Nir Peled

Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.

In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab.Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator's choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting.Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively).With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Abstract KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P &amp;lt; 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P &amp;lt; 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. This article is highlighted in the In This Issue feature, p. 781

Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTVolatile Organic Compounds of Lung Cancer and Possible Biochemical PathwaysMeggie Hakim†, Yoav Y. Broza†, Orna Barash†, Nir Peled‡, Michael Phillips§, Anton Amann∥⊥, and Hossam Haick*†View Author Information† The Department of Chemical Engineering and Russell Berrie Nanotechnology Institute, Technion—Israel Institute of Technology, Haifa 32000, Israel‡ The Thoracic Cancer Research and Detection Center, Sheba Medical Center, Tel-Aviv University, Tel-Aviv 52621, Israel§ Menssana Research, Inc., Fort Lee, New Jersey 07024, United States∥ Breath Research Institute, Austrian Academy of Sciences, 6850 Dornbirn, Austria⊥ University-Clinic for Anesthesia, Innsbruck Medical University, 6020 Innsbruck, Austria*E-mail: [email protected]Cite this: Chem. Rev. 2012, 112, 11, 5949–5966Publication Date (Web):September 19, 2012Publication History Received26 April 2012Published online19 September 2012Published inissue 14 November 2012https://doi.org/10.1021/cr300174aCopyright © 2012 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views13015Altmetric-Citations544LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (8 MB) Get e-AlertsSUBJECTS:Aldehydes,Anatomy,Cells,Chromatography,Volatile organic compounds Get e-Alerts

RET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests — such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements — are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.

Earliest modern humans out of Africa Recent paleoanthropological studies have suggested that modern humans migrated from Africa as early as the beginning of the Late Pleistocene, 120,000 years ago. Hershkovitz et al. now suggest that early modern humans were already present outside of Africa more than 55,000 years earlier (see the Perspective by Stringer and Galway-Witham). During excavations of sediments at Mount Carmel, Israel, they found a fossil of a mouth part, a left hemimaxilla, with almost complete dentition. The sediments contain a series of well-defined hearths and a rich stone-based industry, as well as abundant animal remains. Analysis of the human remains, and dating of the site and the fossil itself, indicate a likely age of at least 177,000 years for the fossil—making it the oldest member of the Homo sapiens clade found outside Africa. Science , this issue p. 456 ; see also p. 389

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the computed tomography–based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics, and artificial intelligence. We list a number of completed, ongoing, or planned trials to show the clinical utility of molecular biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clinical utility of one or several candidate biomarkers.

Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the “accepted standard” biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of “plasma first” versus “tissue first” approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC.

The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs).Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians.Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclin-dependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14.Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

Purpose In addition to prospective trials for non–small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data—clinical, pathologic, and molecular features—were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs).In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients.Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029).Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC.Merck & Co.

In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS.After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off.Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.

Two of the biggest challenges in medicine today are the need to detect diseases in a noninvasive manner and to differentiate between patients using a single diagnostic tool. The current study targets these two challenges by developing a molecularly modified silicon nanowire field effect transistor (SiNW FET) and showing its use in the detection and classification of many disease breathprints (lung cancer, gastric cancer, asthma, and chronic obstructive pulmonary disease). The fabricated SiNW FETs are characterized and optimized based on a training set that correlate their sensitivity and selectivity toward volatile organic compounds (VOCs) linked with the various disease breathprints. The best sensors obtained in the training set are then examined under real-world clinical conditions, using breath samples from 374 subjects. Analysis of the clinical samples show that the optimized SiNW FETs can detect and discriminate between almost all binary comparisons of the diseases under examination with >80% accuracy. Overall, this approach has the potential to support detection of many diseases in a direct harmless way, which can reassure patients and prevent numerous unpleasant investigations.

Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients.

EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes.Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded.In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.

The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown.Multi-institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non-V600E (group B, n = 18). Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression-free survival (PFS) with ICPi, and overall survival were analyzed.High (≥50%), intermediate (1-49%), and no (<1%) PD-L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status-high. Twenty-two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6-6.6), and 4.1 months (95% CI: 0.1-19.6) in groups A and B, respectively (log-rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD-L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13-NR) and comprised 21.1 months (95% CI: 1.8-NR) for patients who were and were not exposed to ICPi, respectively (log-rank test = 5.58, p = 0.018).BRAF mutant NSCLC is associated with high level of PD-L1 expression, low/intermediate TMB and microsatellite-stable status. ICPi have favorable activity both in BRAF V600E and BRAF non-V600E mutant NSCLC.

To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated.cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit.cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887.

In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized.A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined.The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months).Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Background Pembrolizumab plus pemetrexed–platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed–platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1–5, every three cycles thereafter during year 1, and every four cycles during years 2–3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680. Findings Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2–20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed–platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed–platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed–platinum group and 180 (90%) of 200 in the placebo plus pemetrexed–platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·0 point [95% CI −1·3 to 3·2] increase) and placebo plus pemetrexed–platinum (−2·6 points [−5·8 to 0·5] decrease; between-group difference: 3·6 points [−0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·3 points [95% CI −1·2 to 3·6] increase) than with placebo plus pemetrexed–platinum (−4·0 points [−7·7 to −0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed–platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed–platinum (hazard ratio 0·81 [95% CI 0·60–1·09], p=0·16). Interpretation The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed–platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. Funding Merck Sharp & Dohme.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680 ). Eligible patients with previously untreated metastatic nonsquamous non–small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non–small-cell lung cancer without EGFR/ALK alterations.

The search for non-invasive diagnostic methods of lung cancer (LC) has led to new avenues of research, including the exploration of the exhaled breath. Previous studies have shown that LC can, in principle, be detected through exhaled-breath analysis. This study evaluated the potential of exhaled-breath analysis for the distinction of benign and malignant pulmonary nodules (PNs).Breath samples were taken from 72 patients with PNs in a prospective trial. Profiles of volatile organic compounds were determined by (1) gas chromatography/mass spectrometry (GC-MS) combined with solid-phase microextraction and (2) a chemical nanoarray.Fifty-three PNs were malignant and 19 were benign with similar smoking histories and comorbidities. Nodule size (mean ± SD) was 2.7 ± 1.7 versus 1.6 ± 1.3 cm (p = 0.004), respectively. Within the malignant group, 47 were non-small-cell lung cancer and six were small-cell lung cancer. Thirty patients had early-stage disease and 23 had advanced disease. Gas chromatography/mass spectrometry analysis identified a significantly higher concentration of 1-octene in the breath of LC, and the nanoarray distinguished significantly between benign versus malignant PNs (p < 0.0001; accuracy 88 ± 3%), between adeno- and squamous-cell carcinomas [LINE SEPARATOR](p < 0.0001; 88 ± 3%) and between early stage and advanced disease (p < 0.0001; 88 ± 2%).In this pilot study, breath analysis discriminated benign from malignant PNs in a high-risk cohort based on LC-related volatile organic compound profiles. Furthermore, it discriminated adeno- and squamous-cell carcinoma and between early versus advanced disease. Further studies are required to validate this noninvasive approach, using a larger cohort of patients with PNs detected by computed tomography.

Abstract Background. The U.S. Food and Drug Administration-approved method for detecting EML4-ALK rearrangement is fluorescence in situ hybridization (FISH); however, data supporting the use of immunohistochemistry (IHC) for that purpose are accumulating. Previous studies that compared FISH and IHC considered FISH the gold standard, but none compared data with the results of next-generation sequencing (NGS) analysis. Materials and Methods. We studied FISH and IHC (D5F3 antibody) systematically for EML4-ALK rearrangement in 51 lung adenocarcinoma patients, followed by NGS in case of discordance. Results. Of 51 patients, 4 were positive with FISH (7.8%), and 8 were positive with IHC (15.7%). Three were positive with both. NGS confirmed that four of the five patients who were positive with IHC and negative with FISH were positive for ALK. Two were treated by crizotinib, with progression-free survival of 18 and 6 months. Considering NGS as the most accurate test, the sensitivity and specificity were 42.9% and 97.7%, respectively, for FISH and 100% and 97.7%, respectively, for IHC. Conclusion. The FISH-based method of detecting EML4-ALK rearrangement in lung cancer may miss a significant number of patients who could benefit from targeted ALK therapy. Screening for EML4-ALK rearrangement by IHC should be strongly considered, and NGS is recommended in borderline cases. Two patients who were negative with FISH and positive with IHC were treated with crizotinib and responded to therapy.

Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization.Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA.The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease.Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion occurs in 2% to 7% of non–small-cell lung cancer (NSCLC) cases1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar,2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar and is typically identified by Vysis ALK Break-Apart fluorescent in situ hybridization (FISH) assay. Tumors expressing this fusion respond to treatment using crizotinib.1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar A 43-year-old male never-smoker presented with pericardial tamponade. Pericardio/thoracocentesis yielded 2.5 liters of fluid; light microscopy was consistent with lung adenocarcinoma. No epidermal growth factor receptor mutation or EML4-ALK rearrangement was detected. After talc pleurodesis, he was treated with four cycles of cisplatin/pemetrexed. However, he experienced a progression. A specimen from the tumor was sent for comprehensive genomic profiling using a next-generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory (Foundation Medicine), identifying a complex ALK rearrangement. Several steps were then undertaken to characterize better the genomic abnormality. FISH testing was negative using standard criteria (Figure 1). NGS analysis of genomic DNA revealed a complex rearrangement of ALK, involving breakpoints in at least five different genomic loci. One of the breakpoints was in ALK intron 19, the canonical breakpoint for EML4-ALK fusions. No clear fusion product was predicted; we suspected the existence of multiple transcript products that were not readily identifiable. We thus sequenced cDNA from the same sample to study, both, the expression level of ALK and the structure of any potential fusion product. The cDNA sequence demonstrated that the expressed product of the complex rearrangement was the canonical EML4-ALK fusion gene (EML4 exons 1–13, ALK exons 20–29). We hypothesized that at the genomic level the fused EML4 and ALK genes were separated by other small genomic shards; this explained why the EML4-ALK fusion was not detected by FISH. This connective region is likely to be removed during splicing and results in a functional EML4-ALK transcript. We next showed a 39-fold overexpression of exons 20–29 of ALK relative to exons 1–19 (Figure 2). ALK immunohistochemistry was positive, as displayed in Figure 1. On the basis of these results, crizotinib was begun. Within 2 weeks, the patient reported an improvement in pain in the pubic area and in exercise tolerance. Significant improvement was seen on initial computed tomography and positron emission tomography scans, and after 4 months, the positron emission tomography scan was negative and the chest computed tomography scan showed further shrinkage of the primary lesion (Response Evaluation Criteria In Solid Tumors 75%; Figure 3). Approximately 3% to 7% of lung tumors harbor ALK fusions 1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar, 2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar, 3Rikova K Guo A Zeng Q et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.Cell. 2007; 131: 1190-1203Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar, 4Soda M Choi YL Enomoto M et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature. 2007; 448: 561-566Crossref PubMed Scopus (4304) Google Scholar, 5Lipson D Capelletti M Yelensky R et al.Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.Nat Med. 2012; 18: 382-386Crossref PubMed Scopus (714) Google Scholar, 6Wong DW Leung EL So KK et al.The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.Cancer. 2009; 115: 1723-1733Crossref PubMed Scopus (640) Google Scholar ALK fusions are more commonly found in light smokers (<10 pack-years) and/or never smokers.1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar,2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar,4Soda M Choi YL Enomoto M et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature. 2007; 448: 561-566Crossref PubMed Scopus (4304) Google Scholar,6Wong DW Leung EL So KK et al.The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.Cancer. 2009; 115: 1723-1733Crossref PubMed Scopus (640) Google Scholar,7Inamura K Takeuchi K Togashi Y et al.EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.Mod Pathol. 2009; 22: 508-515Crossref PubMed Scopus (401) Google Scholar ALK fusions are also associated with younger age 2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar,6Wong DW Leung EL So KK et al.The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.Cancer. 2009; 115: 1723-1733Crossref PubMed Scopus (640) Google Scholar,7Inamura K Takeuchi K Togashi Y et al.EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.Mod Pathol. 2009; 22: 508-515Crossref PubMed Scopus (401) Google Scholar and adenocarcinomas with acinar histology6Wong DW Leung EL So KK et al.The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.Cancer. 2009; 115: 1723-1733Crossref PubMed Scopus (640) Google Scholar,7Inamura K Takeuchi K Togashi Y et al.EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.Mod Pathol. 2009; 22: 508-515Crossref PubMed Scopus (401) Google Scholar or signet-ring cells.2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar Recent studies demonstrate that the frequency EML4-ALK fusion transcript is detected in 2% to 7% of lung adenocarcinomas1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar,2Shaw AT Yeap BY Mino-Kenudson M et al.Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009; 27: 4247-4253Crossref PubMed Scopus (1632) Google Scholar; these tumors are sensitive to crizotinib. Many ALK rearrangements have been described in NSCLC. Most of these fusion variants comprised various portions of the EML4 gene fused with a consistent portion of the ALK gene. In addition, non-EML4 fusion partners have also been identified, including KIF5B and TFG.3Rikova K Guo A Zeng Q et al.Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.Cell. 2007; 131: 1190-1203Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar The novel rearrangement identified in this case is complex and was not detected by the Break-Apart FISH assay. NGS showed that the patient's tumor harbored a complex EML4-ALK rearrangement at the genomic level. Clinical and radiographic evidence confirmed a rapid response to crizotinib. NGS should be considered in NSCLC patients with high likelihood of a driver kinase alteration when none is identified by other methods.

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.

Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and quality assurance plan. The establishment of a central registry, including biobank and image bank, and preferably on a European level, is strongly encouraged.

Abstract Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors. Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials. Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.

For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

We report on a new concept for profiling genetic mutations of (lung) cancer cells, based on the detection of patterns of volatile organic compounds (VOCs) emitted from cell membranes, using an array of nanomaterial-based sensors. In this in-vitro pilot study we have derived a volatile fingerprint assay for representative genetic mutations in cancer cells that are known to be associated with targeted cancer therapy. Five VOCs were associated with the studied oncogenes, using complementary chemical analysis, and were discussed in terms of possible metabolic pathways. The reported approach could lead to the development of novel methods for guiding treatments, so that patients could benefit from safer, more timely and effective interventions that improve survival and quality of life while avoiding unnecessary invasive procedures. Studying clinical samples (tissue/blood/breath) will be required as next step in order to determine whether this cell-line study can be translated into a clinically useful tool. In this novel study, a new concept for profiling genetic mutations of (lung) cancer cells is described, based on the detection of patterns of volatile organic compounds emitted from cell membranes, using an array of nano-gold based sensors.

Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged.• Lung cancer screening using low dose computed tomography reduces mortality. • Leading US medical societies recommend large scale screening for high-risk individuals. • There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet. • The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. • High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes.

The Response Evaluation Criteria in Solid Tumors (RECIST) serve as the accepted standard to monitor treatment efficacy in lung cancer. However, the time intervals between consecutive computerized tomography scans might be too long to allow early identification of treatment failure. This study examines the use of breath sampling to monitor responses to anticancer treatments in patients with advanced lung cancer.A total of 143 breath samples were collected from 39 patients with advanced lung cancer. The exhaled breath signature, determined by gas chromatography/mass spectrometry and a nanomaterial-based array of sensors, was correlated with the response to therapy assessed by RECIST: complete response, partial response, stable disease, or progressive disease.Gas chromatography/mass spectrometry analysis identified three volatile organic compounds as significantly indicating disease control (PR/stable disease), with one of them also significantly discriminating PR/stable disease from progressive disease. The nanoarray had the ability to monitor changes in tumor response across therapy, also indicating any lack of further response to therapy. When one-sensor analysis was used, 59% of the follow-up samples were identified correctly. There was 85% success in monitoring disease control (stable disease/partial response).Breath analysis, using mainly the nanoarray, may serve as a surrogate marker for the response to systemic therapy in lung cancer. As a monitoring tool, it can provide the oncologist with a quick bedside method of identifying a lack of response to an anticancer treatment. This may allow quicker recognition than does the current RECIST analysis. Early recognition of treatment failure could improve patient care.

Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking.260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1.Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each).In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Tobacco consumption remains the most important risk factor. Although the prevalence of smoking has decreased overall, it continues to be a significant burden for global health. It is estimated that there are still nearly 1 billion cigarette smokers worldwide. Prevention strategies have largely focused on tobacco control and prevention. However, we have witnessed a dramatic increase in the use of e-cigarettes and other vaping products. Primary chemoprevention has historically not been a successful strategy for lung cancer; however, focused approaches in specific groups of patients at high risk for development of lung cancer are underway. The majority of cases with NSCLC are diagnosed with locally advanced or metastatic disease, where the overall prognosis remains very poor. Early-stage NSCLC on the other hand has a much better prognosis and can usually be treated radically with either surgical resection or radical radiotherapy, with relatively favorable long-term outcomes. In addition to image-based screening, other methods such as breath-based and biofluid-based approaches are now being investigated for early detection of NSCLC. This review will focus on recent advancements in the field of prevention, screening, and early detection of NSCLC.

In Europe, lung cancer ranks third among the most common cancers, remaining the biggest killer. Since the publication of the first European Society of Radiology and European Respiratory Society joint white paper on lung cancer screening (LCS) in 2015, many new findings have been published and discussions have increased considerably. Thus, this updated expert opinion represents a narrative, non-systematic review of the evidence from LCS trials and description of the current practice of LCS as well as aspects that have not received adequate attention until now. Reaching out to the potential participants (persons at high risk), optimal communication and shared decision-making will be key starting points. Furthermore, standards for infrastructure, pathways and quality assurance are pivotal, including promoting tobacco cessation, benefits and harms, overdiagnosis, quality, minimum radiation exposure, definition of management of positive screen results and incidental findings linked to respective actions as well as cost-effectiveness. This requires a multidisciplinary team with experts from pulmonology and radiology as well as thoracic oncologists, thoracic surgeons, pathologists, family doctors, patient representatives and others. The ESR and ERS agree that Europe's health systems need to adapt to allow citizens to benefit from organised pathways, rather than unsupervised initiatives, to allow early diagnosis of lung cancer and reduce the mortality rate. Now is the time to set up and conduct demonstration programmes focusing, among other points, on methodology, standardisation, tobacco cessation, education on healthy lifestyle, cost-effectiveness and a central registry.Key Points• Pulmonologists and radiologists both have key roles in the set up of multidisciplinary LCS teams with experts from many other fields.• Pulmonologists identify people eligible for LCS, reach out to family doctors, share the decision-making process and promote tobacco cessation.• Radiologists ensure appropriate image quality, minimum dose and a standardised reading/reporting algorithm, together with a clear definition of a "positive screen".• Strict algorithms define the exact management of screen-detected nodules and incidental findings.• For LCS to be (cost-)effective, it has to target a population defined by risk prediction models.

Background Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non–small-cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)-rearranged NSCLC. Patients and Methods We identified all patients with ALK-rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in 2 tertiary centers in Israel. Results Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). Conclusion The rate of VTE in our ALK-rearranged cohort was 3- to 5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.

Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

In Europe, lung cancer ranks third among the most common cancers, remaining the biggest killer. Since the publication of the first European Society of Radiology and European Respiratory Society joint white paper on lung cancer screening (LCS) in 2015, many new findings have been published and discussions have increased considerably. Thus, this updated expert opinion represents a narrative, non-systematic review of the evidence from LCS trials and description of the current practice of LCS as well as aspects that have not received adequate attention until now. Reaching out to the potential participants (persons at high risk), optimal communication and shared decision-making will be key starting points. Furthermore, standards for infrastructure, pathways and quality assurance are pivotal, including promoting tobacco cessation, benefits and harms, overdiagnosis, quality, minimum radiation exposure, definition of management of positive screen results and incidental findings linked to respective actions as well as cost-effectiveness. This requires a multidisciplinary team with experts from pulmonology and radiology as well as thoracic oncologists, thoracic surgeons, pathologists, family doctors, patient representatives and others. The ESR and ERS agree that Europe's health systems need to adapt to allow citizens to benefit from organised pathways, rather than unsupervised initiatives, to allow early diagnosis of lung cancer and reduce the mortality rate. Now is the time to set up and conduct demonstration programmes focusing, among other points, on methodology, standardisation, tobacco cessation, education on healthy lifestyle, cost-effectiveness and a central registry.

Low spatial resolution is often cited as the most critical limitation of magneto- and electroencephalography (MEG and EEG), but a unifying framework for quantifying the spatial fidelity of M/EEG source estimates has yet to be established; previous studies have focused on linear estimation methods under ideal scenarios without noise. Here we present an approach that quantifies the spatial fidelity of M/EEG estimates from simulated patch activations over the entire neocortex superposed on measured resting-state data. This approach grants more generalizability in the evaluation process that allows for, e.g., comparing linear and non-linear estimates in the whole brain for different signal-to-noise ratios (SNR), number of active sources and activation waveforms. Using this framework, we evaluated the MNE, dSPM, sLORETA, eLORETA, and MxNE methods and found that the spatial fidelity varies significantly with SNR, following a largely sigmoidal curve whose shape varies depending on which aspect of spatial fidelity that is being quantified and the source estimation method. We believe that these methods and results will be useful when interpreting M/EEG source estimates as well as in methods development.

Detection of neural signatures related to pathological behavioral states could enable adaptive deep brain stimulation (DBS), a potential strategy for improving efficacy of DBS for neurological and psychiatric disorders. This approach requires identifying neural biomarkers of relevant behavioral states, a task best performed in ecologically valid environments. Here, in human participants with obsessive-compulsive disorder (OCD) implanted with recording-capable DBS devices, we synchronized chronic ventral striatum local field potentials with relevant, disease-specific behaviors. We captured over 1,000 h of local field potentials in the clinic and at home during unstructured activity, as well as during DBS and exposure therapy. The wide range of symptom severity over which the data were captured allowed us to identify candidate neural biomarkers of OCD symptom intensity. This work demonstrates the feasibility and utility of capturing chronic intracranial electrophysiology during daily symptom fluctuations to enable neural biomarker identification, a prerequisite for future development of adaptive DBS for OCD and other psychiatric disorders.

<h2>Abstract</h2><h3>Introduction</h3> We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. <h3>Methods</h3> We pooled data for patients with previously treated or untreated PD-L1‒positive (tumor proportion score [TPS], ≥1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases. <h3>Results</h3> A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1‒43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS ≥50% (0.67 [95% confidence intervals (CI): 0.44‒1.02] and 0.66 [95% CI: 0.58‒0.76], respectively) and PD-L1 TPS ≥1% (0.83 [95% CI: 0.62‒1.10] and 0.78 [95% CI: 0.71‒0.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without. <h3>Conclusions</h3> Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1‒positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.

The insulin-like growth factor-1 receptor (IGF-1R) pathway is known to play a role in the acquisition of resistance to epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, its exact role in TKI resistance has so far remained unclear. Here, we interrogated the hypothesis that the IGF-1R may serve as a biomarker for, and may play a role in, intrinsic resistance to the EGFR-specific TKI gefitinib in NSCLC. Total-IGF-1R and phosphorylated (p)-IGF-1R expression levels were related to gefitinib sensitivity in 23 NSCLC cell lines. This sensitivity was re-evaluated after knocking down IGF-1R expression and after IGF-1R up‐regulation through exogenous IGF-1 expression. The utility of IGF-1R expression as a predictive biomarker was also evaluated by immunohistochemistry (IHC) in 98 primary NSCLC samples from patients treated with gefitinib. Seventeen of the cell lines tested were resistant to gefitinib, whereas 3 cell lines were sensitive. The three remaining cell lines showed intermediate values. Thirteen resistant cell lines were found to be positive for total-IGF-1R expression, while all the sensitive cell lines were negative, resulting in a positive predictive value (PPV) of 81 % for total-IGF-1R to predict resistance. Seven resistant cell lines exhibited high p-IGF-1R levels, whereas all 3 sensitive cell lines were negative for p-IGF-1R, resulting in a PPV of 100 % for p-IGF-1R to predict resistance. Neither a knock-down of IGF-1R expression nor an activation of the IGF1-R pathway through exogenous IGF-1 expression affected gefitinib sensitivity. In primary NSCLC tissues, IGF-1R expression was found to be significantly higher in patients with progressive disease, i.e., showing gefitinib resistance, as compared to those with a complete or partial response. IGF-1R acts as a predictor for resistance to gefitinib in NSCLC cell lines and NSCLC patients, but does not seem to play a role in the intrinsic resistance to this drug. High total-IGF-1R and p-IGR-1R levels may predict such a resistance. Since the underlying mechanism does not appear to be related to proliferation induction, alternative pathways should be explored.

Our goals were to study the molecular epidemiology and antimicrobial susceptibilities of C. difficile strains in Israel. Microbiology laboratories serving 6 general hospitals (GH) and 10 long-term care facilities (LTCF) were asked to submit all stool samples in January-February 2014 that tested positive for C. difficile. Toxigenic C. difficile isolates were recovered in 208 out of 217 samples (95.8%), of which 50 (23.6%) were from LTCFs. Ribotype 027 was the most common type overall, identified in 65 samples (31.8%), and was the predominant strain in the 3 GHs with the highest incidence of C. difficile infections. Other common strains were slpA types cr-02 (n = 45) and hr-02 (n = 18). The proportions of vancomycin and metronidazole MIC values >2mg/L were high in ribotype 027 (87.7% and 44.6%, respectively) and slpA-cr-02 strains (88.8% and 17.8%, respectively). This study demonstrates that the ribotype 027 strain has disseminated across Israel and is now the most common strain.

<h2>Abstract</h2><h3>Introduction</h3> Targeted therapy significantly prolongs survival in lung adenocarcinoma. Current diagnostic guidelines include only <i>EGFR</i> and anaplastic lymphoma receptor tyrosine kinase gene (<i>ALK</i>) testing. Next-generation sequencing (NGS) reveals more actionable genomic alterations than do standard diagnostic methods. Data on the influence of hybrid capture (HC)-based NGS on treatment are limited, and we investigated its impact on treatment decisions and clinical outcomes. <h3>Methods</h3> This retrospective study included patients with advanced lung cancer on whom HC-based NGS was performed between November 2011 and October 2015. Demographic and clinicopathologic characteristics, treatments, and outcome data were collected. <h3>Results</h3> A total of 101 patients were included (median age 63 years [53% females, 45% never-smokers, and 85% with adenocarcinoma]). HC-based NGS was performed upfront and after <i>EGFR/ALK</i> testing yielded negative or inconclusive results in 15% and 85% of patients, respectively. In 51.5% of patients, HC-based NGS was performed before first-line therapy, and in 48.5%, it was performed after treatment failure. HC-based NGS identified clinically actionable genomic alterations in 50% of patients, most frequently in <i>EGFR</i> (18%), Ret proto-oncogene (<i>RET</i>) (9%), <i>ALK</i> (8%), Mesenchymal-epithelial transition factor (<i>MET</i>) receptor tyrosine kinase gene (6%), and erb-b2 receptor tyrosine kinase 2 gene (<i>ERBB2</i>) (5%). In 15 patients, it identified <i>EGFR</i>/<i>ALK</i> aberrations after negative results of prior standard testing. Treatment strategy was changed for 43 patients (42.6%). The overall response rate in these patients was 65% (complete response 14.7%, partial response 50%). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without an actionable driver, with a presenting disease control rate of 32%, and with an association with tumor mutation burden. <h3>Conclusions</h3> HC-based NGS influenced treatment decisions in close to half of the patients with lung adenocarcinoma and was associated with an overall response rate of 65%, which may translate into a survival benefit.

Early detection of lung cancer (LC) has been well established as a significant key point in patient survival and prognosis. New highly sensitive nanoarray sensors for exhaled volatile organic compounds that have been developed and coupled with powerful statistical programs may be used when diseases such as LC are suspected. Detection of genetic aberration mutation by nanoarray sensors is the next target.Breath samples were taken from patients who were evaluated for suspicious pulmonary lesions. Patients were classified as those with benign nodules, as patients with LC with or without the EGFR mutation, and according to their smoking status. Breath prints were recognized by nanomaterial-based sensor array, and pattern recognition methods were used.A total of 119 patients participated in this study, 30 patients with benign nodules and 89 patients with LC (16 with early disease and 73 with advanced disease). Patients with LC who harbored the EGFR mutation (n = 19) could be discriminated from those with wild-type EGFR (n = 34) with an accuracy of 83%, sensitivity of 79%, and specificity of 85%. Discrimination of early LC from benign nodules had 87% accuracy and positive and negative predictive values of 87.7 and 87.5% respectively. Moderate discrimination (accuracy of 76%) was found between LC of heavy smokers and that of never-smokers or distant past light smokers.Breath analysis could discriminate patients with LC who harbor the EGFR mutation from those with wild-type EGFR and those with benign pulmonary nodules from those patients with early LC. A positive breath print for the EGFR mutation may be used in treatment decisions if tissue sampling does not provide adequate material for definitive mutation analysis.

