IN THIS ISSUE
Joint Effects of Environmental Exposures and Familial Susceptibility to Lung Cancer in Chinese Never Smoking Men and Women
In this study of delineating the joint effects of individual environmental risk factors and familial susceptibility to lung cancer, 345 never-smoking lung cancer cases and 828 community referents (from two case-referent studies between female and male lung cancer studies) were recruited. The authors developed a novel environmental exposure index, in which subjects at high risk of lung cancer with respect to environmental risk factors were assigned a value of 1 and 0 otherwise. The identified factors were then summed over using weights equivalent to the excess odds ratio. Potential additive interactions between environmental exposure index and family cancer history on lung cancer risk were evaluated. Males with high environmental exposures but no family cancer history demonstrated an odds ratio of 6.80 versus those with low environmental exposure and no family cancer history. The ratio increased dramatically to 30.61 when family cancer history was also present, where a statistically significant synergy index between environmental exposure index and family history of 3.98 was detected. Among females with high environmental exposures and a positive family history, the association to lung cancer risk was weaker, with a synergy index of 1.21. The findings suggest that there were joint effects of environmental exposure index and familial susceptibility to lung cancer risk in the never-smoking population and that there was a gender difference in these joint effects. Further studies are required to confirm this interaction in the male and female population. (p. 1066)
Genetic Susceptibility, Residential Radon, and Lung Cancer in a Radon Prone Area
This study sought to investigate the association of residential radon exposure, GSTM1 and GSTT1 polymorphisms, and the risk of lung cancer. Confirmed lung cancer cases and controls, without a previous neoplasm, aged >30 years, and divided into never/light smokers and moderate/heavy smokers, were included in the analysis. Of the 792 individuals analyzed, odds ratios (OR) of 1.38 and 1.13 were observed in cases of GSTM1 and GSTT1 deletion, respectively. When compared with cases with the presence of GSTM1 and residential radon at < 50 Bq/m3, an OR of 1.48 was demonstrated in cases with higher residential radon exposure (> 148 Bq/m3) in the presence of GSTM1, and an OR of 2.64 in the absence of GSTM1. Similar results were observed in the moderate/heavy smokers. The authors concluded that GSTM1 and GSTT1 deletions increase the risk of lung cancer in subjects exposed to residential radon, pointing to the possible modulatory role of these genes on the effect of environmental exposures. Further studies are warranted to confirm this effect in never smokers. (p. 1073)
Surgery for Small Cell Lung Cancer: A Retrospective Analysis of 243 Patients from Japanese Lung Cancer Registry in 2004
Takei et al. conducted a retrospective study of the prognosis and clinicopathologic profiles in a large number of small-cell lung cancer (SCLC) patients from the Japanese Joint Committee of Lung Cancer Registry who underwent surgery in 2004. Of the 11,663 patients from the registry, SCLC patients accounted for 2.1% (n = 243), whose surgical outcomes and clinicopathologic data were analyzed. An overall 5-year survival rate of 52.6% was observed in all 243 cases. When stratified by clinical tumor, node, metastasis (TNM) stage (c-stage) and pathological TNM stage (p-stage), the 5-year survival rates generally declined with higher stage. From IA to IV of c-stage and p-stage, the rates were 64.3% and 72.3%, to 0% and 0%, respectively. Age, gender, c-stage, and surgical curability were significant prognostic factors. The findings suggest that patients with early-stage SCLC, particularly stage I, had survival benefits from surgical resection. The authors suggested that c-stage II SCLC patients might also have good surgical outcome, and a clinical trial on surgery for these patients is recommended. (p. 1140)
Comprehensive Pathological Analyses in Lung Squamous Cell Carcinoma: Single Cell Invasion, Nuclear Diameter and Tumor Budding Are Independent Prognostic Factors for Worse Outcomes
This study by Kadota et al. aimed to determine the prognostic values of pathological findings in lung squamous cell carcinoma. They reviewed 485 slides from resected stages I, II, and III lung squamous cell carcinomas from 1999 to 2009. The comprehensive analyses included tumor differentiation, subtypes, tumor nest size, and nuclear grade. Significantly shorter overall survival (OS) was observed in patients with single cell invasion versus without (p = 0.002 for the entire tumor and p = 0.001 for tumor edge), with large versus small nuclei (p = 0.011), and with high versus low grade tumor budding (p < 0.001 for maximum and p = 0.007 for total). Multivariate analyses demonstrated that single cell invasion, nuclear diameter, and tumor budding, but not histologic subtypes, were independent prognostic factors of OS. The findings, if confirmed and validated by independent cohorts, could have potential implications on the revision of the WHO classification, particularly histologic subtyping and grading according to keratinization. These findings would help stratify SCLC patients for adjuvant therapy. (p. 1126)
Predictive Value of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma in Tumor Recurrence and Patient Survival
Hung et al. sought to evaluate the use of the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification system in resected lung adenocarcinoma to predict tumor recurrence and patient survival. The proportion of each histological component in the resected tumors from 573 patients was determined and their association with recurrence and predictive value were assessed. Significantly higher recurrence was observed in micro-papillary and solid-predominant adenocarcinomas (p < 0.01), which were also found to be significantly highly likely to develop initial extra-thoracic-only recurrence compared with other types (p < 0.01). The predominant micro-papillary and solid pattern was of significant prognostic value for overall survival (OS; p < 0.01), probability of freedom from recurrence (p < 0.01), and disease-specific survival (p < 0.01). Solid-predominant adenocarcinoma significantly predicts for poor OS in patients treated with adjuvant chemotherapy (p = 0.04). Taken together, the IASLC/ATS/ERS classification system exhibits significant predictive value for recurrence and survival, which can help guide selecting patients for aggressive adjuvant chemoradiotherapy.
