Immune suppression in gliomas.

INTRODUCTION: The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy. METHODS: We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body's immune system to evade detection and ensure tumor survival and proliferation. RESULTS: A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments. CONCLUSIONS: Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.

The intersection between immunotherapy and laser interstitial thermal therapy: a multipronged future of neuro-oncology.

The rise of immunotherapy (IT) in oncological treatment has greatly improved outcomes in a number of disease states. However, its use in tumors of the central nervous system (CNS) remains limited for multiple reasons related to the unique immunologic tumor microenvironment. As such, it is valuable to consider the intersection of IT with additional treatment methods that may improve access to the CNS and effectiveness of existing IT modalities. One such combination is the pairing of IT with localized hyperthermia (HT) generated through technologies such as laser interstitial thermal therapy (LITT). The wide-ranging immunomodulatory effects of localized and whole-body HT have been investigated for some time. Hyperthermia has demonstrated immunostimulatory effects at the level of tumor cells, immune cells, and the broader environment governing potential immune surveillance. A thorough understanding of these effects as well as the current and upcoming investigations of such in combination with IT is important in considering the future directions of neuro-oncology.

The presence of atrial fibrillation in Takotsubo cardiomyopathy is predictive of mortality: Systematic review and meta-analysis.

INTRODUCTION: Atrial fibrillation (AF) is known as the most common arrhythmia and an independent risk factor for mortality. Recent studies suggest that AF is associated with morbidity and mortality in Takotsubo cardiomyopathy (TTC). However, a systematic review and meta-analysis of the literature have not been done. We assessed the association between AF in patients with TTC and mortality by a systematic review of the literature and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2018. Included studies were published prospective or retrospective cohort studies that compared all-cause mortality in TTC with AF versus without AF. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Five studies from August 2008 to October 2017 were included in this meta-analysis involving 2,321 subjects with TTC (243 with AF and 2,078 without AF). The presence of AF was associated with all-cause mortality (pooled odds ratio = 2.19, 95% confidence interval: 1.57-3.06, p < 0.001, I 2  = 0%). CONCLUSION: Atrial fibrillation increased all-cause mortality by double among patients with TTC compared to without it. Our study suggests that the presence of AF in TTC is prognostic for all-cause mortality.

Contrast-induced nephropathy is associated with new-onset atrial fibrillation in acute coronary syndrome after cardiac catheterization: Systemic review and meta-analysis.

INTRODUCTION: Contrast-induced nephropathy (CIN) is associated with increased cardiovascular morbidity and mortality in patients with acute coronary syndrome (ACS). Recent studies suggest that CIN is associated with new-onset atrial fibrillation (AF) in patients with acute coronary syndrome (ACS) who underwent catheterization. However, a systematic review and meta-analysis of the literature have not been done. We assessed the association between CIN in patients with ACS and new-onset AF by a systematic review of the literature and a meta-analysis. HYPOTHESIS: CIN is associated with new-onset AF in patients with ACS. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to April 2018. Included studies were published cohort studies that compared new-onset AF after cardiac catheterization in ACS patient with CIN versus without CIN. Data from each study were combined using the random effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Five studies from December 2009 to February 2018 were included in this meta-analysis involving 5,640 subjects with ACS (1,102 with CIN and 4,538 without CIN). Contrast-induced nephropathy significantly correlates with new-onset AF after cardiac catheterization (pooled risk ratio = 2.84, 95% confidence interval: 1.66-4.87, p < 0.001, I2  = 58%) CONCLUSIONS: Contrast-induced nephropathy is associated with new-onset AF threefold among patients with ACS after cardiac catheterization. Our study warranted further study to establish the causality between CIN and new-onset AF.

SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis.

BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmic disease linked to SCN5A mutations. It is controversial whether SCN5A mutation carriers possess a greater risk of major arrhythmic events (MAE). We examined the association of SCN5A mutations and MAE in BrS patients. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort and case-control studies that compared MAE in BrS patients with and without SCN5A mutations. Data from each study were combined using the random-effects model. Generic inverse variance method of DerSimonian and Laird was employed to calculate the risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Seven studies from March 2002 to October 2017 were included (1,049 BrS subjects). SCN5A mutations were associated with MAE in Asian populations (RR = 2.03, 95% CI: 1.37-3.00, p = 0.0004, I2  = 0.0%), patients who were symptomatic (RR = 2.66, 95% CI: 1.62-4.36, p = 0.0001, I2  = 23.0%), and individuals with spontaneous type-1 Brugada pattern (RR = 1.84, 95% CI: 1.05-3.23, p = 0.03, I2  = 0.0%). CONCLUSIONS: SCN5A mutations in BrS increase the risk of MAE in Asian populations, symptomatic BrS patients, and individuals with spontaneous type-1 Brugada pattern. Our study suggests that SCN5A mutation status should be an important tool for risk assessment in BrS patients.

Baseline fragmented QRS is associated with increased all-cause mortality in heart failure with reduced ejection fraction: A systematic review and meta-analysis.

BACKGROUND: Recent studies suggested that fragmented (fQRS) is associated with poor clinical outcomes in heart failure with reduced ejection fraction (HFrEF) patients. However, no systematic review or meta-analysis has been done. We conducted a systematic review and meta-analysis to assess the association between baseline fQRS and all-cause mortality in HFrEF. METHODS: We comprehensively reviewed the databases of MEDLINE and EMBASE from inception to February 2018. Published studies of HFrEF that reported fQRS and outcome of all-cause mortality and major arrhythmic event (sudden cardiac death, sudden cardiac arrest, ventricular fibrillation, or sustained ventricular tachycardia) were included. Data were integrated using the random-effects, generic inverse-variance method of DerSimonian and Laird. RESULTS: Ten studies from 2010 to 2017 were included. Baseline fQRS was associated with increased all-cause mortality (risk ratio [RR] 1.63, 95% confidence interval [CI] 1.22-2.19, p < 0.0001, I2  = 73%) as well as major arrhythmic events (RR = 1.74, 95% CI 1.09-2.80, I2  = 89%). Baseline fQRS increased all-cause mortality in both Asian and Caucasian cohorts (RR = 2.17 with 95% CI 1.33-3.55 and RR = 1.45 with 95% CI 1.05-1.99, respectively) as well as increased major arrhythmic events in Asian cohort (RR = 1.50, 95% CI 1.05-2.13). Baseline fQRS also increased all-cause mortality in patients who had not received implantable cardioverter-defibrillator, significantly more than in patients who had received implantable cardioverter-defibrillator (RR = 2.46 with 95% CI 1.56-3.89 and 1.36 with 95% CI 1.08-1.71, respectively). CONCLUSION: Baseline fQRS is associated with increased all-cause mortality up to 1.63-fold in HFrEF patients. Fragmented QRS could be a predictor of clinical outcome in patients with HFrEF.

Terminal QRS Distortion in ST Elevation Myocardial Infarction as a Prediction of Mortality: Systematic Review and Meta-Analysis.

BACKGROUND: Terminal QRS distortion reflects advanced stage and large myocardial infarction predisposing the heart to adverse outcomes. Recent studies suggest that terminal QRS distortion is associated with morbidity and mortality in ST elevation myocardial infarction (STEMI). However, a systematic review and meta-analysis of the literature have not been done. OBJECTIVE: We assessed the association between terminal QRS distortion in patients with STEMI and mortality by a systematic review of the literature and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published prospective or retrospective cohort studies that compared all-cause mortality in subjects with STEMI with QRS distortion versus those without QRS distortion. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Fifteen studies from January 1993 to May 2015 were included in this meta-analysis involving 7,479 subjects with STEMI (2,906 QRS distortion and 4,573 non-QRS distortion). QRS distortion was associated with increased mortality (pooled risk ratio = 1.81, 95% confidence interval: 1.37-2.40, p < 0.000, I2 = 41.6%). Considering the introduction of clopidogrel in 2004, we performed subgroup analyses before and after 2004, and the associated with higher mortality was still present (before 2004, RR 1.75, 95% CI 1.08-2.82, p = 0.022, I2 = 66.1%; after 2004, RR 1.96, 95% CI 1.44-2.65, p < 0.001, I2 = 0%). CONCLUSIONS: Terminal QRS distortion increased all-cause mortality by 81%. Our study suggests that terminal QRS distortion is an important tool to assess the risk in patients with STEMI.