Lung cancer is the leading cause of cancer death worldwide. Age and smoking are the primary risk factors for lung cancer. Treatment based on surgical removal in the early stages of the disease results in better survival. Screening programmes for early detection that used chest radiography and sputum cytology failed to attain reduction of lung cancer mortality. Screening by low-dose computed tomography (CT) demonstrated high rates of early-stage lung cancer detection in a high-risk population. Nevertheless, no mortality advantage was manifested in small randomised control trials. A large randomised control trial in the U.S.A., the National Lung Screening Trial (NLST), showed a significant relative reduction of 20% in lung cancer mortality and 6.7% reduction in total mortality, yet no reduction was evidenced in the late-stage prevalence. Screening for lung cancer by low-dose CT reveals a high level of false-positive lesions, which necessitates further noninvasive and invasive evaluations. Based primarily on the NLST eligible criteria, new guidelines have recently been developed by major relevant organisations. The overall recommendation coming out of this collective work calls for lung cancer screening by low-dose CT to be performed in medical centres manned by specialised multidisciplinary teams, as well as for a mandatory, pre-screening, comprehensive discussion with the patient about the risks and advantages involved in the process. Lung cancer screening is on the threshold of a new era, with ever more questions still left open to challenge future studies.

In lung cancer, the prognosis and treatment options depend directly on tumor size and its spread at the time of diagnosis. There is therefore a constant search for methods that will allow early detection of cancerous lung nodules. With advancing imaging technology and implantation of screening routines in high-risk populations by low-dose computerized tomography, a significant increase in the number of diagnosed small peripheral lesions can be expected. While early detection of small cancerous lesions carries the benefit of wider treatment options and better prognosis, the process of obtaining a biopsy to confirm a cancerous tissue is not free of complications and bears inconveniences and stress to the patient. This review discusses the potential use of exhaled breath analysis as a simple, noninvasive tool for early detection of lung cancer and characterization of suspicious lung nodules.

Whether differences exist in male and female lumbar lordosis has been debated by researchers who are divided as to the nature of variations in the spinal curve, their origin, reasoning, and implications from a morphological, functional and evolutionary perspective. Evaluation of the spinal curvature is constructive in understanding the evolution of the spine, as well as its pathology, planning of surgical procedures, monitoring its progression and treatment of spinal deformities. The aim of the current study was to revisit the nature of lumbar curve in males and females.Our new automated method uses CT imaging of the spine to measure lumbar curvature in males and females. The curves extracted from 158 individuals were based on the spinal canal, thus avoiding traditional pitfalls of using bone features for curve estimation. The model analysis was carried out on the entire curve, whereby both local and global descriptors were examined in a single framework. Six parameters were calculated: segment length, curve length, curvedness, lordosis peak location, lordosis cranial peak height, and lordosis caudal peak height.Compared to males, the female spine manifested a statistically significant greater curvature, a caudally located lordotic peak, and greater cranial peak height. As caudal peak height is similar for males and females, the illusion of deeper lordosis among females is due partially to the fact that the upper part of the female lumbar curve is positioned more dorsally (more backwardly inclined).Males and females manifest different lumbar curve shape, yet similar amount of inward curving (lordosis). The morphological characteristics of the female spine were probably developed to reduce stress on the vertebral elements during pregnancy and nursing.

Abstract Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Several studies in animal models and human with obstructive sleep apnea syndrome (OSAS) demonstrated an increase in cancer aggressiveness and mortality. However, there is a need for further clinical evidence supporting a correlation between OSAS and cancer incidence. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; To reveal whether OSAS presence and severity is correlated with cancer incidence in a large homogenous patients’ cohort. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We analyzed a cohort of over 5,000 concurrently enrolled patients, age &amp;#x3e; 18, with suspected OSAS, from a tertiary medical academic center. Patients underwent whole night polysomnography, the gold standard diagnostic tool for OSAS, and were classified for severity according to the Apnea Hypopnea Index (AHI). Data on cancer incidence were obtained from the Israel National Cancer Registry. A multivariate Cox proportional-hazards analysis, adjusted for age, gender, and BMI, was performed to estimate the hazard-ratio of new cancer incidence. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Among 5,243 subjects with a median follow-up of 5.9 years, 265 were diagnosed with cancer. The most prevalent cancers were prostate (14.7%), hematological (12.8%), urothelial (9.4%), colorectal (9%), and breast (8.3%). In subjects who were diagnosed at age below 45 years (&lt;i&gt;n&lt;/i&gt; = 1,533), a high AHI (&amp;#x3e; 57/h) was significantly associated with cancer (HR 3.7, CI 1.12–12.45, &lt;i&gt;p&lt;/i&gt; = 0.008). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Patients younger than 45 with severe OSAS have a significantly higher all-type cancer incidence than the general population. These results should encourage clinicians to detect and diagnose young patients with suspected OSAS and to recommend cancer screening methods in this high-risk population.

Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was demonstrated in the National Lung Screening Trial (NLST) to reduce mortality from the disease. European mortality data has recently become available from the Nelson randomised controlled trial, which confirmed lung cancer mortality reductions by 26% in men and 39-61% in women. Recent studies in Europe and the USA also showed positive results in screening workers exposed to asbestos. All European experts attending the "Initiative for European Lung Screening (IELS)"-a large international group of physicians and other experts concerned with lung cancer-agreed that LDCT-LCS should be implemented in Europe. However, the economic impact of LDCT-LCS and guidelines for its effective and safe implementation still need to be formulated. To this purpose, the IELS was asked to prepare recommendations to implement LCS and examine outstanding issues. A subgroup carried out a comprehensive literature review on LDCT-LCS and presented findings at a meeting held in Milan in November 2018. The present recommendations reflect that consensus was reached.

Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown.Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278).Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0-57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6-5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1).In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.

Electrical neuromodulation via implanted electrodes is used in treating numerous neurological disorders, yet our knowledge of how different brain regions respond to varying stimulation parameters is sparse.We hypothesized that the neural response to electrical stimulation is both region-specific and non-linearly related to amplitude and frequency.We examined evoked neural responses following 400 ms trains of 10-400 Hz electrical stimulation ranging from 0.1 to 10 mA. We stimulated electrodes implanted in cingulate cortex (dorsal anterior cingulate and rostral anterior cingulate) and subcortical regions (nucleus accumbens, amygdala) of non-human primates (NHP, N = 4) and patients with intractable epilepsy (N = 15) being monitored via intracranial electrodes. Recordings were performed in prefrontal, subcortical, and temporal lobe locations.In subcortical regions as well as dorsal and rostral anterior cingulate cortex, response waveforms depended non-linearly on frequency (Pearson's linear correlation r < 0.39), but linearly on current (r > 0.58). These relationships between location, and input-output characteristics were similar in homologous brain regions with average Pearson's linear correlation values r > 0.75 between species and linear correlation values between participants r > 0.75 across frequency and current values per brain region. Evoked waveforms could be described by three main principal components (PCs) which allowed us to successfully predict response waveforms across individuals and across frequencies using PC strengths as functions of current and frequency using brain region specific regression models.These results provide a framework for creation of an atlas of input-output relationships which could be used in the principled selection of stimulation parameters per brain region.

There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy.To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy.We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed.The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36).VTE rates were higher among NSCLC patients treated with platinum-based chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted.

We provide an update on the epidemiology of shigellosis in Israel using data generated by a sentinel laboratory-based surveillance network for the period 1998-2012. The average annual incidence of culture-proven shigellosis was 97/100 000. We estimated that each case of shigellosis accounted for 25 cases in the community indicating the high burden of disease. Orthodox Jewish communities, living in highly crowded conditions and with a high number of children aged <5 years were the epicentre of country-wide biennial propagated epidemics of S. sonnei shigellosis. S. flexneri was the leading Shigella serogroup in Israeli Arabs. S. flexneri 2a and S. flexneri 6 alternated as the most common serotypes. Both S. sonnei and S. flexneri isolates showed high rates of resistance to ampicillin and trimethoprim/sulfamethoxazole and very low rates of resistance to quinolones and third-generation cephalosporins. Shigellosis due to S. sonnei conferred 81% (95% confidence interval 69-89) protection against the homologous Shigella serotype when epidemic exposure re-occurred 2 years later. These data are of value in the process of Shigella vaccine development.

Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRASV12 mutation, knockdown of TP53 or both with parental HBEC cells. VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC–MS) or sensor array with discriminant factor analysis (DFA). In TD-GC–MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80–100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%. Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC–MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

We present the case of a patient with multiple EGFR mutations that highlights tumor heterogeneity leading to a mixed response to osimertinib and emphasizes the complexity of EGFR-driven lung cancer. Subclonal tumor evolution was proved by tissue biopsy, monitored by serial analyses of cell-free circulating tumor DNA (cfDNA) at disease progression, and addressed using EGFR tyrosine kinase inhibitor (TKI) combination therapy.

IntroductionNext-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables noninvasive genomic analysis of NSCLC patients. Although plasma-detected genomic alterations (GAs) have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decisions.MethodsThis retrospective study of stage IIIB/IV NSCLC patients between the years 2014 and 2017 in Israel used cfDNA NGS (Guardant360; Guardant Health, Inc., Redwood City, California) to identify targetable GAs.ResultsWe consecutively tested 116 NSCLC patients, 41.4% before first-line therapy (group A), 34.5% upon progression on chemotherapy or immunotherapy (group B1), and 24.1% upon progression on EGFR tyrosine kinase inhibitors (group B2). Targetable GAs were found in 31% of group A (15 of 48 patients), 32.5% in group B1 (13 of 40 patients) and 71% in group B2 (20 of 28 patients). Treatment decision was changed to targeted therapy in 23% (11 of 48 patients), 25% (10 of 40 patients) and 32% (9 of 28 patients), respectively (total cohort 26%; 30/116). Objective response rate (Response Evaluation Criteria in Solid Tumors) was 43% (12 of 28 patients) including one complete response, partial response in 39% (11 of 28 patients), stable disease in 32% (9 of 28 patients), and progressive disease in 25% (7 of 28 patients). Disease control rate was 75% for 5 months median treatment duration.ConclusionsComprehensive cfDNA testing impacted clinical decisions in one-quarter to one-third of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.

