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Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab., (© 2024. The Author(s).)

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier., (© 2023. The Author(s).)

Background: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear., Materials and Methods: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines., Results: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively., Conclusions: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Lorlatinib is an active treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) pretreated with ALK-tyrosine kinase inhibitors (-TKIs). However, there is paucity of data on the activity of platinum/pemetrexed chemotherapy administered at the time of progression on lorlatinib. In addition, it is uncertain whether continuation of lorlatinib beyond progression (LBP) would provide any additional clinical benefit. Here, we describe two cases experiencing an exceptional response to platinum/pemetrexed chemotherapy plus LBP and make an attempt to identify which patients' characteristics and biologic profiles of the tumor could predict benefit from such an approach. In this report, presence of controlled brain metastases, rapidly progressing extracranial disease, and presence of ALK-dependent mechanisms of resistance were associated with benefit from platinum/pemetrexed chemotherapy plus lorlatinib beyond progression.

Non-small-cell lung cancer (NSCLC) is the primary cause of cancer-related death. Gene rearrangements involving the anaplastic lymphoma kinase (ALK) tyrosine kinase identify a clinical and molecular subset of NSCLC patients, who benefit from the monotherapy with ALK tyrosine kinase inhibitors. Nonetheless, responsiveness to TKIs and prognosis of these patients are influenced by several factors, including resistance mechanisms and mutations affecting genes involved in key molecular pathways of cancer cells. In a cohort of 98 NSCLC patients with ALK gene rearrangements, we investigated the role of Tumor Protein (TP53) gene mutations in predicting patients prognosis. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).Results: In patients with available clinical and TP53 mutation information, we found that 13 patients (20.3%) were affected by TP53 mutations. Considered together, even though showing a trend, TP53 mutations were not associated with PFS and OS. Considering the different TP53 mutations by functionality in terms of disruptive and non-disruptive mutations, we observed that TP53 non-disruptive mutations were able to predict worse OS in the overall case series. Moreover, a worse PFS was seen in the subgroup of patients with TP53 non-disruptive mutation, in first-, second-, and third line of treatment. Our results show that mutations affecting TP53 gene, especially non-disruptive mutations, are able to affect prognosis of ALK-rearranged NSCLC patients., (Copyright © 2022. Published by Elsevier Inc.)

Treatment with immune checkpoint inhibitors (ICIs) that target the programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) axis is usually ineffective in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC), either as first-line treatment or in later lines. By contrast, especially for patients with common EGFR mutations (exon 19 deletion/L858R point mutation), an orally bioavailable EGFR tyrosine kinase inhibitor (EGFR-TKI) is the best upfront therapy, being able to provide response rates well above 50% and a median progression-free survival ranging from 11 to 19 months, depending on whether a second-generation (e.g., afatinib) or a third-generation (i.e., osimertinib) EGFR-TKI is used. Unfortunately, treatment options for these patients at the time of acquired resistance are limited. As for afatinib-pretreated patients, those who develop a T790M mutation may benefit from osimertinib, whereas platinum-based chemotherapy is the preferable therapeutic strategy for T790M-negative patients as well as for patients who progress on osimertinib administered as first-line therapy. Here, we describe the case of an exon-19-deleted patient who experienced a complete response to the anti-PD-1 agent pembrolizumab upon the development of T790M-negative acquired resistance to afatinib. Furthermore, we discuss this case in the context of the existing literature, especially focusing on the importance of evaluating multiple markers of immune response post-EGFR-TKI and prior to ICI treatment in order to select the best treatment strategy in this clinical scenario., (© 2022. The Author(s).)