Monitoring Anti-Pythium insidiosum IgG Antibodies and (1→3)-ß-d-Glucan in Vascular Pythiosis.

Despite aggressive treatment, vascular pythiosis has a mortality rate of 40%. This is due to delays in diagnosis and a lack of effective monitoring tools. To overcome this drawback, serum beta-d-glucan (BG) and P. insidiosum-specific antibody (Pi-Ab) were examined as potential monitoring markers in vascular pythiosis. A prospective cohort study of vascular pythiosis patients was carried out from January 2010 to July 2016. Clinical information and blood samples were collected and evaluated by the BG and Pi-Ab assays. Linear mixed-effect models were used to compare BG and Pi-Ab levels. The in vitro susceptibility test was performed with all P. insidiosum isolates from culture-positive cases. A total of 50 patients were enrolled: 45 survived and 5 died during follow-up. The survivors had a significantly shorter time to medical care (P < 0.0001) and a significantly shorter waiting time to the first surgery (P < 0.0001). There were no differences in BG levels among the groups at diagnosis (P = 0.33); however, BG levels among survivors were significantly lower than those of the deceased group at 0.5 months (P < 0.0001) and became undetectable after 3 months. Survivors were able to maintain an enzyme-linked immunosorbent assay (ELISA) value (EV) of Pi-Ab above 8, whereas the EV among deceased patients was less than 4. In vitro susceptibility results revealed no synergistic effects between itraconazole and terbinafine. This study showed that BG and Pi-Ab are potentially valuable markers to monitor the disease after treatment initiation. An unchanged BG level at 2 weeks after surgery should prompt an evaluation for residual disease.

Baseline fragmented QRS increases the risk of major arrhythmic events in hypertrophic cardiomyopathy: Systematic review and meta-analysis.

BACKGROUND: Fragmented QRS reflects disturbances in the myocardium predisposing the heart to ventricular tachyarrhythmias. Recent studies suggest that fragmented QRS (fQRS) is associated with worse major arrhythmic events in hypertrophic cardiomyopathy (HCM). However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between fQRS and major arrhythmic events in hypertrophic cardiomyopathy by a systematic review of the literature and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2017. Included studies were published prospective or retrospective cohort studies that compared major arrhythmic events (sustained ventricular tachycardia, sudden cardiac arrest, or sudden cardiac death) in HCM with fQRS versus non-fQRS. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Five studies from January 2013 to May 2017 were included in this meta-analysis involving 673 subjects with HCM (205 fQRS and 468 non-fQRS). Fragmented QRS was associated with major arrhythmic events (pooled risk ratio = 7.29, 95% confidence interval: 4.00-13.29, p < .01, I2  = 0%). CONCLUSION: Baseline fQRS increased major arrhythmic events up to sevenfold. Our study suggests that fQRS could be an important tool for risk assessment in patients with HCM.

Baseline fragmented QRS increases the risk of major arrhythmic events in Brugada syndrome: Systematic review and meta-analysis.

