Explore the vast range of titles available.

Background AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Methods Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016–December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. Results 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. Conclusion This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Trial registration Clinical trial registration number : NCT03790397 .

Molecular genetic profiling is crucial for treatment choice in patients with advanced non-small cell lung cancer (NSCLC). The Lung-ONE study aimed to determine the clinical utility of comprehensive genomic profile (CGP) tests, such as FoundationOne CDx or FoundationOne Liquid, in guiding second line therapy decisions for advanced NSCLC patients in Spain. Additionally, the study sought to describe the genomic alterations found in these patients. This national, multicenter, prospective study included adult patients diagnosed with advanced/metastatic NSCLC undergoing first line treatment with molecular diagnostic wild-type (or unknown) for at least ALK, EGFR, and ROS-1 genes under clinical practice conditions. Physicians planned their therapeutic decision for second line treatment according to the standard of care (SOC) and subsequently re-evaluated this initial decision after a Foundation One or Foundation ACT test (FMI) report was provided. Patients continue to be followed up for up to 2 years. The study analyzed 151 advanced NSCLC patients. The FMI report identified 542 driver mutations in actionable genes for 132 patients, including mutations in EGFR, ALK, and BRAF that were previously missed by single-gene testing as per SOC. Additional driver alterations were also detected in ERBB2/HER2, MET, and RET genes. FMI identified mutations with designated therapies in 116 patients. Consequently, clinicians identified 44 (29.1%) patients with gene alterations associated with off-label drugs, and 13 (8.6%) patients were directed toward clinical trials. Using FMI data, clinicians were able to direct patients toward clinical trials and to modify SOC clinical management for several NSCLC patients. These results demonstrate the benefit of FMI genomic profiling in identifying actionable driver mutations that would otherwise be missed by SOC methodology. The findings suggest that CGP is a promising and robust tool for improving personalized medicine in NSCLC treatment in Spain.

Objectives: The main objectives of the study were (1) to set-up a droplet digital PCR (ddPCR) assay for the non-invasive detection of G719S EGFR mutation in NSCLC patients; (2) to determine the limits of detection of the ddPCR assay for G719S mutation and (3) to compare COBAS® and ddPCR System for G719S quantification in plasma.Materials and Methods: Blood samples were collected from 22 patients diagnosed with advanced NSCLC. Then, plasma ctDNA was extracted with the Qiagen Circulating Nucleic Acids kit and quantified by QuantiFluor® dsDNA System. The mutational study of EGFR was carried out by digital droplet PCR (ddPCR) with the QX200 Droplet Digital PCR System with specific probes and primers.Results: We observed the lowest percentage of G719S mutant allele could be detected in a wildtype background was 0.058%. In the specificity analysis, low levels of G719S mutation were detected in healthy volunteers with a peak of 21.65 mutant copies per milliliter of plasma and 6.35 MAFs. In those patients whose tissue biopsy was positive for G719S mutation, mutant alleles could also be detected in plasma using both ddPCR and COBAS® System. Finally, when mutational status was studied using both genotyping techniques, higher mutant copies/ml and higher mutant allele fraction (MAF) correlated with higher Semiquantitative Index obtained by COBAS®.Conclusions: Although tissue biopsies cannot be replaced due to the large amount of information they provide regarding tumor type and structure, liquid biopsy and ddPCR represents a new promising strategy for genetic analysis of tumors from plasma samples. In the present study, G719S mutation was detected in a highly sensitive manner, allowing its monitorization with a non-invasive technique.

Toxic epidermal necrolysis (TEN) is an infrequent disease but with a high mortality rate. It is a mucocutaneous reaction resulting from hypersensitivity to a variety of agents including most anticonvulsants. Many patients with primary or metastatic intracranial tumours receive anticonvulsants for seizure prophylaxis despite their efficacy not having been clearly demonstrated. Moreover, several cases have been reported in the literature in which serious adverse drug reactions such as TEN and Stevens-Johnson syndrome (SJS) have occurred following anticonvulsants exposure. In some of these cases the effect of radiation therapy and the tapering of steroid dose on the pathogenesis of these reactions have been highlighted. We report, here, a case of TEN that appeared in a patient receiving phenytoin, and shortly after the end of cranial and thoracic irradiation therapy for brain metastases of non-small cell lung cancer. Clinical considerations about diagnosis of SJS and TEN are presented. The use of prophylactic anticonvulsants is also discussed as well as a review of the literature.

