Localized high grade endometrial stromal sarcoma and localized undifferentiated uterine sarcoma: a retrospective series of the French Sarcoma Group.

OBJECTIVE: High grade endometrial stromal sarcoma and undifferentiated uterine sarcomas are associated with a very poor prognosis. Although large surgical resection is the standard of care, the optimal adjuvant strategy remains unclear. METHODS: A retrospective analysis of patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas (stages I-III) treated in 10 French Sarcoma Group centers was conducted. RESULTS: 39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas treated from 2008 to 2016 were included. 24/39 patients (61.5%) were stage I at diagnosis. 38/39 patients underwent surgical resection, with total hysterectomy and bilateral oophorectomy completed in 26/38 (68%). Surgeries were mostly resection complete (R0, 23/38, 60%) and microscopically incomplete resection (R1, 6/38, 16%). 22 patients (58%) underwent postoperative radiotherapy (including brachytherapy in 11 cases), and 11 (29%) underwent adjuvant chemotherapy. After a median follow-up of 33 months (range 2.6-112), 17/39 patients were alive and 21/39 (54%) had relapsed (9 local relapses and 16 metastases). The 3 year and 5 year overall survival rates were 49.8% and 31.1%, respectively, and 3 year and 5 year disease free survival rates were 42.7% and 16.0%, respectively. Median overall survival and disease free survival were 32.7 (95% CI 16.3-49.1) and 23 (4.4-41.6) months, respectively. Medians were, respectively, 46.7 months and 39.0 months among those who underwent adjuvant radiotherapy and 41.0 months and 10.3 months for those who underwent adjuvant chemotherapy. In multivariate analysis, adjuvant radiotherapy was an independent prognostic factor for overall survival (P=0.012) and disease free survival (P=0.036). Chemotherapy, International Federation of Gynecology and Obstetrics I-II stages, and Eastern Cooperative Oncology Group-performance status 0 correlated with improved overall survival (P=0.034, P=0.002, P=0.006), and absence of vascular invasion (P=0.014) was associated with better disease free survival. CONCLUSIONS: The standard treatment of primary localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas is total hysterectomy and bilateral oophorectomy. The current study shows that adjuvant radiotherapy and adjuvant chemotherapy appear to improve overall survival. A prospective large study is warranted to validate this therapeutic management.

Avalanches dynamics in reaction fronts in disordered flows.

We report on numerical studies of avalanches of an autocatalytic reaction front in a porous medium. The front propagation is controlled by an adverse flow resulting in upstream, static, or downstream regimes. In an earlier study focusing on front shape, we identified three different universality classes associated with this system by following the front dynamics experimentally and numerically. Here, using numerical simulations in the vicinity of the second-order transition, we identify an avalanche dynamics characterized by power-law distributions of avalanche sizes, durations, and lateral extensions. The related exponents agree well with the quenched-Kardar-Parisi-Zhang theory, which describes the front dynamics. However, the geometry of the propagating front differs slightly from that of the theoretical one. We show that this discrepancy can be understood in terms of the nonquasistatic correction induced by the finite front velocity.

PD-L1 protein expression assessed by immunohistochemistry is neither prognostic nor predictive of benefit from adjuvant chemotherapy in resected non-small cell lung cancer.

Background: The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Patients and methods: Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results: Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, and KRAS but not with TP53 mutation. EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. Conclusions: PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.

Breaking of non-Newtonian character in flows through a porous medium.

From NMR measurements we show that the velocity field of a yield stress fluid flowing through a disordered well-connected porous medium is very close to that for a Newtonian fluid. In particular, it is shown that no arrested regions exist even at very low velocities, for which the solid regime is expected to be dominant. This suggests that these results obtained for strongly nonlinear fluid can be extrapolated to any nonlinear fluid. We deduce a generalized form of Darcy's law for such materials and provide insight into the physical origin of the coefficients involved in this expression, which are shown to be moments of the second invariant of the strain rate tensor.

Adjuvant cisplatin-based chemotherapy in nonsmall-cell lung cancer: new insights into the effect on failure type via a multistate approach.

