Lung Cancer Screening in People With COPD: The Pamplona-IELCAP Experience.

INTRODUCTION: The Global Initiative for Obstructive Lung Disease (GOLD) recommends lung cancer screening for patients with Chronic Obstructive Pulmonary Disease (COPD), but data is lacking regarding results of screening in this high-risk population. The main goal of the present work is to explore if lung cancer screening with Low Dose Chest Tomography (LDCT) in people with COPD, allows lung cancer (LC) diagnosis in early stages with survival compatible with curative state. METHODS: This is a post hoc exploratory analysis. Pamplona International Early Lung Cancer Action Program (P-IELCAP) participants with a GOLD defined obstructive pattern (post bronchodilator FEV1/FVC<0.70) were selected for analysis. The characteristics of those who developed LC and their survival are described. A Cox proportional analysis explored the factors associated with LC diagnosis. RESULTS: Eight hundred and sixty-five patients (77% male, 93% in spirometric GOLD stage 1+2) were followed for 102±63 months. LC prevalence was 2.6% at baseline, with an annual LC diagnosis rate of 0.68%. Early-stage tumors predominated (74%) with a median survival (25-75th percentiles) of 139 (76-185) months. Cumulative tobacco exposure, FEV1%, and emphysema were the main predictors of an LC diagnosis. Eight (11%) patients with COPD had a second LC, most of them in early stage (92%), and 6 (8%) had recurrence. Median survival (25-75th percentiles) in these patients was 168 (108-191) months. CONCLUSIONS: Lung cancer screening of selected high-risk participants with COPD allowed the LC diagnosis in early stages with survival compatible with curative state.

Modification of Breast Cancer Milieu with Chemotherapy plus Dendritic Cell Vaccine: An Approach to Select Best Therapeutic Strategies.

BACKGROUND: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. METHODS: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. RESULTS: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). CONCLUSION: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.

Reference standards for gene fusion molecular assays on cytological samples: an international validation study.

AIMS: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. METHODS: Cell lines harbouring EML4(13)-ALK(20) and SLC34A2(4)-ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. RESULTS: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. CONCLUSIONS: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.

TargetPlex FFPE-Direct DNA Library Preparation Kit for SiRe NGS panel: an international performance evaluation study.

AIM: Next generation sequencing (NGS) represents a key diagnostic tool to identify clinically relevant gene alterations for treatment-decision making in cancer care. However, the complex manual workflow required for NGS has limited its implementation in routine clinical practice. In this worldwide study, we validated the clinical performance of the TargetPlex FFPE-Direct DNA Library Preparation Kit for NGS analysis. Impressively, this new assay obviates the need for separate, labour intensive and time-consuming pre-analytical steps of DNA extraction, purification and isolation from formalin-fixed paraffin embedded (FFPE) specimens in the NGS workflow. METHODS: The TargetPlex FFPE-Direct DNA Library Preparation Kit, which enables NGS analysis directly from FFPE, was specifically developed for this study by TargetPlex Genomics Pleasanton, California. Eleven institutions agreed to take part in the study coordinated by the Molecular Cytopathology Meeting Group (University of Naples Federico II, Naples, Italy). All participating institutions received a specific Library Preparation Kit to test eight FFPE samples previously assessed with standard protocols. The analytical parameters and mutations detected in each sample were then compared with those previously obtained with standard protocols. RESULTS: Overall, 92.8% of the samples were successfully analysed with the TargetPlex FFPE-Direct DNA Library Preparation Kit on Thermo Fisher Scientific and Illumina platforms. Altogether, in comparison with the standard workflow, the TargetPlex FFPE-Direct DNA Library Preparation Kit was able to detect 90.5% of the variants. CONCLUSION: The TargetPlex FFPE-Direct DNA Library Preparation Kit combined with the SiRe panel constitutes a convenient, practical and robust cost-saving solution for FFPE NGS analysis in routine practice.

Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma.