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Background: Many deaths in infants from low-middle income countries (LMICs) occur at home or upon arrival to health facilities. Although acute lower respiratory tract illness plays an important role in community mortality, the accuracy of mortality rates due to respiratory syncytial virus (RSV) remains unknown., Methods: An active surveillance study among children aged under 5 years old (U5) was performed in Buenos Aires, Argentina, between January and December 2019, to define the burden and role of RSV in childhood community mortality., Results: A total of 63 families of children U5 participated in the study. Based on a combined approach of tissue sampling, verbal autopsies, and expert's analysis, RSV infection was found in the causal chain of 11 from 12 cases with positive molecular biology results in respiratory samples. The estimated mortality rate due to RSV among infants was 0.27 deaths/1000 live births. The mean age of RSV-related household deaths was 2.8 months of age (standard deviation [SD] 1.7), and 8/12 were male infants (66.7%). Dying at home from RSV was associated with Streptococcus pneumoniae and/or Moraxella catarrhalis lung coinfection (75%), living in slums and settlement (odds ratio [OR], 17.09; 95% confidence interval [CI], 1.3-219.2), and other underlying comorbidities (OR, 14.87; 95% CI, 1.3-164.6)., Conclusions: Infant community mortality rates due to RSV are higher than those reported in industrialized countries and similar to those reported in hospital-based studies in the same catchment population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated ( p < 0.05) and two genes (IFNB1 and MKI67) upregulated ( p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy ( p < 0.0001) and worse outcome in terms of both PFS ( p < 0.001) and OS ( p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16-7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1-5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of "individualized" treatments for NSCLC in the era of immunotherapy.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16-OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis ( p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation.

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical-pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (≥68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients.

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v / v ) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing.

Background: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness., Methods: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible., Results: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed., Conclusions: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.)., (Copyright © 2021 Massachusetts Medical Society.)

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT 2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology ( p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage ( p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13-3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06-2.51, p = 0.024; HR 1.54 95% CI, 1.02-2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

Analysis of circulating cell-free tumor DNA (cftDNA) has emerged as a specific and sensitive blood-based approach to detect epidermal growth factor receptor ( EGFR ) mutations in non-small cell lung cancer (NSCLC) patients. Still, there is some debate on what should be the preferential clinical method for plasma-derived cftDNA analysis. We tested 31 NSCLC patients treated with anti-EGFR tyrosine kinase inhibitors (TKIs), at baseline and serially during therapy, by comparing three methodologies in detecting EGFR mutations (L858R, exon 19 deletion, and T790M) from plasma: scorpions-amplification refractory mutation system (ARMS) methodology by using EGFR Plasma RGQ PCR Kit-QIAGEN, peptide nucleic acid (PNA) clamp and PANA RealTyper integration by using PNAClamp EGFR -PANAGENE, and digital real time PCR by using QuantStudio 3D Digital PCR System-Thermo Fisher Scientific. Specificity was 100% for all three mutations, independently from the platform used. The sensitivity for L858R (42.86%) and T790M (100%) did not change based on the method, while the sensitivity for Del 19 differed markedly (Scorpion-ARMS 45%, PNAClamp 75%, and Digital PCR 85%). The detection rate was also higher (94.23%) as measured by Digital PCR, and when we monitored the evolution of EGFR mutations over time, it evidenced the extreme inter-patient heterogeneity in terms of levels of circulating mutated copies. In our study, Digital PCR showed the best correlation with tissue biopsy and the highest sensitivity to attain the potential clinical utility of monitoring plasma levels of EGFR mutations.

Patients with epidermal growth factor receptor and anaplastic lymphoma kinase positive non-small cell lung cancer (NSCLC) generally respond poorly to treatment with immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or anti-programmed cell death ligand-1 (PD-L1) given with or without anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) drugs. However, the efficacy of immunotherapy in patients with oncogene-addicted NSCLC harboring minor drivers, such as fusions in the rearranged during transfection (RET) gene, is still unclear. Here we describe two patients with RET-positive advanced NSCLC with PD-L1 expression ≥ 50% who developed progressive disease during first-line treatment with the anti-PD-1 agent pembrolizumab. In particular, while patient 2 was immediately switched to treatment with a selective RET inhibitor within the setting of a clinical trial, patient 1 responded to cytotoxic chemotherapy delivered at the time of progression while on pembrolizumab. These cases of NSCLC are discussed in the context of current literature, which seems to support our observation that patients with RET-positive NSCLC are unlikely to benefit from immunotherapy. Therefore, we suggest that for RET-positive patients with PD-L1 ≥ 50%, consideration should be given to upfront treatment approaches other than single-agent immunotherapy, namely selective RET inhibitors (if available) or regimens including cytotoxic chemotherapy.

