A systematic review of secondhand smoke exposure in a car: Attributable changes in atmospheric and biological markers.

Exposure to secondhand smoke (SHS) has been linked to disease, disability, and premature death. While several countries have enacted smoke-free legislations, exposure to SHS may still occur in unregulated private environments, such as in the family car. We performed a systematic review of peer-reviewed literature in PubMed and Web of Science up to May 2013. Articles were selected if they provided a quantitative measure of SHS exposure (biological or atmospheric markers); the study was conducted inside a car; and the assessed exposure was attributable to cigarette combustion. From 202 articles identified, 12 met the inclusion criteria. Among all studies that assessed smoking in cars with at least one window partially open, the particulate matter 2.5 µm or less in diameter (PM2.5) concentrations ranged from 47 µg/m(3) to 12,150 µg/m(3). For studies with all windows closed, PM2.5 ranged from 203.6 µg/m(3) to 13,150 µg/m(3). SHS concentration in a car was mediated by air-conditioning status, extent of airflow, and driving speed. Smoking in cars leads to extremely high exposure to SHS and increased concentration of atmospheric markers of exposure-even in the presence of air-conditioning or increased airflow from open windows. This clearly shows that the only way to protect nonsmokers, especially children, from SHS within cars is by eliminating tobacco smoking.

A one-shot germinal center model under protein structural stability constraints.

The germinal center reaction is the process by which low-affinity B cells evolve into potent, immunoglobulin-secreting plasma and memory B cells. Since the recycling hypothesis was created, experimental studies have both tracked movement of a small population of B cells from the light zone into the dark zone, supporting the recycling model, and parallel to the light zone-dark zone interface, indicating a one-way trajectory. We present a novel, sequence-based ab initio model of protein stability and protein interactions. Our model contains a dark zone region of clonal expansion and somatic hypermutation and a light zone site of antigenic selection. We show not only that a one-shot model is sufficient to achieve biologically-realistic rates of affinity growth, population dynamics, and silent:non-silent mutation ratios in the complementary determining region and framework region of antibodies, but also that a stochastic recycling program with or without realistic constraints on the structural stabilities of GC antibodies cannot produce biologically-observed affinity growth, population dynamics or silent:non-silent mutation profiles. The effect of recycling erases affinity gains made by potent antibodies cycling back from the light zone and causes B cells to pool in the dark zone under high replication rates.

Surgical resection as a predictor of cancer-specific survival by stage at diagnosis and cancer type, United States, 2006-2015.

BACKGROUND: When solid tumors are amenable to definitive resection, clinical outcomes are generally superior to when those tumors are inoperable. However, the population-level cancer survival benefit of eligibility for surgery by cancer stage has not yet been quantified. METHODS: Using Surveillance, Epidemiology and End Results data allowing us to identify patients who were deemed eligible for and received surgical resection, we examined the stage-specific association of surgical resection with 12-year cancer-specific survival. The 12-year endpoint was selected to maximize follow-up time and thereby minimize the influence of lead time bias. RESULTS: Across a variety of solid tumor types, earlier stage at diagnosis allowed for surgical intervention at a much higher rate than later-stage diagnosis. At every stage, surgical intervention was associated with a substantially higher rate of 12-year cancer-specific survival, with absolute differences of up to 51% for stage I, 51% for stage II, and 44% for stage III cancer, and stage-specific mortality relative risks of 3.6, 2.4, and 1.7, respectively. CONCLUSIONS: Diagnosis of solid cancers in early stages often enables surgical resection, which reduces the risk of death from cancer. Receipt of surgical resection is an informative endpoint that is strongly associated with long-term cancer-specific survival at every stage.

For insights into the real world, consider real-world data.

Randomized control trials (RCTs) are required before drug and device approvals and have contributed to patient safety, but they have also increased the cost and time of regulatory assessments. We propose that using real-world evidence to complement or, in some settings, to replace RCTs will accelerate delivery of new drugs to patients.

Multicancer Early Detection Technologies: A Review Informed by Past Cancer Screening Studies.

