Genome-wide Detection of Chimeric Transcripts in Early-stage Non-small Cell Lung Cancer.

BACKGROUND/AIM: Lung cancer remains the main culprit in cancer-related mortality worldwide. Transcript fusions play a critical role in the initiation and progression of multiple cancers. Treatment approaches based on specific targeting of discovered driver events, such as mutations in EGFR, and fusions in NTRK, ROS1, and ALK genes led to profound improvements in clinical outcomes. The formation of chimeric proteins due to genomic rearrangements or at the post-transcriptional level is widespread and plays a critical role in tumor initiation and progression. Yet, the fusion landscape of lung cancer remains underexplored. MATERIALS AND METHODS: We used the JAFFA pipeline to discover transcript fusions in early-stage non-small cell lung cancer (NSCLC). The set of detected fusions was further analyzed to identify recurrent events, genes with multiple partners and fusions with high predicted oncogenic potential. Finally, we used a generalized linear model (GLM) to establish statistical associations between fusion occurrences and clinicopathological variables. RNA sequencing was used to discover and characterize transcript fusions in 270 NSCLC samples selected from the Glans-Look specimen repository. The samples were obtained during the early stages of disease prior to the initiation of chemo- or radiotherapy. RESULTS: We identified a set of 792 fusions where 751 were novel, and 33 were recurrent. Four of the 33 recurrent fusions were significantly associated with clinicopathological variables. Several of the fusion partners were represented by well-established oncogenes ERBB4, BRAF, FGFR2, and MET. CONCLUSION: The data presented in this study allow researchers to identify, select, and validate promising candidates for targeted clinical interventions.

The role of mind body interventions in the treatment of irritable bowel syndrome and fibromyalgia.

Introduction: Irritable bowel syndrome and fibromyalgia share similar pathophysiologic mechanisms including sensitization of peripheral and central pain pathways, autonomic dysfunction and are often co-diagnosed. Co-diagnosed patients experience increased symptom severity, mental health comorbidities, and decreased quality of life. The role of mind-body interventions, which have significant effects on central pain syndromes and autonomic dysregulation, have not been well-described in co-diagnosed patients. The aim of this state-of-the art narrative review is to explore the relationship between irritable bowel syndrome and fibromyalgia, and to evaluate the current evidence and mechanism of action of mind-body therapies in these two conditions. Methods: The PubMed database was searched without date restrictions for articles published in English using the following keywords: fibromyalgia, irritable bowel syndrome, mind-body interventions, cognitive behavioral therapy, mindfulness based stress reduction, and yoga. Results: Mind-body interventions resulted in improved patient-reported outcomes, and are effective for irritable bowel syndrome and fibromyalgia individually. Specifically, cognitive behavioral therapy and yoga trials showed decreased symptom severity, improved mental health, sleep and quality of life for both conditions individually, while yoga trials demonstrated similar benefits with improvements in both physical outcomes (gastrointestinal symptoms, pain/tenderness scores, insomnia, and physical functioning), mental health outcomes (anxiety, depression, gastrointestinal-specific anxiety, and catastrophizing), and quality of life, possibly due to alterations in autonomic activity. Conclusion: Mind-body interventions especially CBT and yoga improve patient-reported outcomes in both irritable bowel syndrome and fibromyalgia individually. However, limited available data in co-diagnosed patients warrant high quality trials to better tailor programs to patient needs.

CXCR4 expression in lung carcinogenesis: Evaluating gender-specific differences in survival outcomes based on CXCR4 expression in early stage non-small cell lung cancer patients.

INTRODUCTION: Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. METHODS: Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). RESULTS: 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. CONCLUSIONS: CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.

The prevalence and prognostic significance of estrogen receptor beta expression in non-small cell lung cancer.