Oncogene-addicted non-small cell lung cancer (NSCLC) comprises a number of distinct disease subtypes, each of which is characterised by druggable genetic alterations. Among them, the receptor tyrosine kinase protein human epidermal receptor 2 (HER2) is occasionally found deregulated via gene mutation and/or amplification and/or protein overexpression. HER2 mutation, in particular, is a relatively rare condition which occurs in 1-4% of NSCLC patients, especially in those with adenocarcinoma histology and a never/light smoking history. However, the clinical relevance of a HER2 mutation in NSCLC relies on the fact that this genetic alteration has been associated with sensitivity to anti-HER2 therapies such as the monoclonal antibody trastuzumab or the pan-HER-tyrosine kinase inhibitor poziotinib. Here we describe the case of a NSCLC patient with an activating exon 20 G776VinsC mutation in the HER2 gene who responded well to multiple lines of trastuzumab-based therapies administered beyond progression and poziotinib given sequentially. In this specific case, the discovery of a druggable genetic alteration such as a mutation in the HER2 gene allowed for long-term control of the disease through the use of highly effective anti-HER2 therapies.

Purpose: KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown., Methods: Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status., Results: Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03-2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27-2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12-4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis., Conclusion: Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.

Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor ( EGFR )-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR -TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results., Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR -mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients., Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59-6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25-18.90, p = 0.023)., Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs., Competing Interests: The authors declare no conflict of interest.

Severe respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) in infants has proven challenging to prevent. In the last 50 years, conceptually different approaches failed to evolve into viable preventive alternatives for routine use. Inactivated RSV vaccine (that is, formalin-inactivated RSV) elicited severe LRTI in RSV-infected toddlers pre-immunized as infants; early purified F protein approaches in pregnant women failed to elicit sufficient immunity more than a decade ago; a second-generation monoclonal antibody (mAb) of high potency against the virus (that is, motavizumab) caused severe adverse reactions in the skin, and owing to lack of efficacy against RSV subgroup B, an extended half-life mAb targeting site V in the RSV fusion protein (that is, REG2222) did not meet its primary endpoint. In the meantime, two protein F vaccines failed to prevent medically attended LRTI in the elderly. However, palivizumab and the recent results of the Novavax maternal immunization trial with ResVax demonstrate that severe RSV LRTI can be prevented by mAb and by maternal immunization (at least to a certain extent). In fact, disease prevention may also decrease the rates of recurrent wheezing and all-cause pneumonia for at least 180 days. In this review, we discuss the history of RSV vaccine development, previous and current vaccine strategies undergoing evaluation, and recent information about disease burden and its implications for the effects of successful preventive strategies., Competing Interests: Competing interests: FPP reports grants and personal fees from Novavax, personal fees from Medimmune, grants and personal fees from Janssen, personal fees from Sanofi, personal fees from Bavarian Nordic, personal fees from Pfizer, personal fees from Merck, personal fees from ArkBio, personal fees from VirBio, personal fees from Regeneron and personal fees from Daiichi Sankyo. SJB reports no conflicts of interest.No competing interests were disclosed.No competing interests were disclosed.

