Value contribution of blood-based neurofilament light chain as a biomarker in multiple sclerosis using multi-criteria decision analysis.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology. Materials and methods: A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence. Conclusion: Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.

Evaluation of 2- and 3-dimensional anatomic parameters of C-shaped root canals with cone beam computed tomography, microcomputed tomography, and nanocomputed tomography.

OBJECTIVE: The objective of this study was to evaluate 2-dimensional (2D) and 3D morphometric parameters of C-shaped root canals on cone beam computed tomography (CBCT) and microcomputed tomography (microCT) images using nanocomputed tomography (nanoCT) as the reference standard. STUDY DESIGN: Sixty mandibular molars with C-shaped canals were individually scanned using nanoCT and microCT. Cone beam computed tomography acquisitions were then performed with 4 CBCT systems, using high and standard resolutions. The 2D parameters of roundness and major and minor diameters were obtained in the cross sections of the root canals at 1, 2, and 3 mm from the root apex. The 3D parameters of surface area, volume, and structure model index were measured considering the entire extension of the root canals. Absolute error (AE) in measurement was calculated against the nanoCT values. Data were statistically analyzed with the Shapiro-Wilk test and analysis of variance (α = 0.05). RESULTS: No significant differences in AE were discovered for the 2D parameters among microCT and the CBCT scans. The AE values for the 3D parameters of volume and surface area were significantly smaller in microCT compared to all CBCT units (P < .05). Significantly lower AE values for surface area were observed in high resolution compared to standard resolution for all CBCT units (P < .05). Structure model index did not differ significantly among microCT and all CBCT protocols. CONCLUSIONS: Cone beam computed tomography images showed accuracy for evaluating 2D parameters and over- and underestimation for 3D parameters.

Baseline Profiles of Drug Prescriptions Prior to Diagnosis of Mild Cognitive Impairment (MCI) Obtained by Latent Class Analysis (LCA), and Assessment of Their Association with Conversion to Dementia.

Polypharmacy has been linked to cognitive decline. However, interventions targeting modifiable risk factors, some of which are targets of the most commonly used drugs, could reduce the prevalence of dementia. Our aim was to determine the drug prescription regimen at baseline, prior to the diagnosis of mild cognitive impairment (MCI), and its possible association with progression to dementia. Data were collected from the electronic medical records of 342 MCI outpatients diagnosed during 2006-2017 at their first neurology consultation. We followed the classical three-step method of statistical analysis, starting with a Latent Class Analysis (LCA) to discover subgroups of drug prescription probability. Half of the patients were under polypharmacy (≥5 drugs), 17.5% had no recorded medication, 33.3% progressed to dementia (94.7% in ≤5 years), and 84.1% of them to Alzheimer's disease (AD). According to the LCA and based on 20 therapeutic indicators obtained from 240 substances and regrouped according the Anatomical Therapeutic Chemical Classification, we identified a four-profile model: (1) low (35.7% of patients); (2) mixed (28.7%); (3) cardio-metabolic (19.3%); and (4) psychotropic (16.4%). The binomial regression logistic model showed that profiles 2 and 3 (and 4 for AD), with a higher drug prescription conditioned probability against classic risk factors, were protective than profile 1 (OR = 0.421, p = 0.004; OR = 0.278, p = 0.000; OR = 0.457, p = 0.040, respectively), despite polypharmacy being significant in profiles 2 and 3 (mean > 7 drugs) vs. profile 1 (1.4 ± 1.6) (p = 0.000). Patients in the latter group were not significantly older, although being aged 65-79 years old quadrupled (OR = 4.217, p = 000) and being >79 tripled (OR = 2.945, p = 0.010) the conversion risk compared to patients <65 years old. According to the proposed analytical model, profiling the heterogeneous association of risk factors, which were taken prior to diagnosis, could be explored as an indicator of prior care and a predictor of conversion to dementia.

Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells.

EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.

Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry.

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

Influencia de la infección SARS-Cov2 sobre Enfermedades Neurodegenerativas y Neuropsiquiátricas: ¿Una pandemia demorada? / Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?

