B cell reductive therapy with rituximab in the treatment of rheumatoid arthritis.

The approach to treating autoimmune disorders is currently undergoing a significant change in focus. As therapies are developed that are more precise in targeting the pathogenesis for these diseases, patients experience significantly fewer side effects. At the same time, as more precise therapies are discovered, the etiologies of these diseases become further elucidated. It is now widely accepted that B-lymphocytes play a significant role in the pathogenesis of various autoimmune diseases, the extent of which continues to be the focus of ongoing research. Rheumatoid arthritis is one such disease process that has been the focus of various B-lymphocyte-directed therapeutic trials. In this paper we review the current research available on rituximab as treatment for rheumatoid arthritis. This review details results from four main studies, as well as others, which used rituximab in at least one of the arms in treatment of rheumatoid arthritis. The results are promising and will likely lead to longer term studies as well as a potential focus on B cell subsets

Apolipoprotein E alters the association of neuroinflammation with Alzheimer's disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors. The apolipoprotein E (APOE) allele e4 imparts a dramatic increase in the risk of developing Alzheimer’s disease, but the exact mechanism of this relationship is unknown. The e4 allele is associated with increased Ab plaques, neurofibrillary tangles, and a heightened inflammation state, all pathological hallmarks of Alzheimer’s disease. To test the hypothesis that microglia and related cytokines were differentially associated with Alzheimer’s disease pathology based on the presence of e4, we compared individuals with and without the APOE e4 allele within a community based aging cohort (n = 186). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology as measured by AT8 immunostaining (B = 0.459, p = 0.028) in e4 positive participants but not in e4 negative participants. Analysis of cytokines implicated in AD, i.e. IL-10, IL-13, IL-4, IL-1a, revealed a significant negative association with AT8 in e4 negative participants. The association of the anti-inflammatory cytokines IL-10, IL-13, and IL-4 on tau pathology appeared to be mediated by ApoE protein levels, suggesting that these cytokines and the ApoE protein may interact to prevent increased tau pathology within e4 negative individuals. The pro-inflammatory cytokine, IL-1, was negatively associated with AT8 (B = -0.241, p = 0.009) independent of Ab1-42 in e4 negative participants but not in e4 positive participants, suggesting a potential novel protective association. Overall, in e4 negative participants, elevated levels of IL-10, IL-13, IL-4, IL-1a are associated with less tau pathology. These associations are largely absent in the presence of e4 where tau pathology is significantly associated with microglial cell density. Taken together, these results suggest that APOE e4 mediates an altered inflammatory response and increased tau pathology independent of Ab pathology.2019-07-03T00:00:00

The expanding capability and clinical relevance of molecular diagnostic technology to identify and evaluate EGFR mutations in advanced/metastatic NSCLC.

Epidermal growth factor receptor (EGFR) mutation testing in advanced non-small-cell lung cancer (NSCLC) has evolved rapidly over the past decade, largely triggered by the introduction of the targeted EGFR tyrosine kinase inhibitors (TKIs). Initially used to detect common EGFR mutations and determine the most appropriate first-line therapy at diagnosis, testing methodologies have expanded to test for multiple mutations at multiple time points throughout the disease course. Here we review the current mutation testing approaches, including types of biopsies, and the available assays commonly used in the clinic. Specific application of these approaches in advanced NSCLC, including current guideline recommendations, and potential future developments are discussed

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO)

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (\u3e4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy

Treating patients with platinum-sensitive extensive-stage small-cell lung cancer in a real-world setting