Major guidelines do not recommend routine molecular profiling of lung squamous-cell carcinoma (LUSC) because the prevalence of actionable alterations is thought to be low. Increased utilization of next-generation sequencing (NGS), particularly with cell-free circulating tumor DNA, facilitates reevaluation of this premise. PATIENTS AND METHODS: We retrospectively evaluated the prevalence of actionable alterations in 2 distinct LUSC cohorts totaling 492 patients. A total of 410 consecutive patients with stage 3B or 4 LUSC were tested with a targeted cell-free circulating DNA NGS assay, and 82 patients with LUSC of any stage were tested with a tissue NGS cancer panel.In the overall cohort, 467 patients (94.9%) had a diagnosis of LUSC, and 25 patients (5.1%) had mixed histology with a squamous component. A total of 10.5% of the LUSC subgroup had somatic alterations with therapeutic relevance, including in EGFR (2.8%), ALK/ROS1 (1.3%), BRAF (1.5%), and MET amplification or exon 14 skipping (5.1%). Sixteen percent of patients with mixed histology had an actionable alteration. In the LUSC subgroup, 3 evaluable patients were treated with targeted therapy for an actionable alteration; all of them experienced partial response.In this large, real-world LUSC cohort, we observed a clinically significant prevalence of actionable alterations. Accurate local histopathologic assessment in advanced-stage LUSC can be challenging. Further evaluation of the genomic landscape in this setting is warranted to potentially identify underappreciated treatment options.

Abstract Objective . Here, our objective was to develop a binary decoder to detect task engagement in humans during two distinct, conflict-based behavioral tasks. Effortful, goal-directed decision-making requires the coordinated action of multiple cognitive processes, including attention, working memory and action selection. That type of mental effort is often dysfunctional in mental disorders, e.g. when a patient attempts to overcome a depression or anxiety-driven habit but feels unable. If the onset of engagement in this type of focused mental activity could be reliably detected, decisional function might be augmented, e.g. through neurostimulation. However, there are no known algorithms for detecting task engagement with rapid time resolution. Approach . We defined a new network measure, fixed canonical correlation (FCCA), specifically suited for neural decoding applications. We extracted FCCA features from local field potential recordings in human volunteers to give a temporally continuous estimate of mental effort, defined by engagement in experimental conflict tasks. Main results . Using a small number of features per participant, we accurately decoded and distinguished task engagement from other mental activities. Further, the decoder distinguished between engagement in two different conflict-based tasks within seconds of their onset. Significance . These results demonstrate that network-level brain activity can detect specific types of mental efforts. This could form the basis of a responsive intervention strategy for decision-making deficits.

Lung cancer remains a major cause of death worldwide. While in the past it was considered to primarily afflict males, in recent decades the number of female patients has risen, such that rates among females are similar to those among males. Nevertheless, it has been found previously (e.g., in cardiovascular disease) that when there is a sex-specific stereotype to a disease, it may remain entrenched in medical diagnostic processes, so as to cause belated diagnosis among the other sex. Gender-based differences in incidence and diagnosis are likely to exist with respect to lung cancer because of smoking habits and stereotypes, geographic and socioeconomic differences, and past epidemiologic differences between the sexes. Here we aim to characterize the effects of gender on lung cancer diagnosis and whether such effects have changed over time. The SEER (Statistics, Epidemiology, and End Results) database was used to check for sex-based differences by tumor type and stage at diagnosis and to investigate whether these patterns have changed with time by comparing staging data in different age cohorts over time. Results were stratified by location and analyzed with data regarding possible confounders such as smoking and socioeconomic factors. We examined 458,132 cases of lung cancer from the years 2004–2012; 243,021 (53%) in males and 215,111 (47%) in females. Lung cancer rates were 73.8 (73.5–74.1) per 100k in males and 51.6 (51.4–51.8) per 100k in females. Of these, 400,800 had the stage listed, 214,479 (54%) in males, and 186,321 (46%) in females. Total lung cancer rates were higher in males than females at all disease stages. Male patients were more likely than female patients to be diagnosed at stage 3–4, consistent across lung cancer types, cancer registries, smoking, and socioeconomic backgrounds. The difference between the percentage of males versus females diagnosed in stages 3–4 correlated negatively with increased female ever-smokers and with squamous and small cell carcinoma and were not correlated with the rate of cancer in females, or the difference between male and female cancer rates. Our study showed that there is no belated diagnosis of lung cancer in females. Results appear to point to the fact that smoking females are more likely to be diagnosed at later stages, which is consistent with the current literature.

The COVID-19 pandemic, caused by the SARS-CoV2 virus, has infected millions worldwide with cancer patients demonstrating a higher prevalence for severe disease and poorer outcomes. Recently, the BNT162b2 mRNA COVID-19 vaccine was released as the primary means to combat COVID-19. The currently reported incidence of local and systemic side effects was 27% in the general public. The safety of the BNT162b2 mRNA COVID-19 vaccine has not been studied in patients with an active cancer diagnosis who are either ongoing or plan to undergo oncologic therapy.This single center study reviewed the charts of 210 patients with active cancer diagnoses that received both doses of the BNT162b2 mRNA COVID-19 vaccine. The development of side effects from the vaccine, hospitalizations or exacerbations from various oncologic treatment were documented. Type of oncologic treatment (immunotherapy, chemotherapy, hormonal, biologic, radiation or mixed) was documented to identify if side effects were related to treatment type. The time at which the vaccine was administered in relation to treatment onset (on long term therapy, within 1 month of therapy or prior to therapy) was also documented to identify any relationships.Sixty five (31%) participants experienced side effects from the BNT162b2 mRNA COVID-19 vaccine, however most were mild to moderate. Treatment protocol was not linked to the development of vaccine related side effects (P = .202), nor was immunotherapy (P = .942). The timing of vaccine administered in relation to treatment onset was also not related to vaccine related side effects (P = .653). Six (2.9%) participants were hospitalized and 4 (2%) died.The incidence of side effects in cancer patients is similar to what has been reported for the general public (31% vs 27%). Therefore, we believe that the BNT162b2 mRNA COVID-19 vaccine is safe in oncologic patients undergoing numerous cancer treatments.

Cancer cells prefer hyperglycolysis versus oxidative phosphorylation, even in the presence of oxygen. This phenomenon is used through the FDG-PET scans, and may affect the exhaled volatile signature. This study investigates the volatile signature in lung cancer (LC) before and after an oral glucose tolerance test (OGTT) to determine if tumor cells' hyperglycolysis would affect the volatile signature. Blood glucose levels and exhaled breath samples were analyzed before the OGTT, and 90 min after, in both LC patients and controls. The volatile signature was measured by proton transfer reaction mass spectrometry (PTR-MS). Twenty-two LC patients (age 66.6 ± 12.7) with adenocarcinoma (n = 14), squamous (n = 6), small cell carcinoma (n = 2), and twenty-one controls (age 54.4 ± 13.7; 10 non-smokers and 11 smokers) were included. All LC patients showed a hyperglycolytic state in their FDG-PET scans. Both baseline and post OGTT volatile signatures discriminate between the groups. The OGTT has a minimal effect in LC (a decrease in m/z 54 by 39%, p v = 0.0499); whereas in the control group, five masses (m/z 64, 87,88, 142 and 161) changed by -13%, -49%, -40% and -29% and 46% respectively. To conclude, OGTT has a minimal effect on the VOC signature in LC patients, where a hyperglycolytic state already exists. In contrast, in the control group the OGTT has a profound effect in which induced hyperglycolysis significantly changed the VOC pattern. We hypothesized that a ceiling effect in cancerous patients is responsible for this discrepancy.

Lung cancer (LC) is the leading cause of cancer mortality worldwide. Despite advances in the treatment strategy, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy, 5-year survival is estimated as 9% to 20%.1,2 During the past decade, LC incidence has been increasing and age at the time of diagnosis continues to decrease.3,4 Median age at diagnosis is 70 years, and approximately 13% of all patients with LC are younger than age 50 years. Numerous studies have suggested that LC in young patients constitutes an entity with unique characteristics, such as a higher percentage of female patients, a lower rate of smoking history, a higher percentage of family history of LC, a higher rate of adenocarcinoma histology, and more advanced stage at diagnosis.5-13 However, it is still controversial whether youthful patients with LC have better or worse outcomes.14-16 In addition, most of the literature regarding young patients is associated with Asian cohorts, whereas less data about white communities are available. Currently, a considerable percentage of patients with non–small-cell lung cancer (NSCLC) benefit from personalized therapy protocols that are based on the genomic profile of tumors.17,18 Mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes affect the prognosis of patients. Recent studies have shown that young patients with NSCLC harbor more driver mutations than older patients. The rate of mutations documented in the young white population varies between articles and is approximately 20% to 30% for EGFR mutation and 10% to 20% for ALK rearrangement.17-19 There are conflicting data on whether younger patients with NSCLC achieve better or worse outcomes compared with the older population, yet most studies show that younger patients have better survival rates.7-10 Identifying the clinicopathologic characteristics and making appropriate proactive molecular profiling of the youthful population can guide treatment strategy in the clinical setting. Therefore, in the current study, we carried out a comprehensive analysis of patient clinicopathologic features and clinical outcomes in both young (age ≤ 50 years) and older (age > 60 years) patients with NSCLC.