BACKGROUND: Estrogen receptor beta (ERß) is the predominant estrogen receptor (ER) expressed in non-small cell lung cancer (NSCLC); however, due to methodological disparities among prior studies, the prognostic value of ERß expression in NSCLC remains unclear. Our objective was to apply improved detection and analysis techniques to assess the prognostic value of ERß expression in NSCLC. METHODS: A tissue microarray (TMA) was used which contained resected and biopsy specimens from 299 patients diagnosed at a single center with stages I-IV NSCLC. Sections of this array were stained using high-sensitivity fluorescence immunohistochemistry, with the well-validated PPG5/10 monoclonal antibody. Digital images of the stained array slides were analyzed using software-based image analysis, which reported ERß expression as a continuous variable in different subcellular domains. RESULTS: There were no differences in ERß expression between male and female patients. High expression of ERß was not a prognostic factor, but was significantly associated with stage IV disease in both tumor and stroma (P<0.001). In multivariable analysis, a high nuclear/cytoplasmic (N/C) ratio of ERß expression was significantly associated with shorter overall survival, based on expression in the tumor [hazard ratio (HR): 1.65; 95% confidence interval (CI): 1.25-2.19; P<0.001] and in the stroma (HR: 1.57; 95% CI: 1.16-2.12; P=0.003). CONCLUSIONS: These results suggest that subcellular localization of ERß, but not absolute expression, is a prognostic factor in NSCLC.

Impact of Asian ethnicity on outcome in metastatic EGFR-mutant non-small cell lung cancer.

AIM: To determine factors associated with survival in de novo stage IV, non-small cell lung cancer (NSCLC) patients possessing epidermal growth factor receptor mutations (EGFRmut+ ) receiving tyrosine kinase inhibitors (TKI) in the first-line setting. METHODS: The Glans-Look Lung Cancer Database was used to retrospectively review stage IV EGFRmut+ NSCLC patients diagnosed 2010-2016 receiving first-line TKI. Patients with overall survival times in the upper quartile (≥34 months) were designated "long-term survivors" (LTS), the remaining deemed "average-term survivors" and characteristics between these groups were compared in univariate analysis, and multivariable models constructed to determine predictors of outcome. RESULTS: Of 170 eligible patients, median overall survival was 21 months. LTS were significantly more likely to be of Asian ethnicity, be never-smokers and not possess brain or bone metastases at diagnosis. Asian and non-Asian patients were comparable, save for an increased propensity of Asian patients to be never smokers and have normal-range BMI. Multivariable analysis revealed Asian ethnicity [hazard ratio (HR) = 0.65; P = 0.016] and never-smoking history (HR = 0.65; P = 0.034) as indicators of improved outcome, and presence of brain metastasis at diagnosis an indicator of poor outcome (HR = 2.21; P < 0.001). CONCLUSIONS: Analysis of this population-based cohort identifies never-smoking history and absence of brain metastasis along with Asian ethnicity as an independent prognosticators of favorable outcome, and reveals Asian patients to be clinicopathologically similar to non-Asian patients. These findings suggest Asian patients represent a unique subpopulation within EGFRmut+ NSCLC who may possess different biological underpinnings of NSCLC.

Factors associated with early mortality in non-small cell lung cancer patients following systemic anti-cancer therapy: A 10 year population-based study.

OBJECTIVES: To investigate how clinical, demographic and treatment-related factors in non-small cell lung cancer (NSCLC) patients impact the risk of mortality in the 30 days following receipt of systemic anti-cancer therapies (SACT), and undertake a comprehensive review of the treatment decisions and experiences of a real-world population. MATERIALS AND METHODS: We reviewed NSCLC patients receiving SACT from 2005 to 2014, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data. The 30-day post-SACT mortality rate was calculated, and regimen changes in the last 14 days of life were identified. Univariate analysis and multivariate logistic regression were used to identify demographic, tumor and treatment-related factors that correlated with mortality risk. RESULTS: 1044 patients receiving ≥ 1 cycle of SACT in 2005-2014 were identified. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt; 32 (13.7%) of which had new SACT regimens ≤ 14 days prior to death. Risk of 30-day mortality and regimen changes at the end of life increased in association with being male [OR: 1.48 (1.12-1.95), p = 0.005], advanced disease at diagnosis [OR: 1.85 (1.19-2.88), p = 0.006], palliative-intent treatment [OR: 6.75 (3.88-11.77), p < 0.001], and use of EGFR-targeting agents [OR: 4.5 (3.27-6.18) p < 0.001]. Risk of early mortality decreased for never-smokers [OR: 0.62 (0.41-0.95), p = 0.028], and those receiving SACT in more recent years (2010-2014) [OR: 0.65 (0.49-0.86), p = 0.002]. CONCLUSION: Our findings identified several factors that affected the risk of early mortality in NSCLC patients following SACT. These results from a representative population provide insights regarding the benefits and risks of SACT and can serve to inform clinical and palliative best practices.