Introduction: Treatment with immune checkpoint inhibitors beyond progression is associated with improved survival in patients with melanoma and clear-cell renal carcinoma. Whether this association exists for patients with non-small-cell lung cancer (NSCLC) is currently still unclear., Patients and Methods: We performed a multi-institutional retrospective study based on landmark and multivariable analyses to evaluate the safety and efficacy of treatment with nivolumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression in patients with advanced NSCLC. Criteria for receiving nivolumab beyond progression were investigator-assessed clinical benefit, stable performance status, tolerance of treatment, and no need of immediate intervention to prevent serious complication of progression., Results: Of 176 patients progressed to nivolumab according to RECIST v1.1, 60 (34.1%) were treated beyond progression (TBP) and 116 (65.9%) were not-TBP (NTBP). The median overall survival was significantly longer in the TBP group compared with the NTBP group (17.8 vs. 3.7 months; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.21-0.46; P < .0001). In a landmark analysis of evaluable patients beginning 6 weeks from first progression, the median overall survival for patients TBP was 10.7 months and for those NTBP, 3.4 months (HR, 0.48; 95% CI, 0.30-0.77; P = .002). Discontinuation of nivolumab at first progression was associated with shorter survival in multivariable analysis (HR, 2.98; 95% CI, 1.95-4.54; P < .001). No safety concerns emerged in patients who were in the TBP group., Conclusion: A subset of patients with NSCLC and progressive disease may continue to benefit from nivolumab beyond progression. Discontinuation of immunotherapy based only on RECIST v1.1 may be premature., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Immunotherapy through immune checkpoint blockers (ICBs) is quickly transforming cancer treatment by improving patients' outcomes. However, innate and acquired resistance to ICBs remain a major challenge in clinical settings. Indoleamine 2,3-dioxygenases (IDOs) are enzymes involved in tryptophan catabolism with a central immunosuppressive function within the tumor microenvironment. IDOs are over-expressed in cancer patients and have increasingly been associated with worse outcomes and a poor prognosis. Preclinical data have shown that combining IDO and checkpoint inhibition might be a valuable strategy to improve the efficacy of immunotherapy. Currently, several IDO inhibitors have been evaluated in clinical trials, showing favorable pharmacokinetic profiles and promising efficacy. This review describes the mechanisms involved in IDO-mediated immune suppression and its role in cancer immune escape, focusing on the potential clinical application of IDO inhibitors as an immunotherapy strategy for cancer treatment., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Immune-checkpoint inhibitors (ICIs) represent the standard of care for platinum-pretreated advanced non-small cell lung cancer patients. Patients treated with ICIs may experience immune-related adverse events (irAEs), that might reflect antitumor responses. Here we evaluated nivolumab efficacy according to the development of irAEs., Methods: We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions., Results: Among 195 patients [median (range) age, 63 (30-84) years; 128 men (65.6%), 67 women (34.4%)], irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in irAEs group compared to 2.0 months of no-irAEs group [HR: 0.41 (95% CI 0.3-0.57), P < 0.0001]. Median OS was 17.8 months compared to 4.0 months of no-irAEs group [HR: 0.33 (95% CI 0.23-0.47), P < 0.0001]. IrAEs were significantly associated with improved clinical outcome in 12- and 6-week landmark analysis. Patients who developed ≥ 2 irAEs during treatment (n: 37) had a significantly longer median PFS and OS compared to those with one (n: 48) or none AEs (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2.0, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4.0, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with PFS [HR: 0.48 (95% CI 0.34-0.67), P < 0.0001] and OS [HR: 0.38 (95% CI 0.26-0.56), P < 0.0001]., Conclusion: In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients treated with nivolumab monotherapy in landmark and multivariable models. Patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE further suggesting a mechanistic association between irAEs and immunotherapy efficacy.

Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted.

