The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first-line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC.

Summary. Introduction:  A pulmonary embolism (PE) is a leading cause of mortality in hospitalized patients, yet the prevalence of PE in sickle cell disease (SCD) and its relation to disease severity or intrinsic hypercoagulability are not established. Methods:  We estimated inpatient PE incidence and prevalence among SCD and non‐SCD populations in Pennsylvania, and compared severity of illness and mortality, using Pennsylvania Health Care Cost Containment Council (PHC4) discharge data, 2001–2006. Risk factors for PE were assessed in a case–control study of discharges from the University of Pittsburgh Medical Archival Records System (MARS). Results:  The incidence of inpatient PE was higher in the SCD PA population than in the non‐SCD Pennsylvania population, 2001–2006. The PE prevalence among SCD discharges ≤ 50 years of age, 0.57%, was similar to that in non‐SCD Pennsylvania discharges, 0.60%, and unchanged after adjustment for race. Among SCD discharges, those developing PE were significantly older, with a longer length of stay, greater severity of illness and higher mortality, P < 0.001, than SCD without a PE. Among PE discharges, SCD had a similar severity of illness, P = 0.77, and mortality, P = 0.39, but underwent fewer computerized tomographic scans, P = 0.006, than non‐SCD with PE. In the local case–control study, no clinical or laboratory feature was associated with PE. Conclusions:  The incidence of PE is higher and chest computed tomography (CT) utilization is lower in SCD than non‐SCD inpatients, suggesting that PE may be under‐diagnosed.

The promise of portable diagnostic devices relies on three basic requirements: comparable sensitivity to established platforms, inexpensive manufacturing and cost of operations, and the ability to survive rugged field conditions. Solid state nanopores can meet all these requirements, but to achieve high manufacturing yields at low costs, assays must be tolerant to fabrication imperfections and to nanopore enlargement during operation. This paper presents a model for molecular engineering techniques that meets these goals with the aim of detecting target sequences within DNA. In contrast to methods that require precise geometries, we demonstrate detection using a range of pore geometries. As a result, our assay model tolerates any pore-forming method and in-situ pore enlargement. Using peptide nucleic acid (PNA) probes modified for conjugation with synthetic bulk-adding molecules, pores ranging 15-50 nm in diameter are shown to detect individual PNA-bound DNA. Detection of the CFTRΔF508 gene mutation, a codon deletion responsible for ∼66% of all cystic fibrosis chromosomes, is demonstrated with a 26-36 nm pore size range by using a size-enhanced PNA probe. A mathematical framework for assessing the statistical significance of detection is also presented.