BACKGROUND: Fragmented QRS reflects disturbances in the myocardium predisposing the heart to ventricular tachyarrhythmias. Recent studies suggest that fragmented QRS (fQRS) is associated with major arrhythmic events in Brugada syndrome. However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between fQRS and major arrhythmic events in Brugada syndrome by a systematic review of the literature and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2017. Included studies were published prospective or retrospective cohort studies that compared major arrhythmic events (ventricular fibrillation, sustained ventricular tachycardia, sudden cardiac arrest, or sudden cardiac death) in Brugada syndrome with fQRS versus normal QRS. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Nine studies from January 2012 to May 2017 were included in this meta-analysis involving 2,360 subjects with Brugada syndrome (550 fQRS and 1,810 non-fQRS). Fragmented QRS was associated with major arrhythmic events (pooled risk ratio =3.36, 95% confidence interval: 2.09-5.38, p < .001, I2  = 50.9%) as well as fatal arrhythmia (pooled risk ratio =3.09, 95% confidence interval: 1.40-6.86, p = .005, I2  = 69.7%). CONCLUSIONS: Baseline fQRS increased major arrhythmic events up to 3-fold. Our study suggests that fQRS could be an important tool for risk assessment in patients with Brugada syndrome.

Fragmented QRS and mortality in patients undergoing percutaneous intervention for ST-elevation myocardial infarction: Systematic review and meta-analysis.

BACKGROUND: Fragmented QRS reflects disturbances in the myocardium predisposing the heart to ventricular tachyarrhythmias. Recent studies suggest that fragmented QRS (fQRS) is associated with mortality in ST-elevation myocardial infarction (STEMI) patients who underwent percutaneous coronary intervention (PCI). However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between fQRS and overall mortality in STEMI patients who subsequently underwent PCI by a systematic review and meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Studies included in our analysis were published cohort (prospective or retrospective) and case-control studies that compared overall mortality among STEMI patient with and without fQRS who underwent PCI. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian, and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Six studies from 2014 to 2017 were included in this meta-analysis involving 2,516 subjects with STEMI who underwent PCI (888 fQRS and 1,628 non-fQRS). Fragmented QRS was associated with overall mortality in STEMI patients who underwent PCI (pooled risk ratio = 3.87; 95% CI 1.96-7.66, I2  = 43%). CONCLUSION: Fragmented QRS was associated with increased overall mortality up to threefold. Our study suggests that fQRS could be an important tool for risk assessment in STEMI patients who underwent PCI.

Frequent premature atrial complexes as a predictor of atrial fibrillation: Systematic review and meta-analysis.

BACKGROUND: Frequent premature atrial complexes (PACs) are associated with higher morbidity and mortality. Recent studies suggest that frequent PACs are associated with new onset atrial fibrillation (AF). However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between frequent PACs and new onset AF by a systematic review and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort (prospective or retrospective) that compared new onset AF among patients with and without frequent PACs documented by Holter monitoring or 12-lead electrocardiogram. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Twelve studies from 2009 to 2017 were included in this meta-analysis involving 109,689 subjects (9217frequent and 100,472 non-frequent PACs). Frequent PACs were associated with increased risk of new onset AF (pooled risk ratio = 2.76, 95% confidence interval: 2.05-3.73, p < 0.000, I2 = 90.6%). CONCLUSION: Frequent PACs are associated with up to three-fold increased risk of new onset AF. Our study suggests that frequent PACs in general population is an independent predictor of new onset AF.

Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors.

PURPOSE: Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. EXPERIMENTAL DESIGN: The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel-based phantoms of control and GNS-infused central "tumors." In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation. RESULTS: Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control. CONCLUSIONS: Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.

Creation of Non-Contact Device for Use in Metastatic Melanoma Margin Identification in ex vivo Mouse Brain.