BACKGROUND: Tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). METHODS: We performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). RESULTS: The mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48×10-5) was located in the tumor-suppressor gene ALPK2. CONCLUSIONS: We describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic approaches.

Histopathological findings in fatal COVID-19 severe acute respiratory syndrome: preliminary experience from a series of 10 Spanish patients.

In December 2019, an outbreak of severe acute respiratory syndrome associated to SARS-CoV2 was reported in Wuhan, China. To date, little is known on histopathological findings in patients infected with the new SARS-CoV2. Lung histopathology shows features of acute and organising diffuse alveolar damage. Subtle cellular inflammatory infiltrate has been found in line with the cytokine storm theory. Medium-size vessel thrombi were frequent, but capillary thrombi were not present. Despite the elevation of biochemical markers of cardiac injury, little histopathological damage could be confirmed. Viral RNA from paraffin sections was detected at least in one organ in 90% patients.

Emergency stabilisation by single-stage posterior transpedicular approach for treatment of unstable lumbar spine fracture with neurological injury.

Management of unstable thoracolumbar fractures remains controversial. Furthermore, when these are accompanied by related neurological injury, the choice of approach, decompression technique and timing of the intervention could have a neuroprotective effect. In terms of site, the lumbar spine represents only 1.2% of cases, yet fractures with severe instability and neurological injury call for attainment of the same goals, i.e., neurological stability and decompression. After suffering high-energy trauma as a result of an accidental fall, a young male patient presenting with unstable injury of the lumbar spine and neurological impairment compatible with incomplete cauda equina syndrome was treated with emergency stabilisation and decompression through single-stage posterior transpedicular approach. At one year of the intervention, the patient is making good progress, with absence of lumbar pain, isolated deficit in left ankle dorsiflexion with no need of orthosis or cane, adequate sphincter control and return to his previous activity. Patients who present with unstable injury of the lumbar spine and incomplete neurological involvement can benefit from emergency stabilisation and decompression treatment by posterior transpedicular approach, with improvement in neurological status and functional recovery.

Incidental lesions of the pancreas. A clinicopathological study of 100 cases surgically treated.

OBJECTIVE: the objective of the present study was to analyze the characteristics of resected incidental lesions of the pancreas. MATERIAL AND METHODS: a retrospective study was performed of pancreatectomies due to incidentalomas between 1995 and 2018. RESULTS: one hundred pancreatectomies were performed due to incidental lesions; 64 (64%) were solid and 36 (36%) were cystic lesions. The cytological analysis agreed with the diagnosis in 67/71 (88.7%) cases. Thirty-six tumors were cystic, 48 were neuroendocrine and 16 were adenocarcinomas. Disease-free survival for patients with cystic, neuroendocrine tumors and adenocarcinomas was 100%, 79% and 57.7% (p < 0.04). CONCLUSION: pancreatic incidentalomas have a heterogeneous phenotype and should be treated in experienced centers.

TMPRSS4: A Novel Tumor Prognostic Indicator for the Stratification of Stage IA Tumors and a Liquid Biopsy Biomarker for NSCLC Patients.

Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47-3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25-3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients.

Impact of amyloid-PET in daily clinical management of patients with cognitive impairment fulfilling appropriate use criteria.