Neuromodulation is a promising treatment modality for disorders of learning and memory, offering the possibility of precise alteration of disordered neural circuits. Studies to date have failed to identify an optimal target and stimulation paradigm. Six epilepsy patients with depth electrodes implanted for seizure localization participated in our study. We recorded local field potentials from implanted electrodes while subjects participated in an associative learning task requiring them to learn an association between presented images and a button press. Three subjects participated in stimulation sessions during which caudate or putamen stimulation was delivered for some images during feedback after correct responses. Caudate stimulation enhanced learning. Both caudate and dorsolateral prefrontal cortex demonstrated a beta power increase during the feedback period of the learning task that was greater following correct than incorrect trials. In dorsolateral prefrontal cortex, this difference increased with learning and persisted beyond the end of the feedback period. Caudate stimulation was associated with increased dorsolateral prefrontal cortex beta power following feedback. These findings suggest that temporally specific caudate stimulation is a promising neuromodulation strategy to improve learning in disorders of learning and memory.

Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive-compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.

Resistance mechanisms following 1st line therapy with osimertinib in EGFR + NSCLC have become focus of investigation. This retrospective study aims to deepen the understanding and clarify possible mechanisms of osimertinib 1st line resistance in comparison to the 2nd line by examining NGS results of 30 patients who developed resistance to osimertinib. Furthermore, we followed clinical outcomes of select patients who received combined therapy following EGFR resistance, a novel strategy not yet widely tested.Liquid biopsy technique (Guardant360) was used to monitor tumor dynamics in patients who were treated with osimertinib as 1st-line therapy (Group A, N = 15) and patients who received osimertinib as 2nd-line therapy (Group B, N = 15).At the time of progression under osimertinib all but one patient preserved the primary EGFR mutation. While the C797S mutation was relatively common in the 2nd-line osimertinib setting (5/15), it did not develop in group A patients. TP53 was the most common detected mutation among all patients accounting for 11/15 in group A (73.33 %) and 10/15 in group B (66.67 %). In group A MET amplification was found in 3/15 patients (20 %) whereas MET mutation appeared in only one patient from group B. The outcomes of different treatment approaches post osimertinib resistance is reported including chemotherapy with/without osimertinib for maintaining control of brain metastases, drug combination such as osimertinib with crizotinib, chemo-immunotherapy and others. Overall survival in this cohort ranged from 12 to80 months.Mechanisms of resistance to osimertinib as 1st-line therapy differ from those which develop in the 2nd-line setting and commonly include MET amplification. C797S is not a main resistance mechanism in the 1st-line setting, whereas it is more common in the 2nd-line setting. Combined therapy was effective and well tolerated, making it an acceptable choice in patients for whom there is a reasonable rationale for such treatment, however this approach deserves further investigation.

Seronegative spondyloarthritis (SpA) represents a group of diseases that share certain genetic, clinical, and radiographic features. Enthesitis, inflammation at the site of tendon insertion into the bone, involving both the axial and the peripheral joints, is an important sign of SpA. Clinical diagnosis of enthesitis, however, is neither sensitive nor specific; thus, the diagnosis of enthesitis often relies on typical abnormalities in imaging studies. Due to its low costs and availability, ultrasound is emerging as the preferred technique for detection of enthesitis for both clinical and research purposes. Ultrasonographic features of enthesitis include tendon hypoechogenicity and thickening, calcifications, bone erosions, and Doppler signal. Several semi-quantitative scoring systems have been developed to quantify ultrasonographic abnormalities of the entheses. These methods have been used for early diagnosis and classification of SpA as well as for monitoring response to treatment.

Abstract Purpose: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non–small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation. Experimental Design: A large pool of NSCLC cases was assayed with well-validated, hybrid capture–based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Δex19) were identified, and available clinical history was reviewed. Results: Pathology reports were available for 250 consecutive cases with classical EGFR Δex19 (amino acids 743–754) and were reviewed to assess previous non-hybrid capture–based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR Δex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed. Conclusions: CGP identifies drug-sensitive EGFR Δex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative. Clin Cancer Res; 22(13); 3281–5. ©2016 AACR.

The condition of paraspinal muscles is known to be associated with some variables such as age, gender, and low back pain. It is generally agreed that these muscles play an important role in the stability and functional movements of the lumbar vertebral column. Although spinal instability has been shown to play an essential role in degenerative lumbar spinal stenosis (DLSS), the role of paraspinal muscles remains elusive. The main purpose of this study was to shed light on the relationship between the condition of paraspinal muscles and symptomatic DLSS.Two sample populations were studied. The first included 165 individuals with DLSS (age range: 40-88, sex ratio: 80 M/85 F) and the second 180 individuals without spinal stenosis related symptoms and low back pain (age range: 40-99, sex ratio: 90 M/90 F). Measurements were taken at the middle part of L3 vertebral body, using CT axial images (Philips Brilliance 64). Muscles density was measured in Hounsfield units (HU) using a 50 mm2 circle of the muscle mass at three different locations and the mean density was then calculated. The cross-sectional area (CSA) was also measured using the quantitative CT angiography method. Analysis of Covariance (adjusted for body mass index and age) was performed in order to determine the relationship between the condition of paraspinal muscles and symptomatic DLSS.Individuals in the stenosis group had higher muscle density as compared to the control group. The CSA values for the erector spinae (both sexes) and psoas (males) muscles were significantly greater in the stenosis group as compared to their counterparts in the control group. Additionally, density of multifidus (both sexes) and erector spinae (males) muscles was significantly associated with symptomatic DLSS.Our results show that individuals with symptomatic DLSS manifest greater paraspinal muscles density and CSA (erector spinae), compared to the control group. Density of multifidus increases the likelihood of symptomatic DLSS.

To determine the effect of continuous positive airway pressure (CPAP) on tumor motion, lung volume, and dose to critical organs in patients receiving stereotactic body radiation therapy (SBRT) for lung tumors.After institutional review board approval in December 2013, patients with primary or secondary lung tumors referred for SBRT underwent 4-dimensional computed tomographic simulation twice: with free breathing and with CPAP. Tumor excursion was calculated by subtracting the vector of the greatest dimension of the gross tumor volume (GTV) from the internal target volume (ITV). Volumetric and dosimetric determinations were compared with the Wilcoxon signed-rank test. CPAP was used during treatment if judged beneficial.CPAP was tolerated well in 10 of the 11 patients enrolled. Ten patients with 18 lesions were evaluated. The use of CPAP decreased tumor excursion by 0.5 ± 0.8 cm, 0.4 ± 0.7 cm, and 0.6 ± 0.8 cm in the superior-inferior, right-left, and anterior-posterior planes, respectively (P ≤ .02). Relative to free breathing, the mean ITV reduction was 27% (95% confidence interval [CI] 16%-39%, P<.001). CPAP significantly augmented lung volume, with a mean absolute increase of 915 ± 432 cm(3) and a relative increase of 32% (95% CI 21%-42%, P=.003), contributing to a 22% relative reduction (95% CI 13%-32%, P=.001) in mean lung dose. The use of CPAP was also associated with a relative reduction in mean heart dose by 29% (95% CI 23%-36%, P=.001).In this pilot study, CPAP significantly reduced lung tumor motion compared with free breathing. The smaller ITV, the planning target volume (PTV), and the increase in total lung volume associated with CPAP contributed to a reduction in lung and heart dose. CPAP was well tolerated, reproducible, and simple to implement in the treatment room and should be evaluated further as a novel strategy for motion management in radiation therapy.

Objective Familial Mediterranean fever ( FMF ) is an autoinflammatory disease manifested as recurrent serosal inflammation. An association between FMF and malignancy has not been evaluated. The aim of this study was to estimate cancer risk in a large cohort of FMF patients from a single institution. Methods The study cohort consisted of 8,534 FMF patients registered at the National FMF Center in Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and then stratified by age and sex. Standardized incidence ratios ( SIR s) for cancers were calculated. Results Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970–2011. The overall cancer risk among patients with FMF was significantly lower than was expected in specific sex and ethnic groups of the Israeli population: for males of Jewish ethnicity, SIR 0.66 (95% confidence interval [95% CI ] 0.55–0.77), P &lt; 0.001; for females of Jewish ethnicity, SIR 0.75 (95% CI 0.64–0.86), P &lt; 0.001; and for males of Arab ethnicity, SIR 0.34 (95% CI 0.07–0.99), P = 0.024. Conclusion FMF patients have a significantly lower incidence of cancer than the general population of Israel. This pattern was demonstrated in 2 ethnic populations: Jewish and Arab. We speculate that the lower cancer incidence could be attributed to a direct physiologic effect of FMF or to its treatment.

Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 BRAF alterations in lung cancer.A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements.Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations (P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated.This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.

Discovering the volatile signature of cancer cells is an emerging approach in cancer research, as it may contribute to a fast and simple diagnosis of tumors in vivo and in vitro. One of the main contributors to such a volatile signature is hyperglycolysis, which characterizes the cancerous cell. The metabolic perturbation in cancer cells is known as the Warburg effect; glycolysis is preferred over oxidative phosphorylation (OXPHOS), even in the presence of oxygen. The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. We aimed to profile the volatile signature of the glycolysis activity in lung cancer cells. For that an in vitro model, using lung cancer cell line cultures (A549, H2030, H358, H322), was developed. The volatile signature was measured by proton transfer reaction mass spectrometry under normal conditions and glycolysis inhibition. Glycolysis inhibition and mitochondrial activity were also assessed by mitochondrial respiration capacity measurements. Cells were divided into two groups upon their glycolytic profile (PET positive and PET negative). Glycolysis blockade had a unique characteristic that was shared by all cells. Furthermore, each group had a characteristic volatile signature that enabled us to discriminate between those sub-groups of cells. In conclusion, lung cancer cells may have different subpopulations of cells upon low and high mitochondrial capacity. In both groups, glycolysis blockade induced a unique volatile signature.