The aim of the present study was to assess the expression of select DNA repair and synthesis genes in non-small-cell lung cancer (NSCLC) according to KRAS mutation status. ERCC1, TS, RRM1, and BRCA1 mRNA expression levels were assessed from either primary or metastatic tumor specimens of patients diagnosed with epidermal growth factor receptor ( EGFR ) wild-type (WT) advanced NSCLC. Total RNA was isolated from paraffin-embedded tumor specimens using the RNeasy FFPE kit and automatically purified using a QiaCube instrument. Quantification levels were analyzed by real-time one-step RT-PCR using QuantiFast technology, and the results were compared considering β-actin as the internal reference gene. One hundred and eighty-four patients with advanced NSCLC were evaluated for the analysis, of which 92 were KRAS -mutants. Nearly all patients had adenocarcinoma histology (96.7%). Among KRAS -mutants, the majority had a KRAS codon 12 mutation (88%), the most common being G12C (44.4% of cases). Mean ERCC1 levels were indicated to be significantly higher in KRAS -mutants when compared with KRAS WT patients (3,234±6.63 vs. 184±1.24; P=0.05). However, mean TS levels were significantly lower in the KRAS -mutant subgroup compared with the KRAS WT subgroup (4,481±3.756 vs. 5,941±6.4; P=0.039). KRAS -mutant NSCLCs are more likely to express high ERCC1 and low TS levels. This finding may suggest different sensitivity to cytotoxic chemotherapy according to KRAS mutation status.

Osimertinib is the best treatment choice for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) whose disease progresses on a first- or second-generation EGFR-tyrosine kinase inhibitor due to acquired T790M mutation. On the other hand, there is a lack of therapeutic strategies with proven efficacy at the time of progression on osimertinib. If not administered previously, platinum-based chemotherapy can provide some clinical benefit, while immunotherapy does not seem to work in this setting. Here, we report on a unique case of response to osimertinib rechallenge after intervening chemotherapy in an EGFR T790M-positive NSCLC patient pretreated with the sequence erlotinib-osimertinib.

Although epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) mutations were thought to be mutually exclusive in patients with non-small cell lung cancer (NSCLC), the development of high sensitive large-scale mutation analysis, has increasingly shown that activating EGFR mutations occasionally coexist with other dominant genetic alterations. Herein, we discuss the case of a patient with advanced NSCLC harboring both the uncommon EGFR G719S and the KRAS G12C mutations, who was treated for 9 years with erlotinib achieving a long-term survival. In light of their rarity, multiple mutations are very challenging for the decision of tyrosine kinase inhibitors (TKIs) treatment, especially when EGFR mutations occur together with mutations known to provide resistance to EGFR TKIs, such as KRAS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Anaplastic lymphoma kinase (ALK) rearrangements represent the molecular driver of a subset of non-small cell lung cancers (NSCLCs). Despite the initial response, virtually all ALK-positive patients develop an acquired resistance to the ALK inhibitor crizotinib, usually within 12 months. Several next-generation ALK inhibitors have been developed in order to overcome crizotinib limitation, providing an unprecedented survival for this subset of patients. The aim of this review to summarize the current knowledge on ALK tyrosine kinase inhibitors (TKIs) in the treatment of advanced ALK-positive NSCLC, focusing on the role of novel ALK inhibitors in this setting. In addition, we will discuss their role in the pharmacological management of ALK-positive brain metastasis. Next-generation ALK inhibitors showed an impressive clinical activity in ALK-positive NSCLC, also against the sanctuary site of CNS. Sequential therapy with ALK TKIs appears to be effective in patients who fail a first ALK TKI and translates in clinically meaningful benefit. However, these agents display different activity profiles against crizotinib resistance mutation; therefore re-genotyping the disease at progression in order to administer the right TKI to the right patient is going to be necessary to correctly tailor the treatment. To avoid repeated invasive procedure, noninvasive methods to detect and monitor ALK rearrangement are under clinical investigation.