Exercise interventions and their effect on masculinity, body image, and personal identity in prostate cancer-A systematic qualitative review.

OBJECTIVE: Men with prostate cancer face various body composition and psychosocial challenges following diagnosis. Movement-based interventions such as exercise may represent novel strategies to improve these important biopsychosocial changes. This systematic qualitative review aimed to examine the various exercise interventions and their effect on male perception of masculinity, body image, and personal identity. METHODS: A systematic search across nine electronic databases was conducted in July 2017 and repeated in August 2018. Eligible studies included qualitative works examining masculinity, body image, or personal identity within an exercise intervention. Thematic content analysis allowed for qualitative synthesis across numerous studies. RESULTS: Six studies met eligibility criteria for inclusion. Four interventions used multimodal aerobic and resistance training, one incorporated aerobic exercise through football practice, and one utilized a home-based aerobic plus yoga program. Exercise was implicated to improve masculinity through creation of a safe community, allowed for refocusing on valued male traits, provided a source of distraction, and offered a means of establishing control over one's illness. Exercise also facilitated a process of self-reflection secondary to changes in physique and helped to re-establish male self-efficacy. CONCLUSIONS: Regardless of prostate cancer stage, treatment status, or prior androgen deprivation therapy exposure, both aerobic or aerobic and resistance training exerted positive effects on perceived feelings of masculinity, body image, and personal identity.

Comparison of Clinical Characteristics and Outcomes in Relapsed Versus De Novo Metastatic Non-Small Cell Lung Cancer.

OBJECTIVES: To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed. RESULTS: A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, P<0.001). Relapsed patients demonstrated significant improvements in outcomes over time. In multivariate analysis, de novo metastatic disease continued to bode a worse prognosis (adjusted hazard ratio [HR], 1.4) as did male sex (HR, 1.2), never-smoking history (HR, 1.2), and presence of extrapulmonary metastases (HR, 1.3). Systemic therapy receipt conferred better outcome (HR, 0.4), although the impact of relapsed versus de novo disease on outcomes persisted regardless of systemic therapy receipt. CONCLUSIONS: Relapsed and de novo patients represent significantly different subpopulations within metastatic NSCLC with the latter exhibiting poorer survival. This information facilitates discussions about prognosis with patients and supports screening initiatives aimed at reducing de novo disease.

Evaluating the Evidence on Sitting, Smoking, and Health: Is Sitting Really the New Smoking?

Sitting has frequently been equated with smoking, with some sources even suggesting that smoking is safer than sitting. This commentary highlights how sitting and smoking are not comparable. The most recent meta-analysis of sedentary behavior and health outcomes reported a hazard ratio of 1.22 (95% confidence interval [CI] = 1.09, 1.41) for all-cause mortality. The relative risk (RR) of death from all causes among current smokers, compared with those who have never smoked, is 2.80 (95% CI = 2.72, 2.88) for men and 2.76 for women (95% CI = 2.69, 2.84). The risk is substantially higher for heavy smokers (> 40 cigarettes per day: RR = 4.08 [95% CI = 3.68, 4.52] for men, and 4.41 [95% CI = 3.70, 5.25] for women). These estimates correspond to absolute risk differences of more than 2000 excess deaths from any cause per 100 000 persons per year among the heaviest smokers compared with never smokers, versus 190 excess deaths per 100 000 persons per year when comparing people with the highest volume of sitting with the lowest. Conflicting or distorted information about health risks related to behavioral choices and environmental exposures can lead to confusion and public doubt with respect to health recommendations.

Impact of number versus location of metastases on survival in stage IV M1b non-small cell lung cancer.

