Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada

/pdf/allergic-rhinitis-and-its-impact-on-asthma-20b4c7y0pr.pdf

Allergic Rhinitis and Its Impact on Asthma

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673607614160.pdf

Human papillomavirus and cervical cancer

Toxic equivalency factors (TEFs) for polycyclic aromatic hydrocarbons (PAHs).

The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.

/pdf/tobacco-smoke-carcinogens-and-lung-cancer-151e8tf0fh.pdf

Tobacco Smoke Carcinogens and Lung Cancer

Hoffmann and Wynder Response

Occupational bladder cancer

In Reply. —Several factors including differences in cotinine elimination between smokers and nonsmokers, 1 physicochemical differences between mainstream and sidestream smoke 2,3 and variance in mode of uptake of carcinogenic and cocarcinogenic compounds in mainstream and sidestream smoke lead us to maintain that a direct extrapolation to cigarette equivalents of inhaled smoke cannot be validated in nonsmokers from a single measurement of urinary cotinine. Enlarging on the data presented in our report, we have confirmed a longer residence time for cotinine in the urine of exposed nonsmokers compared with smokers and have observed interindividual variation in both groups. 4,5 This variation does not permit a "magnitude of difference" to be established. Comparing urine cotinine half-life in three studies, we see ratios of 1.3, 6 1.5, 1 and 1.7, 4,5 indicating 30%, 50%, and 70% differences in "average" urine values. Additionally, urine cotinine half-lives of 66 hours have been reported in

Use of Urinary Cotinine to Estimate Exposure to Tobacco Smoke-Reply

Quantitative Analysis of Alkyl-2-hydroxy-2-cyclopenten-1-ones in Tobacco Smoke

Abstract Smoke of a plain 85 mm cigarette, 2 types of cigars, a pipe with standard pipe tobacco, a pipe filled with cigarette tobacco, and a Syrian water pipe was analysed for the mainstream particulate matter, nicotine, benzo[a]pyrene, and phenols. On the basis of equal weights of tobacco consumed, cigarettes gave the highest yields of both nicotine and particulate materials, with lesser amounts, in decreasing order, obtained from an American-type pipe, cigars, and an oriental water pipe. The highest value from 100 g tobacco for benzo[a]pyrene, 27.0 µg, and phenol, 68.7 mg, was found in the smoke of a pipe filled with standard pipe tobacco. A pipe filled with cigarette tobacco yielded benzo[a]pyrene, 10.5 µg, phenol, 21.2 mg; cigarette smoke, benzo[a]pyrene, 7.8 µg, phenol, 25.4 mg; cigar smoke, benzo[a]pyrene, 4.0 and 5.1 µg, phenol, 7.4 and 10.7 mg, with the lowest values for the smoke from an oriental water pipe, benzo[a]pyrene 1.7 µg, phenol, 1.8 mg. The water-filled oriental pipe retained about 90 percent of the phenol of the original smoke. Particulate matter, nicotine, and benzo[a]pyrene were retained to a lesser degree by the water (about 50 %). Increased puff frequency resulted in higher yields of all 4 groups of compounds in the mainstream smoke. Values at 2 puffs per minute frequency ranged from 50 to 120% higher than those at 1 puff per minute when the other smoking factors were held constant. Since biological tests and comparisons of the carcinogenicity of the condensates of cigarettes, cigars, and pipes have previously been carried out on equal weights of condensate, the analytical results of this study were compared in the same manner. One g of the smoke condensates from 85 mm plain cigarettes, 2 types of cigars, and a standard pipe contain 1.25, 3.6, 3.9 and 6.0 µg benzo[a]pyrene, respectively. The corresponding phenol values were 4.1, 6.7, 8.2 and 15.0 mg per 1 g smoke condensate

Comparison of the Yields of Selected Components in the Smoke of Different Tobacco Products / Vergleich der Ausbeute an mehreren ausgewählten Komponenten im Rauch verschiedener Tabakerzeugnisse

Dietrich Hoffmann

Papers

Hoffmann and Wynder Response

Occupational bladder cancer

Use of Urinary Cotinine to Estimate Exposure to Tobacco Smoke-Reply

Quantitative Analysis of Alkyl-2-hydroxy-2-cyclopenten-1-ones in Tobacco Smoke

Comparison of the Yields of Selected Components in the Smoke of Different Tobacco Products / Vergleich der Ausbeute an mehreren ausgewählten Komponenten im Rauch verschiedener Tabakerzeugnisse