Because contemporary intraoperative tumor detection modalities, such as intraoperative MRI, are not ubiquitously available and can disrupt surgical workflow, there is an imperative for an accessible diagnostic device that can meet the surgeon's needs in identifying tissue types. The objective of this paper is to determine the efficacy of a novel non-contact tumor detection device for metastatic melanoma boundary identification in a tissue-mimicking phantom, evaluate the identification of metastatic melanoma boundaries in ex vivo mouse brain tissue, and find the error associated with identifying this boundary. To validate the spatial and fluorescence resolution of the device, tissue-mimicking phantoms were created with modifiable optical properties. Phantom tissue provided ground truth measurements for fluorophore concentration differences with respect to spatial dimensions. Modeling metastatic disease, ex vivo melanoma brain metastases were evaluated to detect differences in fluorescence between healthy and neoplastic tissue. This analysis includes determining required-to-observe fluorescence differences in tissue. H&E staining confirmed tumor presence in mouse tissue samples. The device detected a difference in normalized average fluorescence intensity in all three phantoms. There were differences in fluorescence with the presence and absence of melanin. The estimated tumor boundary of all tissue phantoms was within 0.30 mm of the ground truth tumor boundary for all boundaries. Likewise, when applied to the melanoma-bearing brains from ex vivo mice, a difference in normalized fluorescence intensity was successfully detected. The potential prediction window for the tumor boundary location is less than 1.5 mm for all ex vivo mouse brain tumors boundaries. We present a non-contact, laser-induced fluorescence device that can identify tumor boundaries based on changes in laser-induced fluorescence emission intensity. The device can identify phantom ground truth tumor boundaries within 0.30 mm using instantaneous rate of change of normalized fluorescence emission intensity and can detect endogenous fluorescence differences in melanoma brain metastases in ex vivo mouse tissue.

Sex Difference and Outcome after Percutaneous Intervention in Patients with Chronic Total Occlusion: A Systematic Review and Meta-Analysis.

BACKGROUND: Recent studies suggest that sex difference is an outcome predictor in chronic total occlusion (CTO) patients who are undergoing percutaneous intervention (PCI). However, a systematic review and meta-analysis of the literature have not been done. We assessed the outcome of PCI in CTO between male and female. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort (prospective or retrospective) and case control studies of CTO patients who underwent PCI that compared successful procedure and major cardiac event (MACE), including cardiac death, target vessel revascularization, myocardial infarction, and stroke, between male and female. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Nine studies were included in this meta-analysis involving 30,830 CTO subjects (8350 female and 22,480 male) who underwent PCI. Females were not significantly associated with reduced risk of MACE (pooled risk ratio = 0.86, 95% confidence interval: 0.66-1.12, p = 0.262, I2 = 47.0%) as well as successful rate of PCI (pooled risk ratio = 1.04, 95% confidence interval: 0.99-1.10, p = 0.161, I2 = 76.6%) in CTO patients who underwent PCI. CONCLUSION: Our study suggests that sex is not an independent risk factor of MACE or successful procedure in CTO patients who underwent PCI.

4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers.

PURPOSE: The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti-PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM. EXPERIMENTAL DESIGN: We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo. RESULTS: Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell-dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous tumor location. Proffering 4-1BB expression to T cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective. CONCLUSIONS: Although poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti-PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.

Evaluation of neurapheresis therapy in vitro: a novel approach for the treatment of leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM), late-stage cancer when malignant cells migrate to the subarachnoid space (SAS), have an extremely poor prognosis. Current treatment regimens fall short in effectively reducing SAS tumor burden. Neurapheresis therapy is a novel approach employing filtration and enhanced circulation of the cerebrospinal fluid (CSF). Here, we examine the in vitro use of neurapheresis therapy as a novel, adjunctive treatment option for LM by filtering cells and augmenting the distribution of drugs that may have the potential to enhance the current clinical approach. METHODS: Clinically relevant concentrations of VX2 carcinoma cells were suspended in artificial CSF. The neurapheresis system's ability to clear VX2 carcinoma cells was tested with and without the chemotherapeutic presence (methotrexate [MTX]). The VX2 cell concentration following each filtration cycle and the number of cycles required to reach the limit of detection were calculated. The ability of neurapheresis therapy to circulate, distribute, and maintain therapeutic levels of MTX was assessed using a cranial-spinal model of the SAS. The distribution of a 6 mg dose was monitored for 48 h. An MTX-specific ELISA measured drug concentration at ventricular, cervical, and lumbar sites in the model over time. RESULTS: In vitro filtration of VX2 cancer cells with neurapheresis therapy alone resulted in a 2.3-log reduction in cancer cell concentration in 7.5 h and a 2.4-log reduction in live-cancer cell concentration in 7.5 h when used with MTX. Cranial-spinal model experiments demonstrated the ability of neurapheresis therapy to enhance the circulation of MTX in CSF along the neuraxis. CONCLUSION: Neurapheresis has the potential to act as an adjunct therapy for LM patients and significantly improve the standard of care.

Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease.

PURPOSE: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. EXPERIMENTAL DESIGN: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease. RESULTS: Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors. CONCLUSIONS: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

Orthostatic hypotension is associated with new-onset atrial fibrillation: Systemic review and meta-analysis.

INTRODUCTION: Orthostatic hypotension (OH) is common among elderly patients. Its presence may herald severe underlying comorbidities and be associated with a higher risk of mortality. Interestingly, recent studies suggest that OH is associated with new-onset atrial fibrillation (AF). However, a systematic review and meta-analysis of the literature has not been performed. We assessed the association between AF and OH through a systematic review of the literature and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to November 2018. Published prospective or retrospective cohort studies that compared new-onset AF between male patients with and without OH were included. Data from each study were combined using the random-effects, generic inverse-variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Four studies from October 2010 to March 2018 were included in the meta-analysis involving 76,963 subjects (of which 3318 were diagnosed with OH). The presence of OH was associated with new-onset AF (pooled risk ratio 1.48; 95% confidence interval [1.21, 1.81], p?< 0.001; I2 = 69.4%). In hypertensive patients, analysis revealed an association between OH and the occurrence of new-onset AF (OR 1.46; 95% CI [1.27, 1.68], p < 0.001 with I2 = 0). CONCLUSIONS: OH was associated with new-onset AF up to 1.5-fold compared with those subjects without OH. The interplay between OH and AF is likely bidirectional.

Atrial Fibrillation Is Not Associated With Thromboembolism in Left Ventricular Assist Device Patients: A Systematic Review and Meta-Analysis.

Atrial fibrillation (AF) is a well-established risk factor of thromboembolism (TE). Thromboembolism is one of the most common complications in patients supported by continuous-flow left ventricular assisted devices (CF-LVADs). However, the association between AF and TE complications in this population is controversial. We conducted a systematic review and meta-analysis to assess the association between AF and overall TE, stroke, and device thrombosis events in CF-LVAD patients. We performed a comprehensive literature search through September 2017 in the databases of MEDLINE and EMBASE. Included studies were prospective or retrospective cohort studies that compared the risk of developing overall TE, stroke, and device thrombosis events in CF-LVAD patients with AF and those without AF. We calculated pooled risk ratio (RR) with 95% confidence intervals (CI) and I statistic using the random-effects model. Eleven studies were included involving 6,351 patients who underwent CF-LVAD implantation. Overall, TE outcome was available in four studies involving 1,106 AF and 3,556 non-AF patients. Stroke outcome was available in seven studies (1,455 AF and 4,037 non-AF patients). Device thrombosis outcome was available in three studies (1,010 AF and 3,327 non-AF patients). There was no association between AF and TE events (RR = 0.95; 95% CI: 0.57-1.59, I = 79%, p = 0.85), stroke (RR = 1.10; 95% CI: 0.74-1.64, I = 73%, p = 0.65), and device thrombosis (RR = 0.97; 95% CI: 0.56-1.67, I = 42%, p = 0.91). AF in CF-LVAD patients was not associated with overall TE, stroke, or device thrombosis events. These findings might be explained by the highly thrombogenic property of CF-LVADs that exceeds the thromboembolic risk driven by AF.