Epidermal growth factor receptor (EGFR)-mutated (exons 18-21) advanced non-small cell lung cancers (NSCLCs) are generally characterized by exquisite sensitivity to treatment with an EGFR-tyrosine kinase inhibitor (-TKI). First-generation or reversible EGFR-TKIs include gefitinib and erlotinib, while, more recently, second-generation or irreversible EGFR-TKIs have been developed, namely afatinib and dacomitinib, with the aim of overcoming/delaying acquired resistance to treatment. Nevertheless, clinical trials have shown that resistance eventually emerges after a median time of slightly less than one year, regardless of whether first- or second-generation EGFR-TKIs are used. In this context, a secondary EGFR mutation in exon 20, namely T790M, has been found to be responsible for approximately 60% of cases of acquired resistance. Alternatively, T790M resistance mutation can be found de novo, in which case it limits the antitumor activity of both first- or second-generation EGFR-TKIs. Osimertinb is an orally bioavailable, third-generation EGFR-TKI that acts by irreversibly binding both EGFR activating mutations and T790M, while sparing wild-type EGFR. On this basis, osimertinib has proven more efficacious than platinum-based chemotherapy in the setting of EGFR T790M-positive NSCLCs pretreated with a first- or second-generation EGFR-TKI. More recently, in another phase 3 trial, osimertinib outperformed gefitinib or erlotinib as first-line treatment of EGFR-mutated (ex19del or L858R) advanced NSCLCs, thus emerging as a new standard of care in this setting. In the present review, we will discuss the preclinical and clinical development of osimertinib, briefly touching upon its activity in special populations and biomarkers of sensitivity to treatment.

Epidermal growth factor receptor ( EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent sensitivity to EGFR tyrosine kinase inhibitors (TKIs). First-generation reversible EGFR TKIs, gefitinib and erlotinib have been proven to improve the objective response rate and to prolong the progression-free survival compared with standard chemotherapy in large phase III trials. Unfortunately, virtually all patients develop resistance to treatment, usually within 9-12 months. Afatinib is an irreversible ErbB family inhibitor initially designed to overcome the development of resistance. Compared with gefitinib in a first-line setting, afatinib prolonged progression-free survival and time to treatment failure, without impacting on overall survival in the general population of EGFR-mutant patients. However, afatinib has been shown to prolong overall survival in the subset of patients with an EGFR exon 19 deletion compared with chemotherapy. The aim of this review is to summarize the clinical evidence available to date and to critically discuss the place in therapy of afatinib in the rapidly expanding landscape of EGFR-mutant NSCLC first-line therapy.

Acquired resistance to tyrosine kinase inhibitors (TKIs) represents the Achilles' heel of targeted treatment in lung cancer. Epidermal growth factor receptor (EGFR)-TKIs are considered the standard first-line treatment for patients with EGFR mutant non-small cell lung cancer; however, after a median of 9 to 12 months, virtually all patients develop acquired resistance, which is mediated by the development of an EGFR-T790M secondary mutation in approximately 60% of cases. Different mechanisms of acquired resistance have also been described with lower incidence, including mutations in other driver oncogenes or phenotypic transformation. Herein, we report the first case of a patient with EGFR-mutant lung adenocarcinoma with a long-lasting response to first-line erlotinib treatment who acquired resistance to treatment because of acquisition of both EGFR-T790M mutation and "high-grade" large cell neuroendocrine transformation. This case also shows how resistance to third-generation EGFR-TKI osimertinib can be mediated by the development of phenotypic neuroendocrine transformation, which in the present case occurred during first-line treatment with erlotinib. In addition, our report highlights the pivotal role of rebiopsy and of molecular profiling at the time of progression to guide clinicians to choose the right therapy for the right patient., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

