Endoscopic Endonasal Transclival Approaches: Case Series & Outcomes for Different Clival Regions

Objective Transclival endoscopic endonasal approaches to the skull base are novel with few published cases.We report our institution’s experience with this technique and discuss outcomes according to the clival region involved. Design Retrospective case series. Setting Tertiary care academic medical center Participants All patients who underwent endoscopic endonasal transclival approaches for skull base lesions from 2008 to 2012. Main Outcome Measures Pathologies encountered, mean intraoperative time, intraoperative complications, gross total resection, intraoperative cerebrospinal fluid (CSF) leak, postoperative CSF leak, postoperative complications, and postoperative clinical course. Results A total of 49 patients underwent 55 endoscopic endonasal transclival approaches. Pathology included 43 benign and 12 malignant lesions. Mean follow-up was 15.4 months. Mean operative time was 167.9 minutes, with one patient experiencing an intraoperative internal carotid artery injury. Of the 15 cases with intraoperative cerebrospinal fluid (CSF) leaks, 1 developed postoperative CSF leak (6.7%). There were six other postoperative complications: four systemic complications, one case of meningitis, and one retropharyngeal abscess. Gross total resection was achieved for all malignancies approached with curative intent. Conclusions This study provides evidence that endoscopic endonasal transclival approaches are a safe and effective strategy for the surgical management of a variety of benign and malignant lesions

The International Association for the Study of Lung Cancer Early Lung Imaging Confederation.

PurposeTo improve outcomes for lung cancer through low-dose computed tomography (LDCT) early lung cancer detection. The International Association for the Study of Lung Cancer is developing the Early Lung Imaging Confederation (ELIC) to serve as an open-source, international, universally accessible environment to analyze large collections of quality-controlled LDCT images and associated biomedical data for research and routine screening care.MethodsELIC is an international confederation that allows access to efficiently analyze large numbers of high-quality computed tomography (CT) images with associated de-identified clinical information without moving primary imaging/clinical or imaging data from its local or regional site of origin. Rather, ELIC uses a cloud-based infrastructure to distribute analysis tools to the local site of the stored imaging and clinical data, thereby allowing for research and quality studies to proceed in a vendor-neutral, collaborative environment. ELIC's hub-and-spoke architecture will be deployed to permit analysis of CT images and associated data in a secure environment, without any requirement to reveal the data itself (ie, privacy protecting). Identifiable data remain under local control, so the resulting environment complies with national regulations and mitigates against privacy or data disclosure risk.ResultsThe goal of pilot experiments is to connect image collections of LDCT scans that can be accurately analyzed in a fashion to support a global network using methodologies that can be readily scaled to accrued databases of sufficient size to develop and validate robust quantitative imaging tools.ConclusionThis initiative can rapidly accelerate improvements to the multidisciplinary management of early, curable lung cancer and other major thoracic diseases (eg, coronary artery disease and chronic obstructive pulmonary disease) visualized on a screening LDCT scan. The addition of a facile, quantitative CT scanner image quality conformance process is a unique step toward improving the reliability of clinical decision support with CT screening worldwide

Computer aided diagnosis of coronary artery disease, myocardial infarction and carotid atherosclerosis using ultrasound images: a review

The diagnosis of Coronary Artery Disease (CAD), Myocardial Infarction (MI) and carotid atherosclerosis is of paramount importance, as these cardiovascular diseases may cause medical complications and large number of death. Ultrasound (US) is a widely used imaging modality, as it captures moving images and image features correlate well with results obtained from other imaging methods. Furthermore, US does not use ionizing radiation and it is economical when compared to other imaging modalities. However, reading US images takes time and the relationship between image and tissue composition is complex. Therefore, the diagnostic accuracy depends on both time taken to read the images and experience of the screening practitioner. Computer support tools can reduce the inter-operator variability with lower subject specific expertise, when appropriate processing methods are used. In the current review, we analysed automatic detection methods for the diagnosis of CAD, MI and carotid atherosclerosis based on thoracic and Intravascular Ultrasound (IVUS). We found that IVUS is more often used than thoracic US for CAD. But for MI and carotid atherosclerosis IVUS is still in the experimental stage. Furthermore, thoracic US is more often used than IVUS for computer aided diagnosis systems

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure