Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions.

Lung cancer is one of the most common solid cancers and represents the leading cause of cancer death worldwide. Over the last decade, research on the epithelial-mesenchymal transition (EMT) in lung cancer has gained increasing attention. Here, we review clinical and histological features of non-small-cell lung cancer associated with EMT. We then aimed to establish potential clinical implications of EMT in current therapeutic options, including surgery, radiation, targeted therapy against oncogenic drivers, and immunotherapy.

FHITlow /pHER2high signature in non-small cell lung cancer is predictive of anti-HER2 molecule efficacy.

Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2-targeted therapy has given rise to disappointing results in non-small cell lung cancer (NSCLC). With the aim of refining the target population for anti-HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti-HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT-silenced tumour cell lines. Finally, we showed that the FHITlow /pHER2high phenotype predicts sensitivity to an anti-HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT-inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti-HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prevalence of human herpesviruses infections in nonmalignant tonsils: The SPLIT study.

OBJECTIVE: To assess the prevalence of all known human herpesviruses (HHV) in tonsils of an age-stratified large sample of immunocompetent children and adults. METHODS: Patients undergoing tonsillectomy for benign indications were recruited in 19 French hospitals. After resection, the entire outer surfaces of right and left half tonsils were extensively brushed. A highly sensitive species-specific multiplex assay was used to detect herpes simplex virus 1 (HSV1), HSV2, Epstein-Barr virus (EBV; types 1 and 2), and human cytomegalovirus (CMV) DNA in 688, as well as varicella zoster virus (VZV), HHV6A, HHV6B, HHV7, and Kaposi's sarcoma-associated herpesvirus (KSHV) DNA in a subset of 440 tonsil brushings. RESULTS: Overall 85% of tonsil brushing samples were infected with at least one HHV species. HHV7 and EBV were the most prevalent (≈70%), followed by HHV6B (≈50%), HSV1, CMV, VZV (≈2%), and KSHV and HSV2 (<1%), while HHV6A was not detected. EBV prevalence was significantly higher in adults than in children, whereas it was opposite for HHV6B and VZV. No difference in HHV prevalence was observed by sex. In multivariate analysis, EBV detection was associated with age greater than or equal to 15 years (prevalence ratio [PR] = 1.8; 95% confidence interval [CI]: 1.5-2.3) and marginally with tobacco smoking (PR = 1.2; 95% CI: 1.1-1.3). CONCLUSION: Differing patterns of HHV infection in tonsils in a large age-stratified population were described. This study is by far the largest available and shows that EBV, HHV6B, and HHV7 are commonly detected in the tonsils in both men and women, in contrast to other HHVs.

Prevalence and risk factors of human polyomavirus infections in non-malignant tonsils and gargles: the SPLIT study.

The prevalence of 13 polyomaviruses (PyVs) in the tonsil brushings and gargles of immunocompetent children and adults was assessed. Patients undergoing tonsillectomy for benign indications were recruited in 19 centres in France. After resection, the entire outer surface of the right and left halves of the tonsils was brushed extensively. Gargles were also collected prior to surgery in selected adults. A species-specific multiplex assay was used to detect the DNA of 13 PyVs. In tonsil brushings (n=689), human PyV 6 (HPyV6) and Merkel cell PyV (MCPyV) were the most prevalent (≈15 %), followed by trichodysplasia spinulosa-associated PyV (TSPyV), BKPyV, Washington University PyV (WUPyV) and human PyV 9 (HPyV9) (1 to 5 %), and human PyV 7 (HPyV7), John Cunningham PyV (JCPyV) and Simian virus 40 (SV40) (<1 %), while no Karolinska Institute PyV (KIPyV), Malawi PyV (MWPyV), human PyV 12 (HPyV12) or Lyon IARC PyV (LIPyV) were detected. The prevalence of TSPyV and BKPyV was significantly higher in children versus adults, whereas for HPyV6 the opposite was found. HPyV6 and WUPyV were significantly more prevalent in men versus women. In gargles (n=139), MCPyV was the most prevalent (≈40 %), followed by HPyV6, HPyV9 and LIPyV (2 to 4 %), and then BKPyV (≈1 %), while other PyVs were not detected. MCPyV and LIPyV were significantly more prevalent in gargles compared to tonsil brushings, in contrast to HPyV6. We described differing patterns of individual PyV infections in tonsils and gargles in a large age-stratified population. Comparison of the spectrum of PyVs in paired tonsil samples and gargles adds to the current knowledge on PyV epidemiology, contributing towards a better understanding of PyV acquisition and transmission and its potential role in head and neck diseases.