Hung JJ, Yeh YC, Jeng WJ, et al. Predictive value of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory society classification of lung adenocarcinoma in tumor recurrence and patient survival. J Clin Oncol 2014; doi:10.1200/jco.2013.50.1049.
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
The Lung Cancer Mutation Consortium utilized multiplexed assays to test lung adenocarcinomas for 10 oncogenic drivers and to match therapies targeting the identified drivers. From 2009 to 2012, tumors from patients with metastatic lung adenocarcinomas and a performance status of 0–2 were tested for at least 1 gene (n = 1007) and for 10 genes (n = 733), at 14 different hospitals across the United States. For the latter, actionable oncogenic driver was detected in 64% of lung adenocarcinomas, which included KRAS (25%), sensitizing EGFR (17%), ALK rearrangements (8%), ERBB2 (3%), and BRAF (2%). The findings enabled doctors to recommend a targeted therapy for 28% of the 1007 patients. The median survival for patients with an oncogenic driver, receiving genotype-directed therapy was 3.5 years versus 2.4 years in those with a driver and did not receive genotype-directed therapy (hazard ratio 0.69; p = 0.006). This study demonstrated that multiplexed testing detected actionable oncogenic drivers in 64% of lung adenocarcinomas and assisted therapeutic decision-making for patients with the tumors. Improved survival in patients with drivers receiving a matched targeted therapy warrants further randomized trials to confirm the finding.
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998–2006. doi:10.1001/jama.2014.3741.
FGFR1/3 Tyrosine Kinase Fusions Define a Unique Molecular Subtype of Non-Small Cell Lung Cancer
FGFR1/3 fusions represent 1.3% non–small-cell lung cancer (NSCLC) patients and 3.5% lung squamous cell carcinoma. The authors aimed to determine the frequency, clinicopathologic characteristics, and treatment outcomes of NSCLC patients with or without these fusions. Molecular techniques were employed in detecting 14 known FGFR fusion variants in 1328 NSCLC patients, who were also tested for mutations in EGFR, KRAS, HER2, BRAF, ALK, RET, and ROS1. The analysis found BAG4-FGFR1 fusion (0.2%) and FGFR3-TACC3 fusion (1.1%) in all tumors examined. Six lung adenocarcinomas had FGFR3-TACC3 fusion, whereas 11 lung squamous cell carcinomas had BAG4-FGFR1 or FGFR3-TACC3 fusions. These FGFR fusions were significantly correlated with smokers (94.1%; p < 0.001), tumor >3 cm (88.2%; p < 0.001), and tend to be in poorly differentiated tumors (53.9%; p = 0.095). In this study, FGFR fusions were not associated with prognosis in NSCLC patients. Studies with a larger sample size of patients for a more definitive survival analysis are warranted. The findings identified a distinct subset of NSCLC patients harboring FGFR fusions, with high prevalence in smokers with squamous cell carcinoma and relatively larger tumors. Further studies of FGFR targeted therapy would potentially lead to a major therapeutic advance for this patient population.
Wang R, Wang L, Li Y, et al. FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non–small-cell lung cancer. Clin Cancer Res 2014. doi:10.1158/1078-0432.ccr-14–0284.