In this work high throughput technology and computational analysis were used to study two stage IV lung adenocarcinoma patients treated with standard chemotherapy with markedly different survival (128 months vs 6 months, respectively) and whose tumor samples exhibit a dissimilar protein activation pattern of the signal transduction. Tumor samples of the two patients were subjected to Reverse Phase Protein Microarray (RPPA) analysis to explore the expression/activation levels of 51 signaling proteins. We selected the most divergent proteins based on the ratio of their RPPA values in the two patients with short (s-OS) and long (l-OS) overall survival (OS) and tested them against a EGFR-IGF1R mathematical model. The model with RPPA data showed that the activation levels of 19 proteins were different in the two patients. The four proteins that most distinguished the two patients were BADS155/136 and c-KITY703/719 having a higher activation level in the patient with short survival and p70S6S371/T389 and b-RAFS445 that had a lower activation level in the s-OS patient. The final model describes the interactions between the MAPK and PI3K-mTOR pathways, including 21 nodes. According to our model mTOR and ERK activation levels were predicted to be lower in the s-OS patient than the l-OS patient, while the AMPK activation level was higher in the s-OS patient. Moreover, KRAS activation was predicted to be higher in the l-OS KRAS -mutated patient. In accordance with their different biological properties, the Moment Independent Robustness Indicator in s-OS and l-OS predicted the interaction of MAPK and mTOR and the crosstalk AKT with p90RSK as candidates to be prognostic factors and drug targets., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

The identification of epidermal growth factor receptor ( EGFR ) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR -tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR -TKIs within 9-14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR -TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials.

Introduction: Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC. Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile. In addition, we summarize the most common types of immune-related adverse events (irAEs) associated with nivolumab, mainly due to organ inflammation secondary to autoimmunity. Expert opinion: Nivolumab is the preferred treatment option for platinum-pretreated advanced NSCLC, having convincingly shown higher efficacy compared with standard docetaxel chemotherapy in phase III trials. The same trials showed far less incidence of either any grade and severe treatment-related AEs with nivolumab compared with chemotherapy. IrAEs associated with nivolumab are rarely severe in intensity, and often resolve with prompt management. Future studies will explore nivolumab in combination strategies with either platinum-based chemotherapy or other ICBs in treatment-naïve advanced NSCLC patients.

The bovine leukaemia virus (BLV) envelope protein (Env) is synthesized as a polyprotein precursor (gp72) proteolytically cleaved into the mature surface (SU) and transmembrane (TM) glycoproteins. The amino-terminal region of SU contains conformational epitopes F, G and H, which require a glycosylated SU to be recognized by monoclonal antibodies (MAbs) and antibodies from BLV-infected cattle. The SU contains eight asparagine (N) residues that are putative N-glycosylation sites. The N129, N203, N230 and N251 appear involved in carbohydrate binding, play an essential role in the in vitro infection. To determine which sites were actually glycosylated, we generated mutated SU forms, where each N-glycosylation site was changed to alanine (A). Subsequently, these N to A mutations were inserted into the env gene to generate Env mutants. The increase of electrophoretic mobility of EnvA256 and EnvA271 derived SU showed that the asparagine residues N256 and N271 were also glycosylated. ELISA revealed that only the N129 oligosaccharide determined the antigenic conformation of SU. The syncytium formation induced by EnvA129 showed that fusogenic capacity was independent of amino-terminal SU glycan conformational structure. Finally, anti-BLV serum inhibited syncytia formation even with the EnvA129 mutant. The latter inhibition was higher than Env, suggesting that the oligosaccharides could be also involved in the glycan shield for viral escape., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC.

Objectives: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed., Materials and Methods: We collected the data of 69 advanced ALK-positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded., Results: Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments (P=0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression (P=0.89)., Conclusion: Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of advanced non-small cell lung cancers (NSCLCs) that harbour specific EGFR activating mutations. However, the efficacy of an EGFR-TKI is limited by the onset of acquired resistance, usually within one year, in virtually all treated patients. Moreover, a small percentage of EGFR-mutant NSCLCs do not respond to an EGFR-TKI, thus displaying primary resistance. At the present time, several mechanisms of either primary and acquired resistance have been elucidated, and new drugs are currently under preclinical and clinical development in order to overcome resistance to treatment. Nevertheless, there still remains much to be thoroughly investigated, as so far research has mainly focused on the role of proteincoding genes involved in resistance to EGFR-TKIs. On the other hand, in line with the data underscoring the relevance of non-coding RNAs in the pathogenesis of lung cancer and modulation of response to systemic therapies, microRNAs (miRNAs) have been supposed to play an important role in resistance to EGFR-TKIs. The aim of this review is to briefly summarise the existing relationship between miRNAs and resistance to EGFR-TKIs, and also focusing on the possible clinical applications of miRNAs in reverting and overcoming such resistance.