Epithelial to mesenchymal transition and HPV infection in squamous cell oropharyngeal carcinomas: the papillophar study.

BACKGROUND: Human Papillomavirus (HPV) infection is recognised as aetiological factor of carcinogenesis in oropharyngeal squamous cell carcinomas (OPC). HPV-related OPC respond better to treatments and have a significantly favourable outcome. Epithelial to mesenchymal transition (EMT) implicated in tumour invasion, is a hallmark of a poor prognosis in carcinomas. METHODS: We have studied the relationship of EMT markers (E-cadherin, ß-catenin and vimentin) with HPV infection (DNA and E6/E7 mRNA detection), p16INK4a expression and survival outcomes in a cohort of 296 patients with OPC. RESULTS: Among the 296 OPSSC, 26% were HPV positive, 20.3% had overt EMT (>25% of vimentin positive tumour cells). Lower E-cadherin expression was associated with a higher risk of distant metastasis in univariate (P=0.0110) and multivariate analyses (hazard ratios (HR)=6.86 (1.98; 23.84)). Vimentin expression tends towards worse metastasis-free survival (MFS; HR=2.53 (1.00; 6.41)) and was an independent prognostic factor of progression-free survival (HR=1.55 (1.03; 2.34)). CONCLUSIONS: There was a non significant association of EMT with HPV status. This may be explained by a mixed subpopulation of patients HPV positive with associated risk factors (HPV, tobacco and alcohol). Thus, the detection of EMT in OPC represents another reliable approach in the prognosis and the management of OPC whatever their HPV status.

The human NANOS3 gene contributes to lung tumour invasion by inducing epithelial-mesenchymal transition.

We have explored the role of the human NANOS3 gene in lung tumour progression. We show that NANOS3 is over-expressed by invasive lung cancer cells and is a prognostic marker for non-small cell lung carcinomas (NSCLCs). NANOS3 gene expression is restricted in testis and brain and is regulated by epigenetic events. It is up-regulated in cultured cells undergoing epithelial - mesenchymal transition (EMT). NANOS3 over-expression in human NSCLC cell lines enhances their invasiveness by up-regulating EMT, whereas its silencing induces mesenchymal - epithelial transition. NANOS3 represses E-cadherin at the transcriptional level and up-regulates vimentin post-transcriptionally. Also, we show that NANOS3 binds mRNAs encoding vimentin and regulates the length of their poly(A) tail. Finally, NANOS3 can also protect vimentin mRNA from microRNA-mediated repression. We thus demonstrate a role for NANOS3 in the acquisition of invasiveness by human lung tumour cells and propose a new mechanism of post-transcriptional regulation of EMT.

Deep brush-based cytology in tonsils resected for benign diseases.

A fraction of oropharyngeal cancer (OPC), especially in the tonsil, is caused by human papillomavirus (HPV), mainly HPV16. Noninvasive diagnostic methods to detect precancerous lesions in the tonsil would be useful, e.g., liquid-based cytology (LBC). However, ill-characterized precancerous lesions may be hidden in the depth of the tonsillar crypts. We therefore conducted a study on HPV and tonsillar precancerous lesions to evaluate, among other things, the utility of LBC obtained by deep brushing of the resected tonsils. Two hundred non-paediatric patients (mean age: 30.3 years) who underwent tonsillectomy for infection-related conditions (69%) or other conditions (mainly obstructive sleep apnoea, 31%) were included. An ultra-sensitive Luminex bead-based platform was used to test for the DNA of 21 mucosal HPV types; 56% of slides were unsatisfactory due to low number of squamous epithelial cells or the masking effect of a large number of lymphocytes. Three patients (1.5%; 95% CI: 0.5-4.3) showed suspicious cytological findings (atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion, ASC-H) while 3 others were HPV-positive (2 for HPV16 and 1 for HPV39). None of the ASC-H patients and HPV-positive patients showed dysplasia at histological examination. The rarity of HPV infection in the tonsil conflicts with the relatively frequent detection of the virus in the mouth. In conclusion, aggressive deep brushing of tonsils, while hardly applicable in vivo, is unlikely to be a reliable method to detect precancerous lesions. The absence of OPC screening modalities places the priority on multi-purpose primary prevention strategies, i.e., HPV vaccination and reduction of smoking and drinking.