BACKGROUND: Adjuvant cisplatin-based chemotherapy has become the standard therapy against resected nonsmall-cell lung cancer (NSCLC). Because of variable results on its late effect, we reanalyze the long-term data of the International Adjuvant Lung Cancer Trial (IALT) to describe in details the role of adjuvant chemotherapy. PATIENTS AND METHODS: In the IALT, 1867 patients were randomized between adjuvant cisplatin-based chemotherapy and control, who were followed up for a median of 7.5 years. Of these, 1687 patients were enrolled from 132 centers accepting to report the times to cancer events. We used event history methodology to estimate the effects of adjuvant chemotherapy on the risks of local relapse, distant metastasis, and death. RESULTS: Adjuvant chemotherapy was highly effective against local relapses [HR = 0.73; 95% confidence interval (CI) 0.60-0.90; P = 0.003] and nonbrain metastases (HR = 0.79; 95% CI 0.66-0.94; P = 0.008) but not against brain metastases (HR = 1.1; 95% CI 0.82-1.4; P = 0.61). The effect on noncancer mortality was nonsignificant during the first 5 years (HR = 1.1; 95% CI 0.81-1.5; P = 0.29), whereas the risk of noncancer mortality was subsequently higher with treatment (HR = 3.6; 95% CI 2.2-5.9; P < 0.001). This harmful effect, however, potentially concerned only about 2% of the patients at 8 years. CONCLUSION: Adjuvant cisplatin-based chemotherapy reduced the risk of local relapse and of nonbrain metastasis, thereby improving survival. This treatment exerted no residual effect on mortality during the first 5 years, but a higher risk of noncancer mortality was found thereafter. Detailed long-term follow-up is strongly recommended for all patients in randomized trials evaluating adjuvant treatments in NSCLC.

Velocity distributions in confined flows of some complex fluids: sequence, sample and hardware issues.

The present work addresses the problem of using Pulsed Field Gradient (PFG) experiments to measure velocity probability density functions and/or distributions in restricted flows, without being subjected to the blurring due to diffusive molecular motions. It especially focuses on two important classes of complex yield-stress fluids, i.e. water based colloidal suspensions or polymeric gels, and concentrated emulsions. Taking into account the many constraints owing to fluid diffusive properties, flow rate, hardware characteristics and pore size, it is found that the existence of suitable and optimised sequence parameters can be discussed in a graphical way. To do so, it also shown that Murday and Cotts formula describing diffusion inside emulsion droplets can be efficiently approximated by means of a set of asymptotic expressions. Different tuning regimes are identified for both kind of fluids, highlighting the influence of each of the various constraints on measuring possibilities. A method is given to build quantitative diagrams indicating pore sizes and flow rates allowing pure velocity assessment for a given fluid and Nuclear Magnetic Resonance (NMR) hardware. Measurements are found to be mainly constrained by fluid self-diffusivity and microstructure at low flow rates, and hardware characteristics at high flow rates. Although high gradient strengths can be made necessary to decrease achievable velocities and pore sizes in some specific cases, low gradient systems turn out suitable in many situations thanks to optimised sequence tuning. Due to their larger size, the latter also appear to offer the widest variety of workable experimental conditions. The use of these results is finally exemplified on the practical case of an emulsion flow in a model porous system.

Developments in the treatment of early NSCLC: when to use chemotherapy.

approximately 30% of lung carcinomas are resected and these cases are candidates for adjuvant treatments. The PORT meta-analysis reported in 1999 that postoperative radiotherapy had a detrimental effect for pathological N0 and N1 patients, and a debatable effect for N2 patients. Following the results of the 1995 meta-analysis on the role of chemotherapy (CT) in non-small-cell lung cancer (NSCLC), many randomized, controlled trials were launched to evaluate the effect of adjuvant cisplatin-based CT after the complete resection of NSCLC. The Lung adjuvant Ciplatin Evaluation pooled analysis included a total of 4584 patients recruited in five recent cisplatin-based adjuvant trials. It confirmed that adjuvant CT was associated with an absolute 5-year survival benefit of 5.3% (P = 0.0043). In addition, it showed that adjuvant cisplatin-based CT is detrimental in cases of stage Ia resected NSCLC; it also suggested that the combination of vinorelbine and cisplatin was of more benefit than older two and three drug combinations. The individual data-based meta-analysis was also updated with a total of over 10 000 patients. It confirmed the substantial effect of postoperative CT, with or without postoperative radiotherapy, with a substantial overall benefit of 4% at 5 years. Recent results of biological programs suggest that evaluating the expression of various tumor markers, including excision repair cross-complementation group 1, may allow the identification of patients most likely to benefit from CT. If these results are confirmed, tailored therapy might be the next step forward for resected NSCLC.

Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses.