Recent advances in the understanding of non-small cell lung cancer (NSCLC) biology have revealed a number of 'targetable' genetic alterations that underlie cancer growth and survival in specific patients subgroups. The anaplastic lymphoma kinase (ALK) gene rearrangement identifies a population of NSCLCs in whom dysregulation of ALK-tyrosine kinase (-TK) leads to uncontrolled proliferation of cancer cells, thus providing the basis for the therapeutic use of ALK-TK inhibitors (-TKIs) in ALK-rearranged (-positive) disease. Crizotinib was the first ALK-TKI to undergo clinical development in ALK-positive advanced NSCLC, in which it has been shown to greatly outperform the best available chemotherapy regimen in either second- or first-line setting. More recently, the novel second-generation ALK-TKI ceritinib has been shown to be highly active in either crizotinib-pretreated or -naïve population. Nevertheless, as mechanisms of resistance to crizotinib and ALK-TKIs in general are being progressively elucidated, the treatment landscape of ALK-positive NSCLC is expected to evolve rapidly. In the present review we will briefly discuss the current knowledge of ALK-positive advanced non-small cell lung cancer. Also, we will touch upon new developments on drugs/combination regimens aimed at inhibiting the ALK-TK, in an attempt to delineate how treatment of ALK-positive disease may change in the next future., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The discovery that protein-coding genes represent less than 2% of all human genome, and the evidence that more than 90% of it is actively transcribed, changed the classical point of view of the central dogma of molecular biology, which was always based on the assumption that RNA functions mainly as an intermediate bridge between DNA sequences and protein synthesis machinery. Accumulating data indicates that non-coding RNAs are involved in different physiological processes, providing for the maintenance of cellular homeostasis. They are important regulators of gene expression, cellular differentiation, proliferation, migration, apoptosis, and stem cell maintenance. Alterations and disruptions of their expression or activity have increasingly been associated with pathological changes of cancer cells, this evidence and the prospect of using these molecules as diagnostic markers and therapeutic targets, make currently non-coding RNAs among the most relevant molecules in cancer research. In this paper we will provide an overview of non-coding RNA function and disruption in lung cancer biology, also focusing on their potential as diagnostic, prognostic and predictive biomarkers.

Objective: To determine the effectiveness of developmental screening on the identification of developmental delays, early intervention (EI) referrals, and EI eligibility., Methods: This randomized controlled, parallel-group trial was conducted from December 2008 to June 2010 in 4 urban pediatric practices. Children were eligible if they were <30 months old, term, without congenital malformations or genetic syndromes, not in foster care, and not enrolled in EI. Children were randomized to receive 1 of the following: (1) developmental screening using Ages and Stages Questionnaire-II (ASQ-II and Modified Checklist for Autism in Toddlers (M-CHAT) with office staff assistance, (2) developmental screening using ASQ-II and M-CHAT without office staff assistance, or (3) developmental surveillance using age-appropriate milestones at well visits. Outcomes were assessed using an intention-to-treat analysis., Results: A total of 2103 children were enrolled. Most were African-American with family incomes less than $30,000. Children in either screening arm were more likely to be identified with delays (23.0% and 26.8% vs 13.0%; P < .001), referred to EI (19.9% and 17.5% vs 10.2%; P < .001), and eligible for EI services (7.0% and 5.3% vs 3.0%; P < .001) than children in the surveillance arm. Children in the screening arms incurred a shorter time to identification, EI referral, and EI evaluation than children in the surveillance arm., Conclusions: Children who participated in a developmental screening program were more likely to be identified with developmental delays, referred to EI, and eligible for EI services in a timelier fashion than children who received surveillance alone. These results support policies endorsing developmental screening.