To evaluate the use of amyloid-positron emission tomography (PET) in routine clinical practice, in a selected population with cognitive impairment that meets appropriate use criteria (AUC).A multicenter, observational, prospective case-series study of 211patients from 2 level-3 hospitals who fulfilled clinical AUC for amyloid-PET scan in a naturalistic setting. Certainty degree was evaluated using a 5-point Likert scale: 0 (very low probability); 1 (low probability); 2 (intermediate probability); 3 (high probability); and 4 (practically sure), before and after amyloid PET. The treatment plan was considered as cognition-specific or noncognition-specific.Amyloid-PET was positive in 118 patients (55.9%) and negative in 93 patients (44.1%). Diagnostic prescan confidence according amyloid-PET results showed that in both, negative and positive-PET subgroup, the most frequent category was intermediate probability (45.7% and 55.1%, respectively). After the amyloid-PET, the diagnostic confidence showed a very different distribution, that was, in the negative-PET group the most frequent categories are very unlikely (70.7%) and unlikely (29.3%), while in the positive-PET group were very probable (57.6%) and practically sure (39%). Only in 14/211 patients (6.6%) the result of the amyloid-PET did not influence the diagnostic confidence, while in 194 patients (93.4%), the diagnostic confidence improved significantly after amyloid-PET results. The therapeutic intention was modified in 93 patients (44.1%). Specific treatment for Alzheimer disease was started, before amyloid-PET, in 80 patients (37.9%).This naturalistic study provides evidence that the implementation of amyloid-PET is associated with a significant improvement in diagnostic confidence and has a high impact on the therapeutic management of patients with mild cognitive impairment fulfilled clinical AUC.

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

INTRODUCTION: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. METHODS: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). RESULTS: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). CONCLUSIONS: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

BACKGROUND: Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients. METHODS: Patients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks. RESULTS: A low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage ≥3 and linitis plastica absence, were correlated to a higher risk of death. CONCLUSION: Our model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer.

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.

Metastatic tumors in the pancreas: the role of endoscopic ultrasound-guided fine-needle aspiration.

BACKGROUND AND OBJECTIVES: there are few published data on the use of EUS guided fine-needle aspiration in secondary pancreatic lesions. We describe the largest series published so far in a European country. PATIENTS AND METHODS: a retrospective review of the cases identified in our institution from 2004 to 2016 has been recorded. The clinical data are described, comparing the latency period from the primary tumor diagnosis to the detection of the pancreatic metastasis and the survival of patients according to the cytological diagnosis. RESULTS: forty-four patients were diagnosed with pancreatic metastasis using EUS guided fine needle aspiration. Ancillary cytological studies were performed in 28 (63.6%). The most common primary tumor sites were kidney and lung. Thirty-four patients (77.3%) had a previous history of malignancy, with a latency period ranging from 6 months to 18.8 years. Patients diagnosed with primary renal carcinoma had a significantly longer latency period and longer survival compared to those with primary lung cancer. In 13 patients, EUS was either the only technique that detected the PM or showed a greater number of intrapancreatic lesions. These metastases were significantly smaller than those diagnosed by other imaging studies (11.9 ± 4.1 mm vs 30.7 ± 19.8 mm, p < 0.001). CONCLUSIONS: EUS guided fine-needle aspiration plays a crucial role in the diagnosis of pancreatic metastases and may have a major clinical impact. Patients with renal cell carcinoma could benefit from long-term follow-up with EUS.

Gastrointestinal Endoscopic Ultrasound-Guided Fine-Needle Aspiration for Assessing Suspected Deep Pelvic or Abdominal Recurrence in Gynecologic Cancer: A Feasibility Study.

OBJECTIVES: To assess the feasibility of gastrointestinal endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) for histologic confirmation of cancer recurrence in women with gynecologic cancer. METHODS: This work was a retrospective cohort study comprising 46 consecutive women treated for gynecologic cancer and suspected of having a deep pelvic or abdominal recurrence on ultrasound imaging, computed tomography, positron emission tomography-computed tomography, or magnetic resonance imaging, evaluated at our institution from January 2010 to December 2017. Primary cancer was ovarian (n = 22), cervical (n = 13), endometrial (n = 4), sarcoma (n = 4), and other (n = 3). All women underwent EUS examinations for locating the lesion and guiding FNA. The results of FNA (benign/malignant) were assessed. Procedure-related complications were recorded. RESULTS: The patients' mean age was 57.8 years. A total of 66 procedures were performed. Eleven women underwent 2 procedures; 2 women underwent 3 procedures; and 1 woman underwent 6 procedures at different times during the study period. In 1 case, no lesion was detected on the EUS assessment, and in 2 cases, FNA was not successful. Most lesions were located in the retroperitoneum or involved the intestine. Fine-needle aspiration could be performed in 63 cases (94.5%). Cytologic samples were adequate in 62 of 63 (98.4%). Recurrence was confirmed in 56 cases (90.3%) and ruled out in 6 (9.7%). No patient had any complication related to the procedure. CONCLUSIONS: Endoscopic ultrasound-guided FNA is a minimally invasive, feasible, and safe technique for confirming pelvic/abdominal recurrence of gynecologic cancer.