HPV-driven oropharyngeal cancer burden in Paris and its region (ILE DE FRANCE) from 1981 TO 2021.

BACKGROUND: France has the sixth highest incidence of oropharyngeal cancer (OPC) in Europe, but the epidemiological impact of high-risk HPV (HR-HPV) remains poorly documented. The objective of our study was to assess the proportion of OPCs caused by HR-HPV in Paris, and its suburbs, over the four past decades. This area accounts for almost one-fifth of the total population of France. METHODS: OPCs diagnosed in 1981, 1986, 1991, 1996, 2001, 2006, 2011, 2016 and 2020/2021 in two of the main referral cancer centers for HNCs in Paris and its suburbs were retrieved from the tumor biobanks. HPV status was determined by p16-staining and HPV-DNA detection. Samples were considered HPV-driven if both assays were positive. Results were compared to the French cancer registry data. RESULTS: Samples from 697 OPC patients were assessed (including 82 % of all samples diagnosed in 2001, 2006, 2011, 2016, 2021). The proportion of HPV-driven cases rose from 2.7 % to 53 % between 1981 and 2021. HPV16 was the dominant genotype during the study period. Of patients with HPV-driven OPC, 81 % were male and 42 % were smokers versus 80 % and 92 % in their HPV-negative counterparts. The age of OPC patients increased significantly, during the study period, independent of their HPV status CONCLUSION: The proportion of HPV-driven OPCs has significantly increased in Paris and its suburbs, during the last four decades. OPCs has become the 2nd predominant type of head and neck cancer, in France. This may be linked to the rise in HPV-driven cases and the decrease of tobacco and alcohol consumption in men.

CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis.

Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis. We previously identified, in an Affymetrix GeneChip analysis of 83 HPV-unrelated and 11 HPV-related squamous cell carcinoma of the oropharynx, several candidate genes, including CD8α and CD3ζ. Their expression was validated in this study by qRT-PCR on an independent clinical series of 144 oropharyngeal tumors. Immunohistochemical staining of tumor specimens was performed to evaluate infiltration of tumor stroma by CD8+ and CD4+ lymphocytes. The prognostic value of CD8α and CD3ζ expression levels was measured by Kaplan-Meier and Cox regression model analyses. Immune response-related signaling pathways were found to be deregulated in HPV-positive oropharyngeal tumors. Expression of CD8α, CD3ζ, granzyme K, CD28 and integrin αL RNAs was upregulated in HPV-positive lesions when compared with HPV-unrelated tumors (p < 0.05). Stroma of HPV-positive tumors was frequently and strongly infiltrated by CD8α- and CD3ζ-positive T cells. CD8α RNA expression correlated with both improved global (Kaplan-Meier; p = 0.005; Cox regression: p = 0.003) and disease-free (Cox regression: p = 0.04) survival. CD3ζ RNA expression correlated with improved overall survival (Cox regression: p = 0.024). These results suggest that an increased cytotoxic T-cell-based antitumor immune response is involved in improved prognosis of patients with HPV-positive tumors.

HER2 Alterations in Non-Small Cell Lung Cancer: Biologico-Clinical Consequences and Interest in Therapeutic Strategies.

Lung cancer stands as the first cause of death by cancer in the world. Despite the improvement in patients' outcomes in the past decades through the development of personalized medicine approaches, a substantial portion of patients remains ineligible for targeted therapies due to the lack of a "druggable" molecular target. HER2, a receptor tyrosine kinase member of the EGFR/ErbB family, is known to show oncogenic properties. In this review, we focus on the different HER2 dysregulation mechanisms that have been observed in non-small cell lung cancer (NSCLC): gene mutation, gene amplification, protein overexpression and protein hyper-phosphorylation, the latter suggesting that HER2 dysregulation can occur independently of any molecular aberration. These HER2 alterations inevitably have consequences on tumor biology. Here, we discuss how they are not only involved in abnormal proliferation and survival of cancer cells but also potentially in increased angiogenic properties, mesenchymal features and tumor immune escape. Finally, we review the impact of these HER2 alterations in various therapeutic approaches. While standard chemotherapy and groundbreaking immunotherapy seem rather ineffective for HER2-altered NSCLCs, the development of HER2-targeted therapies such as tyrosine kinase inhibitors, anti-HER2 antibodies and especially antibody-drug conjugates could provide new hopes for patients.