Real-World Effectiveness of e-Cigarettes When Used to Aid Smoking Cessation: A Cross-Sectional Population Study
Following two randomized controlled studies that indicated the role of e-cigarettes in mediating smoking cessation, Brown et al. conducted a cross-sectional survey to evaluate the effectiveness of e-cigarettes to aid smoking cessation compared with over-the-counter nicotine replacement therapy (NRT), and unaided quitting in 5863 English adults, who had smoked within the past 1 year. Self-reported abstinence up to the time of survey, including odds adjusted for nicotine dependence, was analyzed. The findings demonstrated that continued abstinence was more likely to be observed in e-cigarette users versus those using over-the-counter NRT (odds ratio 2.23; adjusted odds 1.63) or those with no aid (odds ratio 1.63; adjusted odds 1.61). Further studies are required to address limitations of the current study and establish if the apparent advantage of e-cigarettes is sustained.
Brown J, Beard E, Kotz D, Michie S, West R. Real-world effectiveness of e-cigarettes when used to aid smoking cessation: a cross-sectional population study. Addiction, n/a-n/a 2014. doi:10.1111/add.12623.
Passive Exposure to Electronic Cigarette (e-Cigarette) Use Increases Desire for Combustible and e-Cigarettes in Young Adult Smokers
Because passive exposure to combustible cigarette use could increase smoking urge, this study aimed to determine whether e-cigarettes and other electronic nicotine delivery systems would have the same impact. Subjective ratings for smoking desire and urge among 60 young adult daily smokers (aged 18–35 years) were measured before and after exposure to a control cue and subsequently the active cue (combustible or e-cigarette). The findings revealed significantly higher desire and urge to smoke a regular cigarette following passive exposure to both combustible and e-cigarette cue (p < 0.05). Furthermore, exposure to e-cigarette cue alone increased the desire to smoke an e-cigarette (p < 0.01). For the first time in a controlled study, these data reflect the potential of e-cigarette exposure in triggering smoking urges in young adult daily smokers. If confirmed by forthcoming studies, these findings could impact electronic nicotine delivery systems regulation and policy.
King AC, Smith LJ, McNamara PJ, Matthews AK, Fridberg DJ. Passive exposure to electronic cigarette (e-cigarette) use increases desire for combustible and e-cigarettes in young adult smokers. Tobacco Control 2014. doi:10.1136/tobaccocontrol-2014–051563.
NEWS IN BRIEF
ASCO Annual Meeting 2014: Clinical Activity of the Mutant-Selective EGFR Inhibitor AZD9291 in Patients with EGFR Inhibitor–Resistant Non-Small Cell Lung Cancer (NSCLC)
AZD9291 is a third generation EGFR-TKI, which shows preclinical efficacy in both EGFR-TKI sensitizing and resistant T790M mutations. At the 50th American Society of Clinical Oncology annual meeting, Jänne et al. reported their findings from a phase I study of AZD9291 in patients with EGFR mutant non–small-cell lung cancer (NSCLC). Patients (n = 199) with advanced NSCLC harboring EGFR mutations, who had at least one prior EGFR-TKI therapy, were enrolled in this study for dose escalation and expansion cohorts. The overall response rate in all evaluable patients was 51% after treatment with AZD9291. Those with T790M mutation (n = 89) had an overall response rate of 64% versus 23% in those without the mutation. A 96% of overall disease control rate was achieved in T790M-positive patients. The responses were still ongoing in 97% of the patients at data cut-off, with the longest response lasting > 8 months. There was also reduced skin toxicities observed with AZD9291 treatment compared with approved EGFR-TKIs. Taken together, the findings suggest that AZD9291 is effective and well-tolerated in EGFR mutant NSCLC patients with acquired resistance to EGFR-TKIs. Patients with EGFR T790M mutation tumors responded much better to AZD9291 than those without the mutation. Longer follow-up will determine improvement in overall survival.