More than 75% of cancer-related deaths occur from cancers for which we do not screen. New screening liquid biopsies may help fill these clinical gaps, although evidence of benefit still needs to be assessed. Which lessons can we learn from previous efforts to guide those of the future? Screening trials for ovarian, prostate, pancreatic, and esophageal cancers are revisited to assess the evidence, which has been limited by small effect sizes, short duration of early-stage disease relative to screening frequency, study design, and confounding factors. Randomized controlled trials (RCT) to show mortality reduction have required millions of screening-years, two-decade durations, and been susceptible to external confounding. Future RCTs with late-stage incidence as a surrogate endpoint could substantially reduce these challenges, and clinical studies demonstrating safety and effectiveness of screening in high-risk populations may enable extrapolation to broader average-risk populations. Multicancer early detection tests provide an opportunity to advance these practical study designs. Conditional approvals based on RCTs with surrogate endpoints, contingent upon real world evidence generation and continuation of trials to definitive endpoints, may lower practical barriers to innovation in cancer screening and enable greater progress.

Liquid Biopsy, Diagnostic Imaging, and Future Synergies.

Imaging plays an integral role in the initial diagnosis and longitudinal care of patients with cancer. Liquid biopsies, which most commonly involve genetic analysis of circulating free DNA, have emerged as important complementary tools in cancer care with the potential to interface with imaging at each step of the cancer care continuum. Here, the authors use non-small-cell lung cancer as a paradigm to elucidate factors driving the need for liquid biopsy in the spectrum of lung cancer care, demonstrate ways in which liquid biopsy has already changed standard clinical practice, and discuss anticipated synergies of liquid biopsy and imaging in screening and early detection and in monitoring of disease.

Definitive re-irradiation of locally recurrent esophageal cancer after trimodality therapy in patients with a poor performance status.

There are few treatment guidelines for locally recurrent esophageal cancer after trimodality treatment (pre-operative chemoradiation followed by surgery) in patients with a poor performance status. The purpose of this single institutional, retrospective study was to evaluate the clinical outcomes and toxicities of definitive-intent re-irradiation for patients with recurrent esophageal cancer with a poor performance status [ECOG (Eastern Cooperative Oncology Group) ≥2]. Seven patients were identified with a median age of 74 years (range, 61-81 years). Four patients were ECOG 2 and three patients were ECOG 3. The median follow-up time after re-irradiation was 49 months. The median interval between initial radiotherapy and re-treatment was 32 months. Six patients received concurrent chemotherapy [carboplatin + paclitaxel in three patients; folinic acid, fluorouracil, oxaliplatin (FOLFOX) + 5-fluorouracil in one patient; FOLFOX in one patient, and capecitabine in one patient]. At the last follow-up, the six patients who underwent concurrent chemotherapy had stable disease (86%), while the one who did not receive chemotherapy progressed (14%). Two patients developed metastases. Three patients developed acute (<6 months) grade 4 toxicities (dysphagia, anemia, esophagitis). There were no early deaths attributable to treatment. Late toxicities (>6 months) were limited to grades 1 and 2 dysphagia and pneumonitis in four patients. In conclusion, definitive re-irradiation of recurrent esophageal cancer in patients with a poor performance status appears to be safe with acceptable acute toxicity and late complications. It also appears to result in durable local control when combined with chemotherapy, albeit with a small number of patients and limited follow-up.

Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer.

Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFRT790M mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified fibroblast growth factor receptor 1 (FGFR1) as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data have not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug-tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.

Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9.

Macrophages undergo fusion to form multinucleated giant cells in several pathologic conditions, including the foreign body response (FBR). We detected high levels of matrix metalloproteinase (MMP)-9 during macrophage fusion in vitro and in foreign body giant cells (FBGCs) in vivo. Wild-type (WT) bone marrow-derived macrophages were induced to fuse with IL-4 in the presence of MMP-9 function-blocking antibodies and displayed reduced fusion. A similar defect, characterized by delayed shape change and abnormal morphology, was observed in MMP-9 null macrophages. Analysis of the FBR in MMP-9 null mice was then pursued to evaluate the significance of these findings. Specifically, mixed cellulose ester disks and polyvinyl alcohol sponges were implanted s.c. in MMP-9 null and WT mice and excised 2-4 weeks later. Histochemical and immunohistochemical analyses indicated equal macrophage recruitment between MMP-9 null and WT mice, but FBGC formation was compromised in the former. In addition, MMP-9 null mice displayed abnormalities in extracellular matrix assembly and angiogenesis. Consistent with a requirement for MMP-9 in fusion, we also observed reduced MMP-9 levels in MCP-1 null macrophages, previously shown to be defective in FBGC formation. Collectively, our studies show abnormalities in MMP-9 null mice during the FBR and suggest a role for MMP-9 in macrophage fusion.