BACKGROUND: To assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Retrospective analysis was conducted on patients diagnosed during 1999-2013 with stage IV, M1b (AJCC 7th edition) NSCLC using the large, institutional Glans-Look Database, which contains patient demographic, clinical, pathological, treatment, and outcome information. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan-Meier method and Cox regression. RESULTS: We identified a total of 2065 NSCLC patients with EPMS. Median age was 67 (IQR 58-75) years, 52% were men, and 78% were current or former smokers. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EPMS, most frequent organ involvement included bone (40%), brain (32%), and liver (13%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p = 0.015). However, outcomes based on site of organ involvement were not significantly different in multivariable analysis. Compared to patients with one EPMS, individuals with two or more EPMS experienced worse outcomes (mOS ≤ 2.9 vs. 3.9 months, p < 0.001), and were associated with worse prognosis in Cox regression analysis (HR 1.5, 95% CI 1.3-1.7, p < 0.001). CONCLUSIONS: Number rather than location of EPMS is a prognostic factor in patients with stage IV M1b NSCLC. This information is relevant for accurate prognostication, stratification of participants in future clinical trials, and timely and appropriate advanced care planning.

Associations of objectively assessed physical activity and sedentary time with health-related quality of life among lung cancer survivors: A quantile regression approach.

OBJECTIVES: No studies have examined objectively assessed physical activity, sedentary time, and patient-reported outcomes among lung cancer survivors. The objective of this study was to determine associations of objectively assessed moderate-to-vigorous intensity physical activity (MVPA) and sedentary time with health-related quality of life (HRQoL) and fatigue among lung cancer survivors. MATERIALS AND METHOD: Lung cancer survivors in Southern Alberta (N = 540) were invited to complete a mailed survey that assessed HRQoL [Functional Assessment of Cancer Therapy-Lung (FACT-L)], physical and functional well-being [Trial Outcome Index (TOI)], and fatigue [Fatigue Scale (FS)]. Physical activity and sedentary time data was collected using an Actigraph® GT3X+ accelerometer that was worn on the hip for seven consecutive days. Quantile regression was used to examine associations of HRQoL and fatigue with physical activity and sedentary time at the 25th, 50th, and 75th HRQoL and fatigue percentiles. RESULTS: A total of 127 lung cancer survivors participated for a 24% response rate (Mean age = 71 years; Mean time since diagnosis = 75 months). Total MVPA minutes was positively associated with fewer fatigue symptoms at the 25th percentile (ß = 0.16, p = 0.046). Total sedentary time was inversely associated with HRQoL at the 75th percentile (ß = -0.07, p = 0.014) and inversely associated with fatigue symptoms at the 50th percentile (ß = -0.04, p = 0.009). Total sedentary time was also inversely associated with physical and functional well-being scores at the 25th (ß = -0.07, p = 0.045), 50th (ß = -0.07, p = 0.004) and 75th (ß = -0.04, p = 0.035) percentiles. CONCLUSION: Across the HRQoL, fatigue, and physical and functional well-being distributions, sedentary time was inversely associated with HRQoL, fatigue, and physical and functional well-being in lung cancer survivors. Small associations were observed between MVPA and fatigue, but no associations emerged with HRQoL or physical and functional well-being.

Cav3.1 overexpression is associated with negative characteristics and prognosis in non-small cell lung cancer.

INTRODUCTION: Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. MATERIALS AND METHODS: From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis. RESULTS: Among the cohort of 193 NSCLC patients, adenocarcinoma (53.9%) and squamous cell carcinoma (SCC) (30.1%) were the most common histologies. There was no difference between SCC and non-SCC subtypes in overall survival (OS) or relapse-free survival (RFS); 74.2 vs 90.1 months (p = 0.543) and 48.8 vs 52.6 months (p = 0.766), respectively. T-type VGCC 3.1 (Cav3.1) overexpression was assessed by tissue microarray immunohistochemistry analysis from 163 available patient samples. Eighteen (11.0%) NSCLC primaries were found to have Cav3.1 overexpression levels, and were significantly associated with SCC histology (p < 0.001), larger tumor size (p < 0.001) and later stage disease at diagnosis (p = 0.019). Median OS was 48.6 vs 106.7 months for Cav3.1 overexpressing and non-overexpressing patients, respectively (p = 0.032). Regression analysis revealed a significantly negative effect for Cav3.1 overexpression on RFS (Hazard ratio [HR] = 2.02, p = 0.048). CONCLUSIONS: Cav3.1 overexpression is a potential biomarker for poorer patient outcomes. These results bring supportive evidence for calcium channels inducing an aggressive phenotype in NSCLC and potentially may serve as a therapeutic target in overexpressing tumors.