ASCO Annual Meeting 2014: A Randomized, Multicenter, Open-Label, Phase III Study of Gemcitabine-Cisplatin (GC) Chemotherapy Plus Necitumumab (IMC-11F8/LY3012211) versus GC Alone in the First-Line Treatment of Patients with Stage IV Squamous Non-Small Cell Lung Cancer (sq-NSCLC)
Necitumumab is a human IgG1 anti-EGFR monoclonal antibody, targeting ligand binding, and receptor activation. In this large phase III SQUIRE trial, 1093 patients with stage IV squamous non–small-cell lung cancer who had no prior treatment were randomized to receive first-line necitumumab plus gemcitabine/cisplatin or gemcitabine/cisplatin alone. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, objective response rate, and safety. Thatcher et al. reported the results, which demonstrated a statistically significant improvement in overall survival in the necitumumab plus chemotherapy arm (hazard ratio = 0.84; p = 0.012) with a median survival of 11.5 months compared with 9.9 months in the chemotherapy-only arm. Significantly improved progression-free survival (hazard ratio = 0.85; p = 0.020) and disease control rate (82% vs. 77%; p = 0.043) in the necitumumab plus gemcitabine/cisplatin arm were also observed. Grade 3 or higher toxicities, such as rash and hypomagnesemia, were more frequent in the necitumumab plus gemcitabine/cisplatin arm. The findings suggest that addition of necitumumab to gemcitabine/cisplatin offers a new first-line treatment option with significant survival benefits and acceptable safety profile for patients with squamous non–small-cell lung cancer.
ASCO Annual Meeting 2014: REVEL–A Randomized, Double-Blind, Phase III Study of Docetaxel (DOC) and Ramucirumab (RAM; IMC-1121B) versus DOC and Placebo (PL) in the Second-Line Treatment of Stage IV Non-Small Cell Lung Cancer (NSCLC) Following Disease Progression after One Prior Platinum-Based Therapy
The antiangiogenic agent ramucirumab (RAM) is a monoclonal antibody targeting vascular endothelial growth factor receptor-2. The REVEL trial aimed to investigate the efficacy and safety of RAM in combination with docetaxel (DOC) versus DOC plus placebo (PL) in 1253 patients with stage IV non-squamous and squamous non–small-cell lung cancer (NSCLC) with prior platinum-based therapy. The primary endpoint was overall survival, whereas the secondary endpoints included progression-free survival, and objective response rate (ORR). Pérol et al. reported the findings that showed reduced risk of death by 14% and improved median overall survival by 1.4 months (from 9.1 to 10.5 months) in the RAM + DOC arm versus the DOC + PL arm (hazard ratio [HR] = 0.857; p < 0.0235). The RAM + DOC arm also showed reduced risk of progression by 24%, extending progression-free survival by 1.5 months (from 3.0 to 4.5 months; HR = 0.762; p < 0.0001), and improved ORR from 13.6% to 22.9% (p < 0.001). The survival benefit was observed in both squamous (26% of study population) and non-squamous subtypes. No unexpected adverse events (AEs) were identified. Grade ≥ 3 AEs in the RAM + DOC versus DOC + PL were neutropenia (34.9% versus 28.0%), febrile neutropenia (15.9% versus 10.0%), fatigue (11.3% versus 8.1%), leukopenia (8.5% versus 7.6%), hypertension (5.4% versus 1.9%), and pneumonia (5.1% versus 5.8%). Grade 5 AEs were comparable between arms (5.4% in RAM + DOC versus 5.8% in DOC + PL) as was pulmonary hemorrhage of any grade in all patients (2.1% versus 1.6%) and in patients with squamous NSCLC (3.8% versus 2.4%). The authors concluded that RAM + DOC regimen, with a good safety profile, significantly improved overall survival, progression-free survival, and ORR compared with DOC + PL in the second-line setting for stage IV NSCLC patients who had received prior platinum-based therapy. Similar survival benefits in both squamous and non-squamous subtypes indicate the possibility of utilizing this regimen in treating all major subtypes of NSCLC.
ASCO Annual Meeting 2014: Overall Response Rate (ORR) as a Potential Surrogate for Progression-Free Survival (PFS) – A meta-Analysis of Metastatic Non-Small Cell Lung Cancer (mNSCLC) Trials Submitted to the U.S. Food and Drug Administration (FDA)
The meta-analysis conducted by Blumenthal et al. aimed to evaluate the relationship between overall response rate (ORR) with progression-free survival (PFS) or overall survival (OS) and determine a surrogate endpoint in metastatic non–small-cell lung cancer patients from 15 trials of 12,534 patients reviewed by the food and drug administration (FDA) since 2003, including three targeted therapy trials in molecularly defined population (EGFR mutant and ALK+) with high ORR. The analysis only included trials that were randomized, active-controlled, multicenter and with a sample size of ≥ 150. A strong correlation between ORR and PFS was observed (R2 = 0.89), whereas neither ORR nor PFS correlated well with OS (R2 = 0.12 and 0.1, respectively). In larger trials, the correlations between OS and the surrogate endpoints appeared to be modestly better: for PFS, R2 = 0.39 in trials with n greater than or equal to 500 versus 0.1 overall; for ORR, R2 = 0.50 versus 0.12, respectively. This meta-analysis supported ORR as a surrogate endpoint in metastatic non–small-cell lung cancer. No correlation was established between OS and PFS or ORR, which was likely because of confounding from high crossover, underpowered trials and long survival after progression in the 3 targeted therapy trials in molecularly enriched populations.
