Alectinib after failure to crizotinib in patients with ALK-positive non-small cell lung cancer: results from the Spanish early access program.

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology.

OBJECTIVES: The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. METHODS: Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. RESULTS: A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54-111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48-2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01-7.36; p < 0.001). CONCLUSION: Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.

Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy, subsequently concomitant with radiotherapy (RT) in patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC). Analysis of survival and value of ctDNA for patient selection.

BACKGROUND: Little progress has been achieved in non-small cell lung cancer (NSCLC) patients with unresectable stage III disease and new drug schemes are warranted. MATERIAL AND METHODS: In this open-label, single-arm, phase II trial 65 treatment-naïve stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m2 every 21 days plus metronomic oral vinorelbine at 50 mg/day every Monday, Wednesday and Friday. During the concomitant treatment with thoracic radiotherapy cisplatin was administered in the same manner but oral vinorelbine was reduced to 30 mg/day. The objective was to administer a total radiotherapy dose of 66 Gy in 33 daily fractions of 2 Gy. The primary endpoint was progression-free survival (PFS). Correlation between circulating tumor DNA (ctDNA) levels and survival was also evaluated. RESULTS: Fifty-five (78.5 %) patients completed treatment. Overall response rate, by RECIST criteria, was 66.2 %. Four (6.2 %) patients had complete response, 39 (60.0 %) partial response and 12 (18.5 %) stable disease. Seven patients (10.8 %) had progressive disease during the induction period. Median follow-up was 29.1 months (m), median PFS was 11.5 m (95 %CI: 9.6-15.4). PFS at 12 m in the intention-to-treat (ITT) population was 47.8 % (95 %CI: 35.1-59.4 %) and median OS was 35.6 m (95 %CI: 24.4-46.8). Grade ≥3 treatment-related adverse events occurred in 14 (21.5 %) patients during induction and in 13 (24.5 %) patients during concomitant treatment with esophagitis occurring in 3% and pneumonitis in 1.5 % of the patients. Patients with undetectable ctDNA after 3 m follow-up had median PFS and OS of 18.1 m (95 %CI: 8.8-NR) and not reached (NR) (95 %CI: 11.3-NR), respectively, compared with 8.0 m (95 %CI: 2.7-NR) and 24.7 m (95 %CI: 5.7-NR) for patients who remained ctDNA positive at that time point. CONCLUSIONS: Metronomic oral vinorelbine and cisplatin obtains similar efficacy results with significantly lower toxicity than the same chemotherapy at standard doses. ctDNA can identify populations with particularly good prognosis.

ASTRIS, a large real-world study to evaluate the efficacy of osimertinib in epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer patients: Clinical characteristics and genotyping methods in a Spanish cohort / ASTRIS, un gran estudio en el mundo real para evaluar la eficacia de osimertinib en pacientes de cáncer de pulmón no microcítico positivo a la mutación de T790M del receptor del factor de crecimiento epidérmico: características clínicas y métodos de genotipificación en una cohorte española

PURPOSE: Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. METHODS: ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. RESULTS: The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. CONCLUSIONS: ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices

OBJETIVO: Osimertinib ha probado su eficacia en los pacientes de cáncer de pulmón no microcítico (CPNM) positivo a la mutación de EGFR T790M; sin embargo, sus beneficios no han sido evaluados en el mundo real. MÉTODOS: ASTRIS es un estudio de brazo único, abierto y multinacional para evaluar la eficacia y la seguridad de osimertinib para el tratamiento del CPNM positivo a la mutación de EGFR T790M. Presentamos el diseño del estudio y los resultados del análisis del punto de corte (octubre de 2017), que describe las características basales y la metodología de la detección de la mutación de T790M en la cohorte española. RESULTADOS: La cohorte española incluyó 131 pacientes de entre un total de 3.014 sujetos. Cuarenta pacientes (28,1%) seguían en terapia en el momento del punto de corte, el 68,7% eran mujeres y el 97,7% eran caucásicos, con una edad media de 64,8 (DE: 11,7) años. El tipo más común de muestra para evaluar las mutaciones de T790M fue tisular (55%), habiéndose obtenido las muestras del tumor primario en el 61,1% de los casos. El análisis de la mutación fue realizado por parte del laboratorio local en el 60,3% de los casos, utilizando el ensayo Roche Cobas® EGFR en el 43,5% de los casos. CONCLUSIONES: Se espera que ASTRIS confirme los beneficios de osimertinib en el mundo real. Los datos sobre las prácticas en el mundo real para la detección de la mutación de EGFR T790M podrían proporcionar información adicional para aportar directrices sobre las mejores prácticas

ASTRIS, a large real-world study to evaluate the efficacy of osimertinib in epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer patients: Clinical characteristics and genotyping methods in a Spanish cohort.

PURPOSE: Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. METHODS: ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. RESULTS: The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. CONCLUSIONS: ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices.

Changes in lung cancer survival by TNM stage in the Basque country from 2003 to 2014 according to period of diagnosis.

INTRODUCTION: The objective of this study was to analyze the survival of patients with lung cancer by TNM stage in the 4-year periods 2003-2006, 2007-2010 and 2011-2014, treated in the Basque Health Service, and to compare this with survival in an equivalent sample of the general population. METHODS: A retrospective observational design was applied to cases from the Hospital Cancer Registry of Euskadi. A cohort of 11,635 patients had complete data for the following variables: TNM stage, age, sex, histology, date of diagnosis, vital status and date of death. Relative survival and Cox and parametric regression models were used to assess changes in survival. RESULTS: The lung cancer 5-year survival probability decreased with increasing stage, from 50-65% in patients with stage I disease to 2-3% in those with stage IV disease. Comparing patients diagnosed from 2011-2014 and 2003-2006, we found that survival improved: (a) the risk of death (hazard ratio) in 2003-2006 was 1.66 for stage I, 1.51 for stage II, 1.21 for stage III, and 1.10 for stage IV; (b) the 5-year relative survival increased from 11.0% to 17.8% in the period 2011-2014; and (c) the years of life lost decreased significantly from 2003-2006 to 2011-2014, varying between 6.16 (stage I) and 16.21 (stage IV). CONCLUSIONS: Survival from lung cancer by stage in the Basque Country has lengthened significantly across all disease stages. Nonetheless, since we estimated that lung cancer patients still have significantly lower mean survival times than the general population, there is a need for more research to improve these outcomes.

Clinical management and outcome of patients with advanced NSCLC carrying EGFR mutations in Spain.

BACKGROUND: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. METHODS: All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. RESULTS: Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. CONCLUSION: EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC.

Overnight observation in stand-alone surgicenters: is the practice safe?

The safety of performing operations in surgery centers that require overnight stays has not been established. To determine whether this practice is safe we performed a retrospective chart review of all cases performed at Paces over a 12-year period. There were 12,072 total cases and 11,147 general anesthesia (GA) or monitored anesthesia care (MAC) cases. Four thousand eight hundred ten patients stayed overnight. The hospital admission rate for patients undergoing either GA or MAC was 0.12% and for local anesthesia it was 0%. Overnight stay patients had a rate of 0.15%, while same day discharge patients had a rate of 0.08%. Excluding local anesthesia cases, the rate increased to 0.10%. For the GA and MAC patients, there was no statistical difference in hospitalization rates between the same day and the overnight stay groups. All patients had good outcomes after hospitalization. Performing operations that require an overnight stay in a surgery center can be a safe practice.

What we know about the structure of NCX1 and how it relates to its function.

NCX1 is modeled to contain nine transmembrane segments (TMS) with a large intracellular loop between TMS 5-6 and two reentrant loops connecting TMS 2-3 and TMS 7-8. NCX1 also contains two regions of internal repeats. The alpha repeats are composed of TMS 2 and 3 and TMS 7 and 8 and are involved in ion binding and transport. The beta repeats are in the large intracellular loop and are involved in binding of regulatory Ca2+. Our studies on the structure/function analysis of NCX1 have focused on the alpha- and beta-repeat regions and on how the TMS pack in the membrane. We have examined the alpha1 repeat by mutagenesis of residues modeled to be in the reentrant loop and TMS 3 and by determination of ion affinities of the mutants. Our results show that TMS 3 and not the reentrant loop is involved in Na+ binding. No mutants demonstrated altered affinity for transported Ca2+. We have synthesized a fusion protein composed of the beta1 repeat. This fusion protein was expressed in Escherichia coli and purified. The fusion protein binds Ca2+ and shows conformational changes on binding. The crystal structure of the beta1 repeat shows that it is composed of a seven-stranded beta-sandwich with Ca2+-binding sites located at one end of the sandwich. Four Ca2+ ions bind to the beta1 repeat in a manner reminiscent of Ca2+ binding to C2 domains. Packing of TMS in the membrane has been studied by cross-linking induced mobility shifts on SDS-PAGE. Interactions between TMS 1, 2, 3, 6, 7, and 8 have been identified.

[Expression of multidrug resistance (MDR)-associated proteins in solid tumors]. / Expresión de proteínas relacionadas con resistencia a múltiples fármacos (MDR-proteínas) en tumores sólidos.

The causes of drug resistance in tumor cells vary widely. The present study aims to provide an update of multidrug resistance in tumor cells and, in particular, of multidrug resistance-associated proteins.

Expresión de proteínas relacionadas con resistencia a múltiples fármacos (MDR-proteínas) en tumores sólidos / Expresssion of multidrug resistance (MDR)-associated proteins in solid tumors

Las causas de que una célula tumoral sea resistente a la quimioterapia son muchas y de variada naturaleza. El motivo del presente trabajo es realizar una revisión y una puesta al día de una de estas posibles causas, en concreto, la expresión de proteínas relacionadas con la resistencia a múltiples fármacos (AU)

The causes of drug resistance in tumor cells vary widely. The present study aims to provide an update of multidrug resistance in tumor cells and, in particular, of multidrug resistance-associated proteins (AU)

Validating three-dimensional imaging of the breast.

The potential to extrapolate accurate data from 3-dimensional (3D) images of the breast is enormous and will greatly improve our ability to qualitatively determine differences in shape, size, and contour. The validity of these calculated measurements is important and needs to be determined before any meaningful data can be evaluated. PART I: Premastectomy 3D images (3dMD patient) were obtained on 19 breasts (14 patients). The volume of the mastectomy specimen was determined intraoperatively using water displacement. Two independent raters then calculated breast volumes using the 3D images and software, and these were compared with the intraoperative volume. Inter- and intrarater reliability was determined. Part II: Surface measurements (nipple to notch) were then evaluated on 20 breasts (10 patients) by comparing the 3D image determined distance to the known measurements. PART I: The average breast volume was 500 mL, compared with 489 mL for rater 1 and 490 mL for rater 2. The relative difference between the measured volume and the calculated volume for rater 1 and rater 2 was about -2%, with a standard deviation of +/- 13% to 16%. The coefficient of reproducibility for each reader was excellent, at 0.80 for rater 1 and 0.92 for rater 2. The level of agreement between the readers was also high at 0.975. Part II: The average nipple to notch measurement for each patient was 27.1 cm, compared the calculated average of 25.1 cm for rater 1 and 26.1 cm for rater 2. The mean relative difference between the measured and calculated distances for raters 1 and 2 was about -6%, with a standard deviation of +/- 6% to 7%. The level of agreement between readers was high, at 0.975. The ability to objectively determine breast volume and surface measurements using 3D imaging technology is now available with consistent and reproducible accuracy. Measurements are typically underestimated, with more variability when calculating volumes. Although inherent subjectivity will always exist when evaluating breast measurements, 3D technology provides invaluable information, particularly in the longitudinal evaluation of results.

The constricted ear.

The constricted ear may be described best as a pursestring closure of the ear. The deformity may include lidding of the upper pole with downward folding, protrusion of the concha, decreased vertical height, and low ear position relative to the face. The goals of surgical correction should include obtaining symmetry and correcting the intra-auricular anatomy. The degree of intervention is based on the severity of the deformity and may range from simple repositioning, soft tissue rearrangement, or manipulation of the cartilage. Multiple surgical techniques are described.

Cryptotia: principles and management.

Adequate treatment of the cryptotic ear must address both recreation of the upper pole and correction of the vertical height. The degree of soft tissue manipulation ia dictated by the severity of the deformity. Often this must be combined with repositioning or reconstruction of the cartilaginous skeleton.