BACKGROUND: Most non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit. PATIENTS AND METHODS: DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression). RESULTS: In patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs. CONCLUSION: Here predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.

Assessment of health claims in the field of bone: a view of the Group for the Respect of Ethics and Excellence in Science (GREES).

UNLABELLED: Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims. INTRODUCTION: Regulation (EC) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims. METHODS: Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science (GREES). RESULTS: The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that well-designed human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength. CONCLUSION: The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim.

Adjuvant chemotherapy for resectable non-small-cell lung cancer: where is it going?

Following the 1995 meta-analysis on the role of postoperative chemotherapy in NSCLC, many randomized controlled trials (RCTs) have evaluated the effect of adjuvant cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC), adding substantially to the existing evidence. The LACE pooled analysis included a total of 4584 patients accrued in five recent cisplatin-based adjuvant trials. It confirmed the benefit of adjuvant chemotherapy (P = 0.0043). In addition, it showed that adjuvant cisplatin-based chemotherapy is detrimental in stage IA resected NSCLC; it also indicated that the combination of vinorelbine and cisplatin offered a higher benefit compared with older doublets or triplets. The individual-databased meta-analysis was also updated with a total of >10,000 patients. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy, with an overall significant benefit of 4% at 5 years. The recent results of biological programmes indicate that the expression of some tumour markers including ERCC1 be evaluated in order to determine which patients are more likely to benefit from chemotherapy. If these results are confirmed, tailored therapy might be the next progress for resected NSCLC.

Should progression-free survival be the primary measure of efficacy for advanced NSCLC therapy?

Non-small-cell lung cancer (NSCLC) is a leading cause of malignancy-related mortality in the Western world. Despite advances in early detection and standard treatment, NSCLC is frequently diagnosed at an advanced stage and therefore patients have a poor prognosis. However, its heterogeneity provides ample opportunity for multiple treatment approaches and target pathways. Considerable progress has been made in identifying novel targets, leading to a growing number of treatment options. Overall survival (OS) may not always be the most appropriate primary end point for assessment of efficacy, as it is likely that patients with NSCLC will receive multiple lines of therapy during their treatment. Additionally, crossover appears as an ethical necessity to many investigators if molecular targeted agents display outstanding early efficacy. While improving OS remains the goal for clinicians, progression-free survival (PFS) is increasingly being utilised as an alternative end point. In this article, we will evaluate the value of PFS as a primary measure of efficacy for advanced NSCLC, compare the clinical situation with that in other solid malignancies and review the growing number of treatment options for NSCLC.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.

BACKGROUND: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy. METHODS: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat. FINDINGS: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup. INTERPRETATION: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy. FUNDING: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Marker placement for movement analysis in scoliotic patients: a critical analysis of existing systems.

Optoelectronic movement analysis systems has provided an opportunity for a detailed study of both normal and abnormal human walking and has contributed to the planning and documentation of corrective surgical procedures. The majority of reported studies have been on the study of lower limbs which, consequently, have received most attention in movement analysis. In contrast, movement of the trunk and pelvis, important in the identification of spinal mobility and maintaining posture, have received limited attention in relation to clinical conditions such as scoliosis. Any movement analysis requires the identification of anatomical landmarks which are essential contributing factors to the accuracy of the analysis. While there are a plethora of studies on marker placements for the lower limbs, there is a paucity of information on the marker locations for spinal analysis. Present study examines a set of markers previously reported in the literature and examines their usefulness in scoliotic gait analysis. The findings highlight the drawbacks in previously reported techniques and leads to the proposal of a new marker set for spine and back movement analysis.

Immunohistochemichal expression of biomarkers: a comparative study between diagnostic bronchial biopsies and surgical specimens of non-small-cell lung cancer.