The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian cancer. Growing evidence suggests that Wnt signaling may also be crucial for tumorigenesis and progression of soft tissue sarcomas (STS), a malignant neoplasm with few therapeutic options at an advanced state. Our study with several STS cell lines and primary cultures shows that inhibition of Wnt/β-catenin signaling with PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates. TCF/β-catenin-mediated transcriptional activity is decreased in treated cells, leading to downregulation of its target genes CCND1 and CDC25A. The latter was critical because its downregulation via siRNA was able to mimic the effect of PRI-724 on cell cycle arrest and cell death induction. An evaluation of NCBI/GenBank data confirmed that CDC25A mRNA is elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergistic manner according to isobolographic analysis, suggesting that Wnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS.

Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

The evolution of performance status, disability, and quality of life (QL) according to the Hebrew Rehabilitation Center for Aged QL (HRCA-QL) index for cancer patients through their terminal period is described. The assessment of HRCA-QL validity and reliability is also described. A total of 200 cancer patients were followed up from the onset of their \"terminal phase\" until they died. Information on symptoms, performance, disability and QL were collected by patient's oncologists in hospital and by their family practitioners and community nurses when the patient was at home. Health measures were: the HRCA-QL index, Karnofsky performance status (KPS) and the Independence in Activities of Daily Living (IADL) index. The three indices were acceptable for a fair number of patients at the start of the terminal phase. Almost two-thirds had a KPS > or =60. With respect to the IADL index, the patients were independent in five of the six functions, with 80% having a HRCA-QL equal to or greater than 4. The median duration of the terminal period was 59 days. All three indices declined progressively, with marked deterioration in the last 2 weeks. The HRCA-QL index was highly correlated with KPS and the IADL index, had good internal consistency and showed an acceptable test-retest and inter-rater reliability. The HRCA-QL index was reactive to clinical changes. All three scales confirmed that terminal patients experience a progressive loss of performance, increase in dependence and deterioration of QL as they approach the end of life. Based in these results, we consider the HTCA-QL index valid for use in terminal cancer patients.

Epigenetic clocks have been widely used to estimate biological age across various tissues, but their accuracy in breast tissue remains suboptimal. Pan-tissue models such as Horvath's and Hannum's clocks, perform poorly in predicting chronological age in breast tissue, underscoring the need for a tissue-specific approach. In this study, we introduce a Breast Tissue-specific Epigenetic Clock (BTEC), developed using DNA methylation data from 553 healthy breast tissue samples across seven different studies. BTEC significantly outperformed pan-tissue clocks, demonstrating superior correlation with chronological age (r=0.88) and lower prediction errors (MAE=3.27 years) without requiring for dataset-specific regressions adjustments. BTEC's chronological age predictions for tumor-adjacent samples showed distortions, with an average deviation of -1.76 years, which was even more pronounced in tumor samples, where the average difference between predicted and chronological age was -12.29 years. When analyzed by molecular subtype, the distortion was greater in the more aggressive HER2+ and TNBC tumors compared to HR+ tumors. The probes used by BTEC were associated with known oncogenes, genes involved in estrogen metabolism, cadherin binding and fibroblast growth factor binding. Despite the general rejuvenation observed in tumor tissue compared to normal breast, the correlation between BTEC's predictions and cancer-related survival indicated that TNBC tumors with increased epigenetic ages had significant lower survival.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We corrected figure 6 and added the description of survival analysis and hazard ratio methods.

Background: AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Methods: Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. 155 patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. Results: 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. 155 patients were evaluable for response, 1.3% complete response, 40.7% partial response, 31% stable disease and 11.6% progressive disease. Objective response rate was 42%. Median progression-free survival was 9.4 months. 49% reported an adverse event, the majority of which (78%) were grade 1 or 2. The resource cost study indicates early use is warranted. Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number: NCT03790397