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive disease with poor 5-year survival. The first-line standard-of-care for ES-SCLC is platinum plus etoposide, along with 1 of the immune checkpoint inhibitors atezolizumab or durvalumab. Although SCLC first-line therapy often leads to rapid responses, treatment becomes more challenging at progression, particularly for those with a chemotherapy-free interval (CTFI) of ≤6 months. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for SCLC no longer specify treatment recommendations in this setting, but options approved by the US Food and Drug Administration include topotecan and lurbinectedin. Participation in a clinical trial is recommended as an option regardless of CTFI. Other NCCN-recommended regimens are paclitaxel, irinotecan, temozolomide, and cyclophosphamide/doxorubicin/vincristine, among others. Nivolumab and pembrolizumab are options in those not previously treated with a checkpoint inhibitor. For patients with platinum-sensitive SCLC (CTFI >6 months), preferred treatment per the NCCN Guidelines® for SCLC is retreatment with platinum and etoposide, although the use of immune checkpoint inhibitors is discouraged if there is progression on a drug in this class. Further research on immunotherapies and combination regimens is ongoing, and continuing work on the subcharacterization of SCLC may lead to better precision of therapies that promote more durable responses in individual patients with ES-SCLC

Recommendations for Measurement and Management of an Elite Athlete

Athletes who merit the title ‘elite’ are rare and differ both quantitatively and qualitatively from athletes of lower qualifications. Serving and studying elite athletes may demand non-traditional approaches. Research involving elite athletes suffers because of the typical nomothetic requirements for large sample sizes and other statistical assumptions that do not apply to this population. Ideographic research uses single-athlete study designs, trend analyses, and statistical process control. Single-athlete designs seek to measure differences in repeated measurements under prescribed conditions, and trend analyses may permit systematic monitoring and prediction of future outcomes. Statistical process control uses control charting and other methods from management systems to assess and modify training processes in near real-time. These methods bring assessment and process control into the real world of elite athletics

Using cfRNA as a tool to evaluate clinical treatment outcomes in patients with metastatic lung cancers and other tumors

Aim: We report an exploratory analysis of cfRNA as a biomarker to monitor clinical responses in non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer (CRC). An analysis of cfRNA as a method for measuring PD-L1 expression with comparison to clinical responses was also performed in the NSCLC cohort. Methods: Blood samples were collected from 127 patients with metastatic disease that were undergoing therapy, 52 with NSCLC, 50 with breast cancer, and 25 with CRC. cfRNA was purified from fractionated plasma, and following reverse transcription (RT), total cfRNA and gene expression of PD-L1were analyzed by real-time polymerase chain reaction (qPCR) using beta-actin expression as a surrogate for relative amounts of cfDNA and cfRNA. For the concordance study of liquid biopsies and tissue biopsies, the isolated RNA was analyzed by RNAseq for the expressions of 13 genes. We had to close the study early due to a lack of follow-up during the Covid-19 pandemic. Results: We collected a total of 373 blood samples. Mean cfRNA PCR signals after RT were about 50-fold higher than those of cfDNA. cfRNA was detected in all patients, while cfDNA was detected in 88% of them. A high concordance was found for the expression levels of 13 genes between blood and solid tumor tissue. Changes in cfRNA levels followed over the course of treatments were associated with response to therapy, increasing in progressive disease (PD) and falling when a partial response (PR) occurred. The expression of PD-L1 over time in patients treated with immunotherapy decreased with PR but increased with PD. Pre-treatment levels of PD-L1 were predictive of response in patients treated with immunotherapy. Conclusion: Changes in cfRNA correlate with clinical response to the therapy. Total cfRNA may be useful in predicting clinical outcomes. PD-L1 gene expression may provide a biomarker to predict response to PD-L1 inhibition

Lung Screening Benefits and Challenges: A Review of The Data and Outline for Implementation

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for almost a fifth of all cancer-related deaths. Annual computed tomographic lung cancer screening (CTLS) detects lung cancer at earlier stages and reduces lung cancer-related mortality among high-risk individuals. Many medical organizations, including the U.S. Preventive Services Task Force, recommend annual CTLS in high-risk populations. However, fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening. In large part, this is owing to delayed implementation of CTLS in many countries throughout the world. Factors contributing to low uptake in countries with longstanding CTLS endorsement, such as the United States, include lack of patient and clinician awareness of current recommendations in favor of CTLS and clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and cost. This review of the literature serves to address these concerns by evaluating the potential risks and benefits of CTLS. Review of key components of a lung screening program, along with an updated shared decision aid, provides guidance for program development and optimization. Review of studies evaluating the population considered "high-risk" is included as this may affect future guidelines within the United States and other countries considering lung screening implementation

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy