT, logistic challenges are anticipated. Robust patient-relevant end points and standardization of perioperative adjuncts are necessary if a surgical RCT is undertaken.

The Role of Stereotactic Radiosurgery in the Management of Brain Metastases From a Health-Economic Perspective: A Systematic Review.

BACKGROUND: Stereotactic radiosurgery (SRS) is an effective option in the management of brain metastases, offering improved overall survival to whole-brain radiation therapy (WBRT). However, given the need for active surveillance and the possibility of repeated interventions for local/distant brain recurrences, the balance between clinical benefit and economic impact must be evaluated. OBJECTIVE: To conduct a systematic review of health-economic analyses of SRS for brain metastases, compared with other existing intervention options, to determine the cost-effectiveness of this treatment across different clinical scenarios. METHODS: The MEDLINE, EMBASE, Cochrane, CRD, and EconLit databases were searched for health-economic analyses, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, using terms relevant to brain metastases and radiation-based therapies. Simple cost analysis studies were excluded. Quality analysis was based on BMJ Consolidated Health Economics Reporting Standards (CHEERS) checklist. RESULTS: Eleven eligible studies were identified. For lesions with limited mass effect, SRS was more cost-effective than surgical resection (6 studies). In patients with Karnofsky performance scale (KPS) >70 and good predicted survival, SRS was cost-effective compared to WBRT (7 studies); WBRT became cost-effective with poor performance status or low anticipated life span. Following SRS, routine magnetic resonance imaging surveillance saved $1326/patient compared to symptomatic imaging due to reduced surgical salvage and hospital stay (1 study). CONCLUSION: Based on our findings, SRS is cost-effective in the management of brain metastases, particularly in high-functioning patients with longer expected survival. However, before an optimal care pathway can be proposed, emerging factors such as tumor molecular subtype, diagnosis-specific graded prognostic assessment, neuroprognostic score, tailored surveillance imaging, and patient utilities need to be studied in greater detail.

Peroral endoscopic myotomy (POEM) for the treatment of pediatric achalasia: a systematic review and meta-analysis.

BACKGROUND: Achalasia is a rare primary esophageal dysmotility disorder in children. Peroral endoscopic myotomy (POEM) is a novel endoscopic technique which has shown promising results for treating achalasia in adults. However, limited data on efficacy and safety in pediatric patients are available. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of POEM in pediatric achalasia. METHODS: We searched MEDLINE, Embase, PubMed, and Web of Science databases through July 2018. Studies were eligible for inclusion if they conducted POEM in pediatric patients. Main outcomes were Eckardt score and lower esophageal sphincter (LES) pressure before and after POEM. Secondary outcomes were clinical success rate and adverse events associated with POEM. Two reviewers independently reviewed the studies, collected data, and assessed quality of evidence using Methodological Index for Non-Randomized Studies (MINORS). Pooled estimates were calculated using random effects meta-analyses. Heterogeneity was quantified using the inconsistency statistic, and funnel plot was used to assess publication bias. RESULTS: A total of 12 studies with 146 pediatric patients (53.68% female) underwent POEM for the treatment of achalasia (mean duration of disease of 19.48 months). There was a significant reduction in Eckardt score by 6.88 points (Mean Difference (MD) 6.88, 95% confidence interval (CI), 6.28-7.48, P < .001) and LES pressure by 20.73 mmHg (MD 20.73, 95% CI, 15.76-25.70, P < .001) following POEM. At least 93% of the patients experienced improvement or resolution of achalasia symptoms both short and long terms after POEM, with small proportion of patients experiencing minor adverse effects which could be managed conservatively. CONCLUSIONS: POEM is efficacious and safe for treating achalasia in pediatric populations. Large comparative or randomized trials are warranted to confirm the efficacy and safety of POEM compared to other surgical procedures for achalasia.

Complete Resolution of Nonalcoholic Fatty Liver Disease After Bariatric Surgery: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Bariatric surgery has been reported to lead to complete resolution of nonalcoholic fatty liver disease (NAFLD) following the sustained weight loss induced in obese patients. We performed a systematic review and meta-analysis to evaluate the effects of bariatric surgery on NAFLD in obese patients. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and Web of Science databases through May 2018 for studies that compared liver biopsy results before and after bariatric surgery in obese patients. Primary outcomes were biopsy-confirmed resolution of NAFLD and NAFLD activity score. Secondary outcomes were worsening of NAFLD after surgery and liver volume. The Grading of Recommendations, Assessment, Development, and Evidence approach was conducted to assess overall quality of evidence. RESULTS: We analyzed data from 32 cohort studies comprising 3093 biopsy specimens. Bariatric surgery resulted in a biopsy-confirmed resolution of steatosis in 66% of patients (95% CI, 56%-75%), inflammation in 50% (95% CI, 35%-64%), ballooning degeneration in 76% (95% CI, 64%-86%), and fibrosis in 40% (95% CI, 29%-51%). Patients' mean NAFLD activity score was reduced significantly after bariatric surgery (mean difference, 2.39; 95% CI, 1.58-3.20; P < .001). However, bariatric surgery resulted in new or worsening features of NAFLD, such as fibrosis, in 12% of patients (95% CI, 5%-20%). The overall Grading of Recommendations, Assessment, Development, and Evidence quality of evidence was very low. CONCLUSIONS: Through this systematic review and meta-analysis, we found that bariatric surgery leads to complete resolution of NAFLD in obese patients. However, some patients develop new or worsened features of NAFLD. Randomized controlled trials are needed to further examine the therapeutic benefits of bariatric surgery for patients with NAFLD.

The effect of omentectomy added to bariatric surgery on metabolic outcomes: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Excess visceral adipose tissue has been identified as an important risk factor for obesity-related co-morbidities. Conflicting information exists on whether omentectomy added to bariatric surgery is beneficial to metabolic variables. OBJECTIVE: To evaluate the impact of omentectomy added to bariatric surgery on metabolic outcomes SETTING: University Hospital, Canada. METHODS: MEDLINE, EMBASE, and PubMed were searched up to May 2018. Studies were eligible for inclusion if they were randomized controlled trials comparing omentectomy added to bariatric surgery with bariatric surgery alone. Primary outcome measures were absolute change in metabolic variables (body mass index, insulin, glucose, cholesterol, lipoproteins, and triglycerides); secondary outcomes were changes in adipocytokines. Pooled mean differences (mean deviation; MD) were calculated using random effects meta-analyses, and heterogeneity was quantified using the I2 statistic. RESULTS: Ten trials involving a total of 366 patients met the inclusion criteria with a median follow-up time of 1 year after surgery. Adding omentectomy to bariatric surgery demonstrated a minimal but statistically significant decrease in body mass index compared with bariatric surgery alone (MD 1.29, 95% confidence interval .35-2.23, P = .007, I2 = 0%, 10 trials). Conversely, patients who underwent bariatric surgery alone had significant increases in high-density lipoprotein (MD -2.12, 95% confidence interval -4.13 to -.11, P = .04, I2 = 0%, 6 trials). Other metabolic outcomes and adipocytokines showed no significant difference between procedures. CONCLUSION: The addition of omentectomy to bariatric surgery results in minimal reduction of body mass index. Considering no overall improvement in metabolic outcomes and the time and effort required, the therapeutic use of omentectomy added to bariatric surgery is not warranted.