Changes in store for early-stage non-small cell lung cancer.

The management of advanced non-small cell lung cancer (NSCLC) has been revolutionized in recent years with the introduction of biomarker-targeted molecular therapies and immune checkpoint inhibitors. In contrast, since adjuvant chemotherapy was first established twenty years ago as the standard of care, little has changed for resected early-stage (IB-IIIA) patients for whom the potential for cure is greatest. In this manuscript we will review recently presented data as well as ongoing/planned studies in this arena. So far, investigative efforts have yielded mixed results regarding the use of tyrosine kinase inhibitors (TKIs) in early-stage NSCLC, though a series of now better planned, biomarker-driven ongoing phase III trials may be more informative. Several innovative immunotherapy studies have already shown promising results principally in the neoadjuvant setting with a large number of pivotal neo-adjuvant and adjuvant trials now in progress. Given the more robust design and biomarker-focused approach of the new generation of studies, significant advances in the optimal curative treatment of early stage NSCLC are anticipated.

Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer.

Background: Radiation exposure is a well-documented risk factor for thyroid cancer; diagnostic imaging represents an increasing source of exposure. Germline variations in DNA repair genes could increase risk of developing thyroid cancer following diagnostic radiation exposure. No studies have directly tested for interaction between germline mutations and radiation exposure.Methods: Using data and DNA samples from a Connecticut population-based case-control study performed in 2010 to 2011, we genotyped 440 cases of incident thyroid cancer and 465 population-based controls for 296 SNPs in 52 DNA repair genes. We used multivariate unconditional logistic regression models to estimate associations between each SNP and thyroid cancer risk, as well as to directly estimate the genotype-environment interaction between each SNP and ionizing radiation.Results: Three SNPs were associated with increased risk of thyroid cancer and with thyroid microcarcinoma: HUS rs2708896, HUS rs10951937, and MGMT rs12769288. No SNPs were associated with increased risk of larger tumor (>10 mm) in the additive model. The gene-environment interaction analysis yielded 24 SNPs with Pinteraction < 0.05 for all thyroid cancer, 12 SNPs with Pinteraction < 0.05 for thyroid microcarcinoma, and 5 SNPs with Pinteraction < 0.05 for larger tumors.Conclusions: Germline variants in DNA repair genes are associated with thyroid cancer risk and are differentially associated with thyroid microcarcinoma and large tumor size. Our study provides the first evidence that germline genetic variations modify the association between diagnostic radiation and thyroid cancer risk.Impact: Thyroid microcarcinoma may represent a distinct subset of thyroid cancer. The effect of diagnostic radiation on thyroid cancer risk varies by germline polymorphism. Cancer Epidemiol Biomarkers Prev; 27(3); 285-94. ©2017 AACR.

Microfluidic on-chip capture-cycloaddition reaction to reversibly immobilize small molecules or multi-component structures for biosensor applications.

Methods for rapid surface immobilization of bioactive small molecules with control over orientation and immobilization density are highly desirable for biosensor and microarray applications. In this Study, we use a highly efficient covalent bioorthogonal [4+2] cycloaddition reaction between trans-cyclooctene (TCO) and 1,2,4,5-tetrazine (Tz) to enable the microfluidic immobilization of TCO/Tz-derivatized molecules. We monitor the process in real-time under continuous flow conditions using surface plasmon resonance (SPR). To enable reversible immobilization and extend the experimental range of the sensor surface, we combine a non-covalent antigen-antibody capture component with the cycloaddition reaction. By alternately presenting TCO or Tz moieties to the sensor surface, multiple capture-cycloaddition processes are now possible on one sensor surface for on-chip assembly and interaction studies of a variety of multi-component structures. We illustrate this method with two different immobilization experiments on a biosensor chip; a small molecule, AP1497 that binds FK506-binding protein 12 (FKBP12); and the same small molecule as part of an immobilized and in situ-functionalized nanoparticle.