In the era of immuno-oncology, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have demonstrated a clear survival benefit as a single agent or in combination compared with standard chemotherapy in both treatment-naive patients^1-4 and patients previously treated^5-8 for advanced non–small cell lung cancer (NSCLC). However, progression rates reported with single-agent PD-1/PD-L1 inhibitors are in some cases equal to or higher than with conventional treatment, ranging from 33% to 44% in pretreated patients with NSCLC.^5-7 Recently, an acceleration of tumor growth during immunotherapy, defined as hyperprogressive disease (HPD), was reported in 9% of advanced cancers⁹ and in 29% of patients with head and neck cancer¹⁰ treated with PD-1/PD-L1 inhibitors.

Coronavirus disease 2019 (COVID-19) is a respiratory disease induced by a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) causing substantial morbidity and mortality.^1-4 Most people with COVID-19 have only mild or uncomplicated symptoms, but approximately 10% to 15% have moderate or severe disease that requires hospitalization and oxygen support, and 3% to 5% require admission to an intensive care unit (ICU).⁵ In severe cases, COVID-19 can be complicated by acute respiratory distress syndrome (ARDS). Older age, male sex, and comorbid diseases are risk factors for death.^6-8

Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy. Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR. Read the Commentary on this article by Rosell and Wannesson, p. 769. This article is highlighted in the In This Issue feature, p. 753.

The objective of the study was to estimate the prevalence and incidence of interstitial lung diseases (ILDs) in Seine-Saint-Denis, a multi-ethnic county of Greater Paris, France.Patients with ILDs were identified between January and December 2012 by using several sources; all potentially involved medical specialists from public and private hospitals, community-based pulmonologists and general practitioners, and the Social Security system. Diagnoses were validated centrally by an expert multidisciplinary discussion.1170 ILD cases were reported (crude overall prevalence: 97.9/10⁵and incidence: 19.4/10⁵/year). In the 848 reviewed cases, the most prevalent diagnoses were sarcoidosis (42.6%), connective tissue diseases associated ILDs (CTDs-ILDs) (16%), idiopathic pulmonary fibrosis (IPF) (11.6%), and occupational ILDs (5.0%), which corresponded to a crude prevalence of 30.2/10⁵for sarcoidosis, 12.1/10⁵for CTDs-ILDs and 8.2/10⁵for IPF. The prevalence of fibrotic idiopathic interstitial pneumonias, merging IPF, nonspecific interstitial pneumonia and cases registered with code J84.1 was 16.34/10⁵. An adjusted multinomial model demonstrated an increased risk of sarcoidosis in North Africans and Afro-Caribbeans and of CTDs-ILDs in Afro-Caribbeans, compared to that in Europeans.This study, with a comprehensive recruitment and stringent diagnostic criteria, emphasises the importance of secondary ILDs, particularly CTDs-ILDs and the relatively low prevalence of IPF, and confirms that sarcoidosis is a rare disease in France.