Soluble biomarkers to predict clinical outcomes in non-small cell lung cancer treated by immune checkpoints inhibitors.

Lung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological-driven decision.

High levels of HPV16-L1 antibody but not HPV16 DNA load or integration predict oropharyngeal patient outcome: The Papillophar study.

The incidence of oropharyngeal cancers (OPC) is increasing in the world. Among OPC, those induced by human papillomaviruses have a better prognosis than non-HPV-associated OPC. The objective of this study was to highlight the relevance of HPV16 load, HPV16 DNA integration and HPV16-L1 serology on progression-free survival and overall survival of OPC patients. The PAPILLOPHAR cohort consists of 362 patients with oropharyngeal squamous cell carcinomas prospectively followed up for 5 years after treatment. Tumor biopsies and sera were collected at inclusion to investigate tumor HPV DNA/RNA characteristics and HPV16 L1 serology, respectively. Twenty-seven percent of tumor biopsies were HPV DNA- and RNA-positive and HPV16 represented 93% of HPV-positive cases. Among them, neither HPV16 viral load nor HPV16 DNA integration was associated with overall survival (OS) or progression-free survival (PFS). In contrast, high anti-HPV16 L1 antibody titers were significantly associated with a better OS and PFS. This study reveals that HPV16 load and integration are not relevant prognosis biomarkers in OPC patients.Clinical Relevance: High levels of HPV16 L1 antibodies may be useful to predict OPC patient outcome following treatment.ClinicalTrials.gov Identifier: NCT00918710, May 2017.

Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer.

Introduction: In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance. Materials and methods: We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI). Results: We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts. Conclusion: These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.

One-year COVID-19 outcomes on the oncology care patient pathway: Results of a French descriptive, cross-sectional comprehensive study (ONCOCARE-COV).

BACKGROUND: The COVID-19 pandemic led to a widely documented disruption in cancer care pathway. Since a resurgence of the pandemic was expected after the first lockdown in France, the global impact on the cancer care pathway over the year 2020 was investigated. AIMS: This study aimed to describe the changes in the oncology care pathway for cancer screening, diagnosis, assessment, diagnosis annoucement procedure and treatment over a one-year period. MATERIALS & METHODS: The ONCOCARE-COV study was a comprehensive, retrospective, descriptive, and cross-sectional study comparing the years 2019 and 2020. All key indicators along the cancer care pathway assessing the oncological activity over four periods were described. This study was set in a high-volume, public, single tertiary care center divided in two complementary sites (Reims University Hospital and Godinot Cancer Institute, Reims, France) which was located in a high COVID-19 incidence area during both peaks of the outbreak. RESULTS: A total of 26,566 patient's files were active during the year 2020. Breast screening (-19.5%), announcement dedicated consultations (-9.2%), Intravenous and Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPECs) (-25%), and oncogeriatric evaluations (-14.8%) were heavily disrupted in regard to 2020 activity. We identified a clear second outbreak wave impact on medical announcement procedures (October, -14.4%), radiotherapy sessions (October, -16%), number of new health record discussed in multidisciplinary tumor board meeting (November, -14.6%) and HIPECs (November, -100%). Moreover, 2020 cancer care activity stagnated compared to 2019. DISCUSSION: The oncological care pathway was heavily disrupted during the first and second peaks of the COVID-19 outbreak. Between lockdowns, we observed a remarkable but non-compensatory recovery as well as a lesser impact from the pandemic resurgence. However, in absence of an increase in activity, a backlog persisted. CONCLUSION: Public health efforts are needed to deal with the consequences of the COVID-19 pandemic on the oncology care pathway.

Long-term quality of life after breast cancer: a French registry-based controlled study.

Population-based studies on quality of life (QOL) of long-term breast cancer survivors are quite recent and insufficient attention has been paid to the effect of time since diagnosis. We compared long-term QOL of population-based breast cancer survivors 5, 10, and 15 years after diagnosis with that of healthy controls. Breast cancer survivors were randomly selected from three population-based cancer registries (Bas-Rhin, Calvados and Doubs, France) along with healthy controls, stratified for age and place of residence, randomly selected from electoral rolls. Participants completed five self-administered questionnaires: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), Short Form-36 (SF-36), Spielberger State-Trait Anxiety Inventory (STAI), Multidimensional Fatigue Inventory (MFI) and a life conditions questionnaire. An analysis of variance was used to compare QOL scores of breast cancer survivors by period (5, 10, or 15 years) of diagnosis with those of controls, adjusted for sociodemographic data and comorbidities. Six hundred and fifty-two cases and 1,188 controls participated in the study. For many QOL scales, scores were significantly different between cancer survivors and controls. A clinically significant difference was evidenced for the fatigue scales, the SF36 physical functioning, role-physical, and role-emotional scales, with more favorable results for controls. Differences decreased with time and 15-year cancer survivors were generally not different from controls. Scores were particularly influenced by age and mean household income. More efforts should be made, specifically during the first 5 to 10 years after diagnosis, to help women with breast cancer to overcome their impairment in QOL.

Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy.

OBJECTIVE: We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16-related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. STUDY DESIGN: In all, 21 patients with HPV 16-related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. RESULTS: Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. CONCLUSION: These promising data warrant further development of TG4001 in CIN 2/3 treatment.

The HPV16 transcriptome in cervical lesions of different grades.

Infections with high-risk human papillomaviruses (HPV), mainly HPV type 16, can cause malignant transformation of the human cervical epithelium and cervical cancer (CxCa). Very little is known about the quantitative expression of HPV16 transcripts in cervical lesions of different grades. We have analysed the viral transcriptome in 80 HPV16 DNA positive cervical smears including lesions of different cytological grades, using nucleic acid sequence-based amplification (NASBA)-Luminex hybridisation assays quantifying spliced and unspliced HPV16 transcripts. Based on the quantitative analysis of single transcripts, highly significant changes in transcript levels were observed between different grades of cervical lesions. In conclusion, quantitative expression changes of HPV16 transcript markers may be involved in tumour progression. This study provides a basis for selection of candidate RNA markers for diagnostics of HPV16-related disease.

Hypoxia in Lung Cancer Management: A Translational Approach.

Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.

An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions.

Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.

Determinants of Human Papillomavirus Vaccine Uptake by Adult Women Attending Cervical Cancer Screening in 9 European Countries.

INTRODUCTION: Human papillomavirus-vaccinated cohorts, irrespective of age, will likely reduce their subsequent screening requirements, thus opening opportunities for global cost reduction and program sustainability. The determinants of uptake and completion of a 3-dose human papillomavirus vaccination program by adult women in a European context were estimated. STUDY DESIGN: This was an intervention study. SETTING/PARTICIPANTS: Study participants were women aged 25-45 years, attending opportunistic or population-based cervical cancer screening in Belgium, Denmark, Finland, France, Germany, Slovenia, Spain, Sweden, and the United Kingdom between April 2016 and May 2018. INTERVENTION: Study participants completed a questionnaire on awareness and attitudes on adult female human papillomavirus vaccination and were invited to receive free human papillomavirus vaccination. MAIN OUTCOME MEASURES: Main outcome measures were acceptance, uptake, and completion of vaccination schedule. Determinants of vaccine uptake were explored using multilevel logistic models in 2019. RESULTS: Among 3,646 participants, 2,748 (range by country=50%-96%) accepted vaccination, and 2,151 (range=30%-93%) received the full vaccination course. The factors associated with higher vaccine acceptance were previous awareness of adult female (OR=1.22, 95% CI=1.00, 1.48) and male (OR=1.59, 95% CI=1.28, 1.97) vaccination. Women in stable relationships (OR=0.56, 95% CI=0.45, 0.69) or with higher educational level (OR=0.76, 95% CI=0.63, 0.93) were more likely to refuse vaccination. Recruitment by postal invitation versus personal invitation from a healthcare professional resulted in lower vaccine acceptance (OR=0.13, 95% CI=0.02, 0.76). Vaccination coverage of >70% of adolescent girls in national public programs was of borderline significance in predicting human papillomavirus vaccine uptake (OR=3.23, 95% CI=0.95, 10.97). The main reasons for vaccine refusal were vaccine safety concerns (range=30%-59%) and the need for more information on human papillomavirus vaccines (range=1%-72%). No safety issues were experienced by vaccinated women. CONCLUSIONS: Acceptance and schedule completion were largely dependent on recruitment method, achieved coverage of national vaccination programs, and personal relationship status. Knowledge of benefits and safety reassurance may be critical to expanding vaccination target ages. Study results suggest that there are no major opinion barriers in adult women to human papillomavirus vaccination, especially when vaccination is offered face to face in healthcare settings. TRIAL REGISTRATION: EudraCT Number 2014-003177-42.