INTRODUCCIÓN: La infección por el coronavirus SARS-CoV2 originada en diciembre de 2019 en la región china de Wuhan ha adquirido proporciones pandémicas. A día de hoy ha ocasionado de más de 1,7 millones de contagios y más de 100.000 muertes en todo el mundo. La investigación científica actual se centra en el mejor conocimiento de la infección aguda y de sus estrategias terapéuticas. Dada la magnitud de la epidemia, planteamos una revisión especulativa sobre las posibles consecuencias en patología neurológica a medio/largo plazo, con especial atención a Enfermedades neurodegenerativas y neuropsiquiátricas con base neuroinflamatoria, teniendo en cuenta la evidencia directa de afectación neurológica a causa de la infección aguda. DESARROLLO: Revisamos de forma sistemática lo conocido sobre los mecanismos patogénicos de la infección por SARS-Cov2, la repercusión de la tormenta de citoquinas sobre el Sistema Nervioso Central y su persistencia en el tiempo y las consecuencias que la neuroinflamación puede tener sobre el Sistema Nervioso Central. CONCLUSIONES: El SARS-CoV2 es un virus neuroinvasivo capaz de provocar una tormenta de citoquinas que podría convertirse en persistente en población seleccionada. Aunque nuestra hipótesis tiene alto componente especulativo, la repercusión que esta situación puede tener en la puesta en marcha y progresión de Enfermedades neurodegenerativas y neuropsiquiátricas con base neuroinflamatoria debe ser considerada como posible germen de una pandemia demorada que podría tener un gran impacto en salud pública a medio o largo plazo. Se hace necesario un estrecho seguimiento de la salud cognitiva y neuropsiquiátrica de los pacientes supervivientes a infección Covid19

INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium-and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. Development:We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system.Conclusions:SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors

Impact of the Mental Health Care Continuity-Chain among Individuals Expressing Suicidal Behaviour in a Spanish Sample.

Poor coordination between different healthcare services means that the proper follow-up of patients cannot be guaranteed, thus increasing the risk of relapse in cases of attempted suicide. This study describes the sociodemographic variables related to suicidal behaviour in a Spanish sample and analyses how the use of a continued nursing care protocol influences the follow-up of patients who have shown suicidal behaviour. A cohort of 213 patient was identified from the emergency department medical records because of suicide attempters during 2011; 51.6% were included in the intervention group (n = 110) and 48.4% (n = 103) in the control group. We used a specific continuity of care chain protocol with the patients in the intervention group. More than half of all the initial suicide attempts were made by women; 80.3% had a previous history of a mental disorder and 65.7% of the attempts were made by ingesting medications. Significantly more patients in the intervention group attended their first follow-up visit. This study highlights the need to implement protocols that favour the continuity of mental health care processes-especially those designed to treat individuals expressing suicidal behaviour-with the aim of reducing the risk of suicide in them by intensifying their monitoring.

Characterising acquired resistance to erlotinib in non-small cell lung cancer patients.

Introduction: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges. Areas covered: In this review we will focus on the mechanisms of resistance to the first-generation EGFR TKI, erlotinib, and will mainly summarize the findings throughout the last 10 years in the field of EGFR-mutant lung cancer. Expert opinion: Widespread research has been performed and several mechanisms of resistance to EGFR TKIs, especially first- and second-generation, have been identified. Still, no adequate combinatory therapies have received regulatory approval for the treatment of EGFR-mutant patients at the time of resistance. The third-generation EGFR TKI, osimertinib has been approved for patients whose tumor has become resistant through the secondary T790M resistant EGFR mutation. The identification of the mechanisms of resistance and the application of the adequate therapy to each patient is still an unmet need.

Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.

Association between the novel classification of lung adenocarcinoma subtypes and EGFR/KRAS mutation status: A systematic literature review and pooled-data analysis.

OBJECTIVES: This study aims to determine the association of EGFR/KRAS mutation status with histological subtypes of lung adenocarcinoma (LAC) based on the IASLC/ATS/ERS classification. METHODS: Pubmed and Cochrane databases were searched from January 2011 to June 2018 for studies that included patients with LAC who underwent surgical resection were classified according to the new IASLC/ATS/ERS classification. EGFR/KRAS status assessment was requireded. The primary outcome was determined by the odds ratio (OR) of the incidence of mutation status of certain of each histological subtype. The reference group consisted of EGFR/KRAS mutation negative patients. RESULTS: Twenty-seven eligible studies involving 9022 patients with mutation gene detection were included for analysis. Among them, 6717 (74.5%) patients were from the Asian region and, 2305 (25.5%) patients were from Non-Asian regions. The most prevalent subtype was acinar (34.7%), followed by papillary (22.9%), lepidic (18.9%), solid (13.6%), micropapillary (6.3%), and invasive mucinous adenocarcinoma (3.5%). EGFR mutations were more common in patients with resected lepidic predominant adenocarcinoma (OR,1.76; 95%CI, 1.38-2.24;p < 0.01) and were rarely found in solid predominant adenocarcinoma (OR,0.28; 95%CI, 0.23-0.34;p < 0.01) or IMA (OR,0.10; 95%CI, 0.06-0.14;p < 0.01). Conversely, KRAS mutations were characterized by IMA (OR,7.01; 95%CI, 5.11-9.62;p < 0.01), and were less frequently identified in lepidic (OR,0.58; 95%CI, 0.45-0.75;p < 0.01) and acinar (OR,0.65; 95%CI, 0.55-0.78;p < 0.01) predominant subtypes. Further analyses were performed in Asian and Non-Asian groups and the results were consistent. CONCLUSIONS: The current study confirms that the IASLC/ATS/ERS classification is associated with driver gene alterations in resected LAC.

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). METHODS: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. RESULTS: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. CONCLUSION: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.

Possible application of circulating free tumor DNA in non-small cell lung cancer patients.

Liquid biopsies have been heralded as a game changer in cancer management. Blood tests offer a minimally invasive, safe and sensitive complementary (or even alternative) approach for tissue biopsies. With lung cancer being the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide, due to the limitations of tissue sampling, liquid biopsies must urgently materialize in the clinic. In this short review, we will present the current applications of cell-free DNA (cfDNA) in lung cancer management, emphasizing on our own experience and previous work. We will also shortly comment on the challenges and need for a coordinated collaboration combining disciplines and sectors (from academia to health economies) in order to accelerate liquid biopsy development in lung cancer and other cancers.

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer.

BACKGROUND: Surgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. METHODS: A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. RESULTS: Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes. CONCLUSIONS: Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients.

Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC).

Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory. Afatinib has great activity in gefitinib-sensitive as well as in gefitinib-resistant EGFR mutant NSCLC cell lines. However, afatinib therapy causes phosphorylation of STAT3 tyrosine 705 (pSTAT3Tyr705) and elevation of STAT3 and RANTES mRNA levels. The combination of afatinib with TPCA-1 (a STAT3 inhibitor) ablated pSTAT3Tyr705 and down-regulated STAT3 and RANTES mRNA levels with significant growth inhibitory effect in both gefitinib-sensitive and gefitinib-resistant EGFR mutant NSCLC cell lines. Aldehyde dehydrogenase positive (ALDH+) cells were still observed with the combination at the time that Hairy and Enhancer of Split 1 (HES1) mRNA expression was elevated following therapy. Although the combination of afatinib with STAT3 inhibition cannot eliminate the potential problem of a remnant cancer stem cell population, it represents a substantial advantage and opportunity to further prolong progression free survival and probably could increase the response rate in comparison to the current standard of single therapy.

Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.

Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-ß pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-ß, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed.

Liquid biopsy in early stage lung cancer.

Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). However, 30% to 80% of these patients will die within 5 yearS of diagnosis. Circulating cell-free DNA (cfDNA) harbors pathologic characteristics of the original tumor, such as gene mutations or epigenetic alterations. Analysis of cfDNA has revolutionized the clinical care of advanced lung cancer patients undergoing targeted therapies. However, the low concentration of cfDNA in the blood of early-stage NSCLC patients has hampered its use for management of early disease. Continuing development of more specific and sensitive techniques for detection and analysis of cfDNA will soon enable its leverage in early stage and, perhaps, even screening settings. Therefore, cfDNA analysis may become a tool used for routine NSCLC diagnosis and for monitoring tumor burden, as well as for identifying hidden residual disease. In this review, we will focus on the current evidence of cfDNA in patients with early-stage NSCLC, new and upcoming approaches to identify circulating-tumor biomarkers, their clinical applications and future directions.

Melanoma: oncogenic drivers and the immune system.

Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches.

PTEN and PI3K/AKT in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. In the last years, the identification of activating EGFR mutations, conferring increased sensitivity and disease response to tyrosine kinase inhibitors, has changed the prospect of NSCLC patients. The PTEN/PI3K/AKT pathway regulates multiple cellular functions, including cell growth, differentiation, proliferation, survival, motility, invasion and intracellular trafficking. Alterations in this pathway, mainly PTEN inactivation, have been associated with resistance to EGFR-tyrosine kinase inhibitor therapy and lower survival in NSCLC patients. In this review, we will briefly discuss the main PTEN/PI3K/AKT pathway alterations found in NSCLC, as well as the cell processes regulated by PTEN/PI3K/AKT leading to tumorigenesis.