ASCO Annual Meeting 2014: Ceritinib in Advanced Anaplastic Lymphoma Kinase (ALK)-Rearranged (ALK+) Non-Small Cell Lung Cancer (NSCLC) – Results of the ASCEND-1 Trial
Kim et al. reported the findings from the phase I study of ceritinib treatment (750 mg/d) in patients with anaplastic lymphoma kinase (ALK) + non–small-cell lung cancer (NSCLC), which served as the basis for the FDA approval of ceritinib in April 2014. Of the 255 patients enrolled in the study, 246 patients with ALK+ NSCLC, included ALK inhibitor (ALKi) naive, and ALKi pretreated. An overall response rate (ORR) of 58.5% and a median progression-free survival (PFS) of 8.2 months were achieved in patients receiving ceritinib. A median duration of response of 9.7 months was observed. ORR was 54.6% and PFS was 6.9 months among patients pretreated with the ALKi crizotinib, whereas the ORR of 66.3% was observed in the ALKi naïve patients, who were still under ceritinib treatment and median PFS had not been reached. Of note, similar findings were also observed in patients with brain metastases receiving ceritinib: ORR was 54.0% and median PFS was 6.9 months. In these patients, 50.0 % of the ALKi pretreated group and 69.2% of the ALKi naïve group had tumor regression after ceritinib treatment. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, and fatigue. The study showed that ceritinib at 750 mg/d has rapid, durable, and high antitumor response in ALK+ NSCLC patients, regardless of ALKi pretreatment and also is effective in brain metastases in this study population.
ASCO Annual Meeting 2014: Overall Survival (OS) in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring Common (Del19/L858R) Epidermal Growth Factor Receptor Mutations (EGFR mut) – Pooled Analysis of Two Large Open-Label Phase III Studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) Comparing Afatinib with Chemotherapy (CT)
The pooled analysis of LL3 and LL6 studies aimed to show mature data on overall survival (OS), comparing afatinib with chemotherapy (CT) in patients with stage III/IV non–small-cell lung cancer (NSCLC) harboring the common epidermal growth factor receptor (EGFR) mutations (Del19/L858R), who had no prior treatments. Patients were randomized to afatinib or CT: cisplatin and pemetrexed (LUX-Lung 3 [LL3], n = 345); cisplatin and gemcitabine (LUX-Lung 6 [LL6], n = 364). Prolonged PFS was previously reported in patients with the common EGFR mutations, receiving afatinib versus CT (HR = 0.47 [LL3], HR = 0.25 [LL6]). OS was followed up for a median of 36.5 months. The afatinib arm showed a significantly improved OS versus CT (median 27.3 versus 24.3 months; HR = 0.81; p = 0.037). Exclusive survival benefit was seen in those patients with Del19 (HR = 0.59; p < 0.001) compared with L858R (HR = 1.25; p = 0.160). This analysis demonstrated that first-line afatinib significantly improves OS compared with CT in patients harboring Del19. The author suggested that two distinct patient populations with Del19 and L858R should be studied separately in the future.
ASCO Annual Meeting 2014: Efficacy and Safety of Crizotinib in Patients with Advanced C-MET-Amplified Non-Small Cell Lung Cancer (NSCLC)
The results of the phase I dose escalation study of crizotinib in 13 patients with advanced non–small-cell lung cancer harboring MET amplification were presented by Camidge et al. at the ASCO Annual Meeting 2014. c-MET amplification status was determined by fluorescent in situ hybridization and categorized into low (MET/CEP7 ratio ≥1.8 to ≤2.2; n = 1), intermediate (>2.2 to <5; n = 6), and high (≥5; n = 6). Of the 12 patients evaluable for response, those with intermediate c-MET amplification had one partial response and four stable diseases whereas those with high c-MET amplification had one complete response, three partial responses and one stable disease. Overall objective response rates were 0% (low), 17% (intermediate), and 67% (high). The response lasted for a median of 35 weeks, with six patients still undergoing treatment at data cut-off. There were five disease-related deaths. Treatment related adverse events, mostly grade 1, occurred in 75% of the patients. The findings suggested antitumor efficacy of crizotinib in patients with c-MET amplified non–small-cell lung cancer, with a tolerable and manageable safety profile. Further studies of crizotinib in this patient population and the association of c-MET amplification with clinical outcomes are warranted.
ISDS Provisions and Big Tobacco
This month we revisit plain packaging for cigarettes and the international legal game of Twister that has ensued. A report in the East Asia Forum ( http://www.eastasiaforum.org/2014/05/29/smoke-and-mirrors-in-trade-disputes-will-harm-public-health/) looks at the effects of Investor-State Dispute Settlement (ISDS) Provisions employed by global tobacco companies in opposition to moves such as Australia’s introduction of plain cigarette packaging as well the use of graphic health warnings by Uruguay and Switzerland. Dr Margaret Chan, WHO’s Director-General, raised the problem of such provisions in a recent speech at the UN, pointing out that the tobacco companies use them to sue governments for lost profits, a step which is “fundamentally wrong” when it permits trade agreements to override public health measures. The article contains a link to the speech; the reference to these provisions occurs about 7 minutes from the start.
Think Globally, Act Locally
A small step was taken on World No Tobacco Day, May 31 2014, when the University of NSW in Sydney, Australia, banned smoking from all of its eight campuses, as reported in the Sydney Morning Herald. The ban includes e-cigarettes, water pipes, and vaporizers ( http://www.smh.com.au/nsw/total-smoking-ban-on-every-unsw-campus-20140530-399rz.html). The university’s website provides more information at the following link, http://sustainability.unsw.edu.au/news/smokefree.
On the other side of the world, The Republic of Ireland is proposing legislation from plain cigarette packaging, reported by the BBC ( http://www.bbc.com/news/world-europe-27781825). Cabinet has approved draft laws as reported in The Irish Times, banning logos on cigarette packs, forbidding the term “low tar” and mandating graphic warnings ( http://www.irishtimes.com/news/health/ireland-leads-eu-on-plain-packaging-of-cigarettes-1.1827268).
In the May issue of the Journal of General Internal Medicine ( http://link.springer.com/article/10.1007/s11606-014-2889-7), a new study has found that e-cigarettes outdo older (and Food and Drug Administration-approved) nicotine inhaler devices in popularity. The small cross-over trial found that e-cigarettes were more acceptable than the inhaler, with a higher perceived benefit and a higher rating for “coolness”. One explanation for this perhaps comes from a study in Pediatrics, published online June 2 2014, looking at e-cigarette TV advertisements across 2011 to 2013. Reported in USA Today ( http://www.usatoday.com/story/news/nation/2014/06/02/e-cigarettes-tv-ads-youth/9760425/), the study found that e-cigarette TV advertisement exposure over that time increased by 256% for 12–17 years of age and by 321% for 18–24 years of age. The advertisements themselves have all of the conventional ingredients (pretty blonde women, night club scenes, health, happiness, and vitality) seen in advertisements for anything, anywhere and were dominated by one brand, blu eCigs, owned by the tobacco company Lorillard. It is interesting to note that a ban on TV advertisements for conventional cigarettes has been in place in the United States since 1971. Advertising expenditure for e-cigarettes, in data published in the American Journal of Preventive Medicine increased almost three fold between 2011 and 2012 (from $6.4 million to $18.3 million; http://www.ajpmonline.org/article/S0749-3797(13)00618-1/abstract). And finally, perhaps there is a flipside to the concerns about e-cigarettes. A study on e-cigarette use and smoking cessation, reported on by the BBC and Britain’s Daily Telegraph, has shown a higher cessation rate in users of e-cigarettes than those who used nicotine replacement therapies or no aid at all. The authors are cautious in their discussion of the findings, citing the potential recall bias, the lack of biochemical verification of abstinence and the heterogeneity of nicotine replacement including the nicotine content of e-cigarettes. The paper’s senior author is among the co-signatories of letter, reported by The Guardian ( http://www.theguardian.com/world/2014/may/29/who-suppress-control-e-cigarettes-uk-health-tobacco) from more than 50 researchers and specialists to Dr Margaret Chan, calling for e-cigarettes to be regulated as part of “tobacco harm-reduction” strategies and expressing concerns about detrimental effects of a total ban. The letter can be viewed at http://nicotinepolicy.net. These research findings, and the calls for e-cigarettes to be considered as part of the tobacco-harm reduction armamentarium, add to the complexity of the e-cigarette debate and to the importance of careful and sophisticated interpretation of data and their application to health care regulations.