Cognitive processes, such as learning and cognitive flexibility, are both difficult to measure and to sample continuously using objective tools because cognitive processes arise from distributed, high-dimensional neural activity. For both research and clinical applications, that dimensionality must be reduced. To reduce dimensionality and measure underlying cognitive processes, we propose a modeling framework in which a cognitive process is defined as a low-dimensional dynamical latent variable-called a cognitive state, which links high-dimensional neural recordings and multidimensional behavioral readouts. This framework allows us to decompose the hard problem of modeling the relationship between neural and behavioral data into separable encoding-decoding approaches. We first use a state-space modeling framework, the behavioral decoder, to articulate the relationship between an objective behavioral readout (e.g., response times) and cognitive state. The second step, the neural encoder, involves using a generalized linear model (GLM) to identify the relationship between the cognitive state and neural signals, such as local field potential (LFP). We then use the neural encoder model and a Bayesian filter to estimate cognitive state using neural data (LFP power) to generate the neural decoder. We provide goodness-of-fit analysis and model selection criteria in support of the encoding-decoding result. We apply this framework to estimate an underlying cognitive state from neural data in human participants (N=8) performing a cognitive conflict task. We successfully estimated the cognitive state within the 95% confidence intervals of that estimated using behavior readout for an average of 90% of task trials across participants. In contrast to previous encoder-decoder models, our proposed modeling framework incorporates LFP spectral power to encode and decode a cognitive state. The framework allowed us to capture the temporal evolution of the underlying cognitive processes, which could be key to the development of closed-loop experiments and treatments.

Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib. Methods 123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria. Results 106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK(+) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 ± 1.6 months and median overall survival (mOS) was 89.1 ± 19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1 ± 2.5 months and mOS of 90.3 ± 24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters. The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1–2 were reported in 18 % of patients. Conclusion Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 ± 19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 ± 24 months is unprecedented for ROS1(+) NSCLC.

Lung cancer has historically been the main responsible for cancer associated deaths.Owing to this is our current inability to screen for and diagnose early pathological findings, preventing us from a timely intervention when cure is still achievable.Over the last decade, together with the extraordinary progress in therapeutical alternatives in the field, there has been an ongoing search for a biomarker that would allow for this.Numerous technologies have been developed but their clinical application is yet to come.In this review, we provide an update on volatile organic compounds, a non-invasive method that can hold the key for detecting early metabolic pathway changes in carcinogenesis.For its compilation, web-based search engines of scientific literature such as PubMed were explored and reviewed, using articles, research, and papers deemed meaningful by authors discretion.After a brief description, we depict how this technique can complement current methods and present the value of electronic noses in the identification of the "breathprint".Lastly, we bring some of the latest updates in the field together with the current limitations and final remarks.

The echinoderm microtubule–associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion occurs in 2% to 7% of non–small-cell lung cancer cases.1Kwak EL Bang YJ Camidge DR et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010; 363: 1693-1703Crossref PubMed Scopus (3812) Google Scholar Tumors expressing this fusion respond to treatment with crizotinib, an ALK tyrosine kinase inhibitor. However, brain metastases frequently occur, even in the presence of systemic response to therapy.2Chun SG Choe KS Iyengar P Yordy JS Timmerman RD Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.Cancer Biol Ther. 2012; 13: 1376-1383Crossref PubMed Scopus (90) Google Scholar A 45-year-old never-smoker man who was previously reported in this journal,3Peled N Palmer G Hirsch FR et al.Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer.J Thorac Oncol. 2012; 7: e14-e16Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar is presented here again for a dramatic response to brain metastases. Previously, he was presented for having abnormality in RNA editing for ALK gene and a complete response to crizotinib 250 mg twice daily therapy. He was diagnosed as harboring EML4-ALK rearrangement through abnormal ALK immunohistochemistry staining and breakpoints in ALK intron 19, detected by next-generation sequence. ALK fluorescence in situ hybridization result was falsely negative. After a follow-up of 20 months, the patient developed asymptomatic milliary spread of brain metastases without any other evidence for active disease and he was treated by whole-brain radiotherapy (WBRT; 30 Gy). Crizotinib was stopped for the radiation period and readministered thereafter in the previous standard schedule of 250 mg twice daily. A follow-up magnetic resonance imaging 3 months later showed lack of response and new brain lesions. Aiming to increase crizotinib brain penetration, we rescheduled crizotinib therapy to a single-day administration of 500 mg every day (morning). Brain magnetic resonance imaging in 2 months showed a dramatic response and elimination of 90% of the brain lesions (Fig. 1). Positron emission tomography computed tomography showed no evidence of active disease elsewhere. Brain metastases are the Achilles’ heel of non–small-cell lung cancer with EML4-ALK translocation.2Chun SG Choe KS Iyengar P Yordy JS Timmerman RD Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.Cancer Biol Ther. 2012; 13: 1376-1383Crossref PubMed Scopus (90) Google Scholar However, there is growing data supporting a therapeutic benefit of crizotinib also in cases of brain metastases.4Kaneda H Okamoto I Nakagawa K Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer.J Thorac Oncol. 2013; 8: e32-e33Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In this case report, the brain metastases were developed under crizotinib therapy and have further shown resistance to WBRT, whereas it responded well to a different treatment schedule of crizotinib. Interestingly enough, Kaneda et al. have also shown a response to crizotinib therapy (standard dose) after a resistance to radiation.4Kaneda H Okamoto I Nakagawa K Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer.J Thorac Oncol. 2013; 8: e32-e33Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Other reports did not show a response to standard dose crizotinib specifically after WBRT.5Kim YH Ozasa H Nagai H et al.High-dose crizotinib for brain metastases refractory to standard-dose crizotinib.J Thorac Oncol. 2013; 8: e85-e86Crossref PubMed Scopus (35) Google Scholar Therefore we hypothesize that the drug penetration might not increase sufficiently on standard crizotinib schedule after WBRT and that increasing in the Cmax, without increasing the daily dose of 500 mg/day could be beneficial. A previous report demonstrated brain response after dose escalation up to 1000 mg/day, however, producing asymptomatic bradycardia of 39 beats per minute.5Kim YH Ozasa H Nagai H et al.High-dose crizotinib for brain metastases refractory to standard-dose crizotinib.J Thorac Oncol. 2013; 8: e85-e86Crossref PubMed Scopus (35) Google Scholar It is important to emphasize that the response might be a late benefit of WBRT and/or related to the increased permeability of the blood–brain barrier to crizotinib secondary to the WBRT. Further studies measuring crizotinib level in the cerebrospinal fluid are required to investigate this effect. In summary, this case report suggests increasing crizotinib schedule to a single administration of the standard daily dose (500 mg/day) for brain metastases may be an option when they have developed under crizotinib therapy, after conventional radiotherapy. This approach would warrant further evaluation, potentially delaying the need for second-generation inhibitors or other new therapies. The authors thank Dr. Shani Shilo for her assistance with this case report.

In Brief Study Design. A descriptive study of the association between demographic factors, and physical characteristics, and degenerative lumbar spinal stenosis (DLSS). Objective. To shed light on the association between socioeconomic parameters, physical characteristics, and DLSS. Summary of Background Data. Lumbar spinal stenosis is a prevalent and disabling condition in the aging population. DLSS is considered to be the most common type and is essentially associated with disc disease, facet joint arthrosis, ligamentum flavum thickening, and osteophyte formation. Although there is ample information regarding the association between body mass index, cardiovascular disorders, smoking habits, and disc disease, very little is known about their association with DLSS. Data on the association of body physique (e.g., height and weight) and DLSS are limited. Methods. Two sample populations were studied. The first included 165 individuals with DLSS (mean age, 64 ± 9.9 yr) and the second 180 individuals without spinal stenosis related symptoms (mean age, 62.5 ± 12.6 yr). An evaluation of the cross-sectional area of the dural sac and degenerative listhesis for all participants was performed using computed tomographic lumbar spine images, obtained by Philips EBW station (Brilliance 64, Philips Medical System, Cleveland, OH). All participants were interviewed to obtain demographic, physical, and health data. Independent t test, Mann-Whitney and χ2 tests were used to determine the association between parametric and nonparametric variables and DLSS. Logistic regression analysis was carried out to reveal predicting variables for DLSS. Results. Females with stenosis were significantly heavier and shorter than their counterparts in the control group. We also noticed that they delivered babies more often than those in the control group. Prevalence of individuals experiencing diabetes mellitus was significantly higher in the males with stenosis than control group. In the stenosis group, the frequencies of individuals engaged in heavy manual labor (males) and housekeeping (females) were significantly higher than that of their counterparts in the control group. Conclusion. Heavy manual labor and diabetes mellitus in males and housekeeping (females) play major roles in the genesis of DLSS. A descriptive study of the association between demographic factors and physical characteristics and degenerative lumbar spinal stenosis (DLSS). Females who underwent stenosis had a higher number of deliveries than the control group. DLSS is a smoking-independent phenomenon. Heavy manual labor and diabetes mellitus in males and housekeeping (females) play major roles in the genesis of DLSS.

Background RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. Materials and Methods We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. Results A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. Conclusion RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.

Existing methods for sorting, labeling, registering, and across-subject localization of electrodes in intracranial encephalography (iEEG) may involve laborious work requiring manual inspection of radiological images. We describe a new open-source software package, the interactive electrode localization utility which presents a full pipeline for the registration, localization, and labeling of iEEG electrodes from CT and MR images. In addition, we describe a method to automatically sort and label electrodes from subdural grids of known geometry. We validated our software against manual inspection methods in twelve subjects undergoing iEEG for medically intractable epilepsy. Our algorithm for sorting and labeling performed correct identification on 96% of the electrodes. The sorting and labeling methods we describe offer nearly perfect performance and the software package we have distributed may simplify the process of registering, sorting, labeling, and localizing subdural iEEG grid electrodes by manual inspection.

