Networks: NSCLC staging, MAPAH, cough in teen athletes

Methamphetamine (ME) as a potential etiology for PAH was first reported in 1993 (Schaiberger et al. Chest. 1993;104[2]:614). More recently, Chin et al suggested an association between stimulant use and PAH in 28.9% of their patients diagnosed with idiopathic PAH (Chest. 2006;130[6]:1657). The growing body of evidence linking ME to PAH resulted in upgrading of ME from “Possible” to “Likely” in the latest revision of the PH classification.

Recent gene sequencing data showed carboxylesterase-1, an enzyme that protects against ME-mediated pulmonary vascular injury, may be downregulated in patients with methamphetamine-associated PAH (MAPAH) (Perez et al. Am J Respir Crit Care Med. 193;2016:A2912). Furthermore, amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension (Chen PI. JCI Insight. 2017;2[2]:e90427). Importantly, Barnett et al demonstrated a poorer prognosis in MAPAH compared with individuals with idiopathic PAH, but they are less likely to be treated with infused prostanoid therapies (Circulation. 2012;126:A13817).

Amphetamine-type stimulants have become the second most widely used class of illicit drugs worldwide (United Nations Office on Drugs & Crime. World Drug Report 2012). An estimated 4.7 million Americans (2.1% of the US population) have tried MA at some time in their lives (J Psychoactive Drugs. 2000;32[2]:137). The true incidence and prevalence of MAPAH remains unknown. One can surmise that with the widespread use of ME, we are only witnessing the “tip of the iceberg.”

Vijay Balasubramanian, MD, FCCP

Steering Committee Member

Franck Rahaghi, MD, FCCP

NetWork Member
 

Thoracic Oncology

Immunotherapy for lung cancer

The management of non-small cell lung cancer has traditionally focused on surgical resection of early and limited stage tumors and radiation and cytotoxic chemotherapy for patients with advanced disease. Recent progress in the management of patients with metastatic lung cancer treatment has concentrated on the precise histologic diagnosis and the characterization of molecular drivers of malignant progression. Distinguishing small cell from non-small cell carcinomas, as well as differentiating adenocarcinoma from squamous cell carcinomas, enables clinicians to more effectively tailor appropriate chemotherapy. The identification of molecular mutations in EGFR (epidermal growth factor receptor) or fusions in ELM4-ALK translocations as drivers of the malignant process has facilitated tumor regression by targeting the molecular pathways with small molecular inhibitors (tyrosine-kinase inhibitors) or synthetic antibodies. Unfortunately, not all lung cancers carry activating mutations, and those that do may develop resistance to this molecular-targeted approach and show tumor progression.

Immunotherapy, an anticancer therapeutic approach that activates the host immune system to target the tumor, has historically been either a broad spectrum management utilizing immune cytokine modifiers to augment host immune activity or a directed adaptive recruitment and stimulation of host lymphocytes to attack targeted tumor cells. More recently, immunotherapy has taken a targeted molecular approach to modify immune checkpoint inhibitory pathways, the “brakes” of the immune system that tumor cells have manipulated to evade immune surveillance. Cancer cells may be attacked by activated T cells through the MHC complex and T cell receptor pathways. However, cancer cells that express a checkpoint ligand can deactivate T cells through its checkpoint pathway. Cancer cells may evade immune recognition by signaling inhibitory checkpoint receptor pathways, such as PD-1/PDL-1, or CTLA-4 receptors. Blocking the checkpoint inhibition may reactivate the immune response and enhance host immune recognition and killing of tumor cells. Infusions containing FDA-approved nivolumab (Opdivo) and pembrolizumab (Keytruda) block the PD-1 receptor checkpoint, whereas atezolizumab (Tecentriq) blocks PD-L1, the ligand that binds PD-1. These immune therapeutic approaches have been successfully utilized in a variety of solid tumors, including lung cancer and malignant melanomas. Impressive clinical results of prolonged tumor regression have been demonstrated in second-line immunotherapy with improvements over chemotherapy; newer immunotherapy trials have demonstrated efficacy in the first-line setting for metastatic disease. Tumors with high PDL-1 expression and high mutational load predict improved immunotherapy outcomes. As expected, blocking checkpoint immune inhibition may lead to autoimmune-like conditions of pneumonitis, hepatitis, colitis, and dermatitis. Tumor tissue markers predictive of a therapeutic immune response are in the research phase. Immunotherapy against lung cancer adds to the therapeutic armamentarium of cancer management and provides an exciting new research arena into the biology and immunology of lung cancer.

Arnold M. Schwartz, MD, PhD, FCCP

Steering Committee Member

References

Cousin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science . 2013;342[6165]:1432.

Sharma P, et al. The future of immune checkpoint therapy. Science . 2015;348[6230]:56.

Garon EB, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med . 2015;372[21]:2018.

Brahmer J, et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med . 2015;373[2]:123.