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Recent advances in lung cancer treatment have led to dramatic improvements in 5-year survival rates. And yet, lung cancer remains the leading cause of cancer-related mortality, in large part, because it is often diagnosed at an advanced stage, when cure is no longer possible. Lung cancer screening (LCS) is essential for intercepting the disease at an earlier stage. Unfortunately, LCS has been poorly adopted in the United States, with less than 5% of eligible patients being screened nationally. This article will describe the data supporting LCS, the obstacles to LCS implementation, and the promising opportunities that lie ahead.
RESUMO
BACKGROUND: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. RESULTS: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. CONCLUSION: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.
RESUMO
Johnston's organ is the largest mechanosensory organ in Drosophila; it analyzes movements of the antenna due to sound, wind, gravity, and touch. Different Johnston's organ neurons (JONs) encode distinct stimulus features. Certain JONs respond in a sustained manner to steady displacements, and these JONs subdivide into opponent populations that prefer push or pull displacements. Here, we describe neurons in the brain (aPN3 neurons) that combine excitation and inhibition from push/pull JONs in different ratios. Consequently, different aPN3 neurons are sensitive to movement in different parts of the antenna's range, at different frequencies, or at different amplitude modulation rates. We use a model to show how the tuning of aPN3 neurons can arise from rectification and temporal filtering in JONs, followed by mixing of JON signals in different proportions. These results illustrate how several canonical neural circuit components-rectification, opponency, and filtering-can combine to produce selectivity for complex stimulus features.