Demographic and clinical correlates of accelerometer assessed physical activity and sedentary time in lung cancer survivors.

OBJECTIVE: To determine demographic and clinical correlates of accelerometer assessed physical activity and sedentary time among a population-based sample of lung cancer survivors. METHODS: Lung cancer survivors in Southern Alberta, Canada (N = 527) were invited to complete a mailed survey assessing socio-demographics and wear an Actigraph® GT3X+ accelerometer for 7 days. Average daily minutes of physical activity and sedentary time were derived from the accelerometer data. Accelerometer data were processed using standard Freedson cutpoints, and correlates of physical activity and sedentary time were determined with linear regression. RESULTS: A total of 127 lung cancer survivors participated (mean age = 71 years), for a 24% response rate. Moderate-to-vigorous physical activity was negatively associated with being >60 years of age (ß = -7.4, CI: -14.7, -0.10). Moderate-to-vigorous physical activity accumulated in 10-minute bouts was associated with receiving surgery and adjuvant chemotherapy (ß = 9.1, CI: 2.1, 16.1). Sedentary time was associated with being >60 years of age (ß = 32.4, CI: 3.1, 61.7), smoking (ß = 63.9, CI: 22.5, 105.4), and being overweight/obese (ß = 28.6, CI: 6.4, 50.1). CONCLUSION: Age, smoking history, and body mass index emerged as correlates of accelerometer assessed light, moderate, and vigorous physical activity, and sedentary time among lung cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Identifying correlates of physical activity and sedentary time may aid in the development of targeted behavioral interventions for this population.

Beyond disease-progression: Clinical outcomes after EGFR-TKIs in a cohort of EGFR mutated NSCLC patients.

PURPOSE: Treatment and clinical-outcomes were described in a sub-cohort of non-small-cell lung cancer (NSCLC) patients with disease-progression (PD) after epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) treatment. PATIENTS AND METHODS: We retrospectively analyzed a single-institutional EGFR mutation positive (EGFRmut+) NSCLC cohort for post-TKI-PD management, and assessed overall survival (OS) and post-progression survival (PPS). All de-novo (first lung-cancer occurrence) stage IIIA-IV patients, as well as de-novo stage IV subset was analyzed. Multi-state modeling (MSM) and a Cox PH regression model with propensity score weights adjusted for clinicopathological variables between: diagnosis and PD and PD to death. RESULTS: 123 stage IIIA-IV patients were identified with 104 meeting RECIST-1.1-PD criteria. This RECIST-1.1-PD criteria subset included females (64.6%), Asians (39.4%), never/non-smokers (55.8%), and exon 19 deletion carriers (44.2%). Commonest treatment beyond initial-PD was continuing TKI alone (46/104), with another 21 patients continuing TKI plus additional systemic therapy. The median OS for patients who continued TKI treatment at initial-PD was 21.1 months versus 15.6 months for patients who discontinued TKI, p = 0.006. Via MSM analysis, continuing TKI at initial-PD followed by other systemic therapy was associated with an 83% reduced death risk, adjusted HR: 0.17 (95% CI: 0.07, 0.39). In the Cox PH model, ever-smokers with an exon 19 deletion had increased risk of death after PD (adjusted HR: 3.19, 95% CI: 1.54, 6.58), as did exon 21 mutation carriers, (adjusted HR: 2.10, 95% CI: 1.10, 4.00) and females (adjusted HR: 3.19, 95% CI: 1.54, 6.58). CONCLUSION: Subsequent systemic therapy after continuing TKI at initial-PD reduced the risk of death. Additionally, our data suggest that positive smoking history increases death risk for some EGFR mutation types and females.