Citations

Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)–modified T cells in the solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR T cells in immunocompetent mouse models, we have defined a mechanism by which OVs can potentiate CAR T cell efficacy against solid tumor models of melanoma and glioma. We show that stimulation of the native T cell receptor (TCR) with viral or virally encoded epitopes gives rise to enhanced proliferation, CAR-directed antitumor function, and distinct memory phenotypes. In vivo expansion of dual-specific (DS) CAR T cells was leveraged by in vitro preloading with oncolytic vesicular stomatitis virus (VSV) or reovirus, allowing for a further in vivo expansion and reactivation of T cells by homologous boosting. This treatment led to prolonged survival of mice with subcutaneous melanoma and intracranial glioma tumors. Human CD19 CAR T cells could also be expanded in vitro with TCR reactivity against viral or virally encoded antigens and was associated with greater CAR-directed cytokine production. Our data highlight the utility of combining OV and CAR T cell therapy and show that stimulation of the native TCR can be exploited to enhance CAR T cell activity and efficacy in mice.

Abstract BRAF plus MEK inhibitor combinations are currently FDA-approved for melanoma, non–small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600–mutated colorectal cancer has prevented its tissue-agnostic drug development. We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We reviewed the literature for case reports of clinical responses, outcomes in patients with BRAF V600 mutation—positive nonmelanoma malignancies who received BRAF inhibitor therapy, and data from published adult and pediatric trials. BRAF V600 mutations are prevalent across multiple nonmelanoma malignancies (>40 different tumor types), lead to oncogene addiction, and are clinically actionable in a broad range of adult and pediatric nonmelanoma rare malignancies. Continued tissue-agnostic drug development is warranted beyond the current BRAF plus MEK approved cancers.

Abstract Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. Highlights The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.

BACKGROUND: Dural arteriovenous fistulas (dAVFs) are often treated with stereotactic radiosurgery (SRS) to achieve complete obliteration (CO), prevent future hemorrhages, and ameliorate neurological symptoms. OBJECTIVE: To summarize outcomes after SRS for dAVFs and propose relevant practice recommendations. METHODS: Using a PICOS/PRISMA/MOOSE protocol, we included patients with dAVFs treated with SRS and data for at least one of the outcomes of the study. Relevant outcomes were CO, symptom improvement and cure, and post-SRS hemorrhage or permanent neurological deficits (PNDs). Estimated outcome effect sizes were determined using weighted random-effects meta-analyses using DerSimonian and Laird methods. To assess potential relationships between patient and lesion characteristics and clinical outcomes, mixed-effects weighted regression models were used. RESULTS: Across 21 published studies, we identified 705 patients with 721 dAVFs treated with SRS. The CO rate was 68.6% (95% CI 60.7%-76.5%) with symptom improvement and cure rates of 97.2% (95% CI 93.2%-100%) and 78.8% (95% CI 69.3%-88.2%), respectively. Estimated incidences of post-SRS hemorrhage and PNDs were 1.1% (95% CI 0.6%-1.6%) and 1.3% (95% CI 0.8%-1.8%), respectively. Noncavernous sinus (NCS) dAVFs were associated with lower CO ( P = .03) and symptom cure rates ( P = .001). Higher grade was also associated with lower symptom cure rates ( P = .04), whereas previous embolization was associated with higher symptom cure rates ( P = .01). CONCLUSION: SRS for dAVFs results in CO in the majority of patients with excellent symptom improvement rates with minimal toxicity. Patients with NCS and/or higher-grade dAVFs have poorer symptom cure rates. Combined therapy with embolization and SRS is recommended when feasible for clinically aggressive dAVFs or those refractory to embolization to maximize the likelihood of symptom cure.

Abstract Introduction Lumbar spinal stenosis affects more than 200,000 adults in the United States, resulting in approximately 38,000 operations among the Medicare population and greater than $1.5 billion in hospital bills alone. Fortunately, Minimally Invasive Lumbar Decompression (MILD) and the Superion Indirect Decompression System have shown lasting benefit and cost savings compared to more aggressive surgical options. Objective Our primary objective was to retrospectively determine the rate of lumbar decompression surgery following the MILD and Superion procedures. Materials and Methods This was a pooled retrospective review of LSS patients who received MILD and/or Superion procedures between January 2011 and July 2019. Adult patients with CPT codes for MILD and Superion procedures were identified. Patients were included if they had a follow‐up visit at least 2 years from the procedure date, preprocedural MRI results, and surgical notes. Results A total of 199 patients were included in the final analysis, of which 57 patients (28.6%) underwent MILD procedure only, 124 patients (62.3%) underwent Superion only, and 18 patients (9.0%) underwent an MILD procedure initially followed by a Superion procedure. Two patients had an MILD procedure performed twice at the same level at separate encounters. A total of four patients in the entire cohort (2.0%; MILD 5.3%, Superion 0.8%) underwent subsequent lumbar spine surgery when followed for at least 2 years. It is notable that some of these patients may not have been surgical candidates and this may have skewed the results. Conclusions Patients undergoing minimally invasive decompression treatment of lumbar spinal stenosis have low rates of subsequent open surgery which potentially results in cost savings and a reduction in severe adverse events. The reason for low surgical rate may reflect improvement in their symptoms, a preference to avoid surgery, or being deemed not a surgical candidate.

AbstractINTRODUCTIONAs the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others.METHODSWe used hierarchical clustering to group 19 cross‐sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation.RESULTSThree primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors.DISCUSSIONThese results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance.

Abstract Objective Leucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with APS. We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis. Methods Two independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic aPL carriers and 150 healthy controls (HCs) from Peking University People’s Hospital. The second included 99 APS patients, 25 aPL carriers and 40 HCs from United States APS centres. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes. Results Both positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort. Conclusion Our study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.