IntroductionLung cancer is the most common cancer worldwide. Latest guidelines from the College of American Pathologist and the European society of medical oncologists indicate anaplastic lymphoma kinase (ALK) rearrangement testing is standard practice. Historically, diagnostics for ALK used fluorescence in situ hybridisation (FISH); however, immunohistochemical (IHC) assays are becoming common practice. Unfortunately, recent assessment of current practice indicated that not all patients who should be tested for ALK translocation are undergoing ALK testing.MethodsFrom a series of European and Israeli labs, we collected patients with discordant IHC and FISH testing, which were subsequently treated with ALK-targeted therapy, for discussion of the question, to treat or not to treat?ResultsOur study may support ALK IHC testing as a better predictor of response to targeted therapy provided that the labs implement controlled preanalytical procedures, use correct clone, run protocols on automated staining platforms and validate using external quality assessments.

The aim of this study was to shed light on the association between lumbosacral transitional vertebra (LSTV) and degenerative lumbar spinal stenosis (DLSS). A cross-sectional retrospective study was performed on 165 individuals that were diagnosed with clinical picture of DLSS (age range: 40-88 years; sex ratio: 80M/85F) and 180 individuals without DLSS related symptoms (age range: 40-99 years; sex ratio: 90M/90F). All participants had undergone high-resolution CT scan for the lumbar region in the same position. We also used the volume rendering method to obtain three-dimensional CT images of the lumbosacral area. Both males and females in the stenosis group manifest greater prevalence of LSTV than their counterparts in the control group (P<0.001). Furthermore, the presence of LSTV increases the likelihood of degenerative spinal stenosis (odds ratio= 3.741, P<0.001). In the control group, LSTV was more common in males, and sacral slope angle of males was significantly greater in LSTV group compared to non-LSTV. This study indicates that LSTV was significantly associated with symptomatic DLSS.

Ictal electrographic patterns are widely thought to reflect underlying neural mechanisms of seizures. Here we studied the degree to which seizure patterns are consistent in a given patient, relate to particular brain regions and if two candidate biomarkers (high-frequency oscillations, HFOs; infraslow activity, ISA) and network activity, as assessed with cross-frequency interactions, can discriminate between seizure types. We analyzed temporal changes in low and high frequency oscillations recorded during seizures, as well as phase-amplitude coupling (PAC) to monitor the interactions between delta/theta and ripple/fast ripple frequency bands at seizure onset. Seizures of multiple electrographic patterns were observed in a given patient and brain region. While there was an increase in HFO rate across different electrographic patterns, there are specific relationships between types of HFO activity and onset region. Similarly, changes in PAC dynamics were more closely related to seizure onset region than they were to electrographic patterns while ISA was a poor indicator for seizure onset. Our findings suggest that the onset region sculpts neurodynamics at seizure initiation and that unique features of the cytoarchitecture and/or connectivity of that region play a significant role in determining seizure mechanism. To learn how seizures are initiated, researchers would do well to consider other aspects of their manifestation, in addition to their electrographic patterns. Examination of onset pattern in conjunction with the interactions between different oscillatory frequencies in the context of different brain regions might be more informative and lead to more reliable clinical inference as well as novel therapeutic approaches.

The aim of this study is to establish whether facet tropism (FT) and orientation (FO) are associated with degenerative lumbar spinal stenosis (DLSS). A retrospective computerized tomography (CT) study including 274 individuals was divided into two groups: control (82 males and 81 females) and stenosis (59 males and 52 females). All participants have undergone high-resolution CT scan of the lumbar spine in the same position. FT and FO were measured at L1-2 to L5-S1. Significant sagittal FO was noted in the stenosis males (L2-3 to L4-5) and females (L2-3 to L5-S1) compared to the controls. The prevalence of FT was remarkably greater in the stenosis males (L4-5, L5-S1) and females (L3-4, L5-S1) compared to their counterparts in the control group. Our results also showed that FT (L3-4 to L5-S1) increases approximately 2.9 times the likelihood for DLSS development. This study indicates that FO and FT in the lower lumbar spine are significantly associated with DLSS.

Abstract Objectives: According to the “brain reserve hypothesis,” a larger premorbid brain protects against the development of dementia. The aim of this study was to reveal a possible pathophysiology of brain degenerative diseases by studying intracranial bone lesions that act to reduce intracranial volume (ICV), such as hyperostosis frontalis interna (HFI). Methods: Three hundred and eighty postmenopausal females (aged 60+) who had undergone a head computerized tomography scan (Brilliance 64, Philips Healthcare, Cleveland, OH) at the Carmel Medical Center, Haifa, Israel, before the study were included. The subjects were divided into four groups according to their degree of HFI. Six measurements of the skull and brain were taken. Results: As HFI becomes more severe, the cranial bone thickness and cranial bone volume increase. This process is accompanied by a decrease in ICV. In none of the HFI groups studied there was a significant association between ICV and cranial bone thickness. The inter‐relationships between the various thickness parameters are not disturbed by the degree of HFI. Conclusion: HFI is accompanied by an increase in thickness of all calvarial bones and reduced ICV. In addition, the thickening process initiated by HFI is synchronized among the calvarial bones. Presence of HFI suggests a decrease in brain volume and has a major clinical significance as it may indicate the beginning of degenerative processes of the brain. In addition, as females age, their skulls tend to develop more robust characteristics. Am. J. Hum. Biol. 2012. © 2012Wiley Periodicals, Inc.

Rapid changes in medical knowledge are forcing continuous adaptation of the basic science courses in medical schools. This article discusses a three‐year experience developing a new Computed Tomography (CT)‐based anatomy curriculum at the Sackler School of Medicine, Tel Aviv University, including describing the motivations and reasoning for the new curriculum, the CT‐based learning system itself, practical examples of visual dissections, and student assessments of the new curriculum. At the heart of this new curriculum is the emphasis on studying anatomy by navigating inside the bodies of various living individuals utilizing a CT viewer. To assess the students’ experience with the new CT‐based learning method, an anonymous questionnaire was administered at the end of the course for three consecutive academic years: 2008/2009, 2009/2010, 2010/2011. Based upon the results, modifications were made to the curriculum in the summers of 2009 and 2010. Results showed that: (1) during these three years the number of students extensively using the CT system quadrupled (from 11% to 46%); (2) students' satisfaction from radiologists involvement increased by 150%; and (3) student appreciation of the CT‐based learning method significantly increased (from 13% to 68%). It was concluded that discouraging results (mainly negative feedback from students) during the first years and a priori opposition from the teaching staff should not weaken efforts to develop new teaching methods in the field of anatomy. Incorporating a new curriculum requires time and patience. Student and staff satisfaction, along with utilization of the new system, will increase with the improvement of impeding factors. Anat Sci Educ 6: 332–341. © 2013 American Association of Anatomists.

Thymidine kinase 1 (TK1) is a metabolic enzyme involved in DNA synthesis. Most standard treatment protocols for lung cancer (LC) include cytotoxic agents, which are potential modulators of TK1. We aimed to assess the prognostic significance of serum TK1 activity and its role in monitoring chemotherapy in LC patients.TK1 activity was measured using the DiviTum (Biovica) assay in sera from 233 patients with non-small-cell lung cancer (NSCLC), 91 with small-cell lung cancer (SCLC), and 90 with benign lung disease.TK1 activity was significantly associated with age, performance status, and stage in NSCLC and with stage and weight loss in SCLC. In multivariate analysis, pretreatment TK1 activity, adjusted for performance status, stage, and weight loss, independently affected survival in NSCLC (relative risk =1.45, p = 0.031) and SCLC (relative risk = 2.49, p = 0.001). In NSCLC patients, adjusted elevated TK1 activity (>100 Du/L) at pretreatment was a significant predictor of treatment failure (odds ratio = 2.55, p = 0.01). A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was significantly associated with treatment failure and poor overall survival.Elevated pretreatment serum TK1 activity was an independent, adverse prognostic factor, based on survival, in the two main histological types of LC. A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was associated with treatment failure and poor overall survival.

Adenocarcinoma (AC) and squamous cell carcinoma (SCC), sub-types of non-small cell lung cancer (NSCLC), both present unique features at the genome, epigenome, transcriptome and proteome levels, as well as shared clinical and histopathological characteristics, but differ in terms of treatment.To ensure proper treatment, one must be able to distinguish between these sub-types.Here, we identify novel biomarker proteins in NSCLC, allowing for distinguishing between the AC and SCC sub-types.Proteomics analysis distinguished between healthy and tumor tissues, with the expression level of 1,494 proteins being altered, 378 of which showed a ≥|100|-fold change.Enrichment of proteins related to protein synthesis and degradation, and of proteins associated with mitochondria, metabolism, and apoptosis, was found.Network analysis defined groups of proteins, such as those associated with cell metabolic processes or with fatty acid/lipid metabolism and transport.Several biomarkers that enable for distinguishing between AC and SCC were identified here for the first time, and together with previous reports confirmed here, led us to propose a list of proteins differentially expressed in SCC and AC.Some of these biomarkers are clear signatures for AC or SCC and four of them are secreted proteins.The presence of the mitochondrial protein SMAC/Diablo in the nucleus was found to be a signature for SCC.Precise diagnosis of AC and SCC is essential for selecting appropriate treatment and thus, increasing patient life expectancy.Finally, the search for drugs that target some of these biomarkers may lead to new treatments for lung cancer.

Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood-brain barrier compared with previous EGFR-TKIs, and thus, a 52% reduction in the risk of intracranial disease progression is seen when it is used as a first line of therapy compared with gefitinib and erlotinib. It is also efficient as second-line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report 11 patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either first- or second-line setting.This is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M-).Eleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6-30.7) months for arm A, 8.7 ± 1.8 (6.3-11.2) for arm B, and 14.5 ± 7.8 (6.7-22.3) for arm C. Intracranial response rate to dose escalation was 54% (6 of 11) with 2 of 11 having intracranial stability. Median iPFS was 4.3 ± 7.4 (0.7-25.5) months; 3.8 ± 6.4 (1.8-18.9), 5.6 ± 9.7 (0.7-25.5), and 7.0 ± 2.7 (4.3-9.6) for arms A/B/C, respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose-limiting symptoms.Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80 mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.