Usefulness of Dual-Point Amyloid PET Scans in Appropriate Use Criteria: A Multicenter Study.

BACKGROUND: Biomarkers of neurodegeneration play a major role in the diagnosis of Alzheimer's disease (AD). Information on both amyloid-ß accumulation, e.g., from amyloid positron emission tomography (PET), and downstream neuronal injury, e.g., from 18F-fluorodeoxyglucose (FDG) PET, would ideally be obtained in a single procedure. OBJECTIVE: On the basis that the parallelism between brain perfusion and glucose metabolism is well documented, the objective of this work is to evaluate whether brain perfusion estimated in a dual-point protocol of 18F-florbetaben (FBB) PET can be a surrogate of FDG PET in appropriate use criteria (AUC) for amyloid PET. METHODS: This study included 47 patients fulfilling international AUC for amyloid PET. FDG PET, early FBB (pFBB) PET (0-10 min post injection), and standard FBB (sFBB) PET (90-110 min post injection) scans were acquired. Results of clinical subjective reports and of quantitative region of interest (ROI)-based analyses were compared between procedures using statistical techniques such as Pearson's correlation coefficients and t-tests. RESULTS: pFBB and FDG visual reports on the 47 patients showed good agreement (k  >  0.74); ROI quantitative analysis indicated that both data modalities are highly correlated; and the t-test analysis does not reject the null hypothesis that data from pFBB and FDG examinations comes from independent random samples from normal distributions with equal means and variances. CONCLUSIONS: A good agreement was found between pFBB and FDG data as obtained by subjective visual and quantitative analyses. Dual-point FBB PET scans could offer complementary information (similar to that from FDG PET and FBB PET) in a single procedure, considering pFBB as a surrogate of FDG.

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer.

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined  = 5.66 × 10-5 ; ORcombined  = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined  = 1.02 × 10-4 ; ORcombined  = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.

A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients.

Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early-stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n = 239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p < 0.001) and overall survival (p < 0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n = 114, p = 0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p ≤ 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Traditional gender roles and substance-use behaviors, attitudes, exposure, and resistance among early adolescents in large cities of Mexico.

This study investigated the associations between traditional gender roles (TGRs) and substance use among early adolescents in Mexico's largest cities. The sample of seventh grade students (n = 4,932) attended 26 public schools in Mexico City, Guadalajara, or Monterrey in 2014. Outcomes included recent alcohol, binge drinking, cigarette and marijuana use, and lifetime poly-substance use; substance-use intentions, norms, attitudes, and expectancies; and substance-use exposure (peer use, offers) and resistance (refusal confidence, refusal skills, and decision-making skills). A TGR scale assessed endorsement of a polarized gender division of family labor and power. As hypothesized, among males, TGRs were consistently associated with poorer outcomes, and this association was usually stronger for males than for females. In contrast, among females there was no evidence that TGRs were associated with desirable outcomes. Contrary to expectations, TGRs predicted poorer outcomes for both females and males, and to equivalent degrees, for binge drinking, cigarette use, positive substance-use expectancies, and friends' approval of substance use, and they predicted poorer outcomes for females but not for males on parental disapproval of substance use and drug-resistance skills. Interpretations highlight the persisting aspects of TGRs in the family and conflicting messages for females as Mexico undergoes changes in its gender order.

Dual modulation of MCL-1 and mTOR determines the response to sunitinib.

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3ß activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.