BACKGROUND: The increasing use of biomarkers as molecular determinants of responsiveness to conventional chemotherapy or molecular targeted therapy has raised the question of the reliability and reproducibility of their evaluation in bronchial biopsies as compared with corresponding resected surgical specimens. PATIENTS AND METHODS: Immunohistochemical expression of five markers related to signal transduction [epidermal growth factor receptor (EGFR), phospho-Akt], cell proliferation (Ki-67), DNA repair [excision repair cross-complementing (ERCC)1] and cellular 'immortality' [human telomerase catalytic component (hTERT)], was assessed in 41 patients with operable non-small-cell lung cancer in both bronchial biopsies and whole surgical specimens. RESULTS: High correlation coefficients were observed between the expression of ERCC1, hTERT and Ki-67 in the biopsies and the surgical specimens [0.83 (P < 0.0001); 0.55 (P < 0.001) and 0.64 (P < 0.0001), respectively]. On the other hand, biomarker expression in biopsy was less correlated with the expression in the whole tissue sample for the markers of signal response and transduction [0.24 (P = 0.17) and 0.29 (P = 0.09) for EGFR and phospho-Akt, respectively]. CONCLUSIONS: Our results indicate a lack of association in the expression of important biomarkers between lung biopsies and corresponding resected tumors, with discordance rates ranging between 9% and 41%. Although these results need to be further validated in larger cohorts, they indicate that the evaluation of the expression of biomarkers in bronchial biopsies can be misleading.

Review of the pemetrexed and gemcitabine combination in patients with advanced-stage non-small cell lung cancer.

Pemetrexed is a new multitargeted antifolate that can be easily administered as a 10-min infusion every 3 weeks. The use of folic acid, vitamin B(12), and corticoid prophylaxis has significantly reduced pemetrexed-induced toxicity. Single-agent pemetrexed has shown antitumor activity in a wide range of solid tumors, including non-small cell lung cancer (NSCLC). Association with vinorelbine, cisplatin, carboplatin, and oxaliplatin have been tried, but the pemetrexed and gemcitabine combination, an easy to administer cisplatin-free doublet, has been documented in many phase 2 trials in the first-line treatment of advanced NSCLC. In vitro cytotoxic assays and phase I studies have defined several schedules of administration for pemetrexed and gemcitabine. The recommended dose is pemetrexed 500 mg/m(2) on day 1 or 8, and gemcitabine 1250 mg/m(2) on day 1 and 8, but it is unknown if pemetrexed should precede or follow gemcitabine and at what time interval. Published studies have failed to show significant differences in overall survival times despites response rates oscillating between 15% and 41%. The main toxicities are neutropenia, fatigue, skin rashes and elevated transaminases and seem to occur with similar rates in the many phase 2 trials. Hopes for the future are in tailored chemotherapy, since molecular markers of sensitivity are available for gemcitabine and pemetrexed, allowing to determinate in the future which patients will be most likely to benefit from the gemcitabine-pemetrexed doublet.

Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients.

BACKGROUND: Despite several randomised trials comparing radiotherapy alone with concomitant radio-chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC), it is not clear whether the addition of chemotherapy improves survival. PATIENTS AND METHODS: This meta-analysis was based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy. Trials with accrual completed after 2000 were excluded. Trials were sought in electronic databases, clinical trial registries and by additional manual searches. The primary endpoint was overall survival analysed using the log-rank test stratified by trials. RESULTS: There were twelve eligible trials that included a total of 1921 patients. The data from 3 trials were not available. Therefore, the analysis was based on 9 trials including 1764 patients. Median follow-up was 7.2 years. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (95% confidence interval, 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone. CONCLUSIONS: Concomitant platin-based radio-chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers.

BACKGROUND: Non-small-cell lung cancer arising in never-smokers is usually of adenocarcinoma subtype. The oncogenic pathway of such tumors is poorly understood. To better define the biological characteristics of these tumors, we have compared the expression of a panel of epidermal growth factor receptor (EGFR)-related biomarkers in lung adenocarcinomas from smokers versus those in never-smokers. PATIENTS AND METHODS: Using immunohistochemical analysis, we retrospectively analyzed EGFR, pAKT, PTEN, Ki-67, p27 and hTERT expression in specimens from 190 patients with completely resected lung adenocarcinomas (43 never-smokers and 147 smokers). These analyses were performed on tissue microarrays. RESULTS: EGFR expression was higher in tumors from smokers (P < 0.01), while pAKT was overexpressed mainly in tumors from never-smokers (P = 0.01). As expected, the tumors from smokers presented a higher expression of Ki-67 and a more frequent loss of expression of p27 (P < 0.01). In a multivariate model, two biological factors (p27 and Ki-67) and two clinical factors (age and sex) showed independent significant correlation with never-smoking status. CONCLUSIONS: Lung adenocarcinomas in never-smokers have a very distinct immunohistochemical expression profile of EGFR-related biomarkers as compared with lung adenocarcinomas in smokers. High levels of EGFR and Ki-67 are observed in smokers, while never-smokers are characterized by high levels of pAKT and p27.