Liquid biopsy in clinical outcomes and detection of T790M mutation in metastatic non-small cell lung cancer after progression to EGFR-TKI.

BACKGROUND: Liquid biopsy (LB) is used to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and has been demonstrated to have prognostic and predictive value. OBJECTIVE: To associate the rates of EGFR and T790M mutations detected by LB during disease progression after first- or second-generation EGFR-TKIs with clinical characteristics and survival outcomes. METHODS: From January 2018 to December 2021, 295 patients with advanced EGFR mutant (EGFRm) NSCLC treated with first- or second-generation EGFR-TKIs were retrospectively analyzed. LB was collected at the time of progression. The frequency of EGFRT790M mutations, overall survival (OS), and the clinical characteristics associated with LB positivity were determined. RESULTS: The prevalence of EGFRT790M mutation detected using LB was 44%. In patients with negative vs. positive LB, the median OS was 45.0 months vs. 25.0 months (p= 0.0001), respectively. Patients with a T790M mutation receiving osimertinib had a median OS of 44 months (95% CI [33.05-54.99]). Clinical characteristics associated with positive LB at progression extra-thoracic involvement, > 3 metastatic sites, and bone metastases. CONCLUSIONS: Our findings showed that LB positivity was associated with worse survival outcomes and specific clinical characteristics. This study also confirmed the feasibility and detection rate of T790M mutation in a Latin American population.

Quality of life, anxiety, depression, and distress in patients with advanced and metastatic lung cancer.

OBJECTIVE: Lung cancer (LC) patients have shown a predisposition for developing emotional and physical symptoms, with detrimental effects on the quality of life (QoL). This study evaluates the bidirectional relationship between main psychological disorders and clinical/sociodemographic factors with the QoL. METHODS: In this observational cross-sectional study, patients with a confirmed LC diagnosis from February 2015 to March 2018 were eligible for this study. Each participant completed screening instruments of anxiety, depression, distress, and QoL assessment. Other relevant clinical data were extracted from electronic health records. Then comparisons, correlations, and logistic regression analyses were performed. RESULTS: Two hundred and four cases were eligible; of them, the median age was 61 (24-84) years, most had clinical stage IV (95%), and most were under first-line therapy (53%). Concerning psychological status, 46% had symptoms of emotional distress, 35% anxiety, and 31% depression. Patients with psychological disorders experienced a worse global QoL than those without psychological impairment (p < 0.001). Increased financial issues and physical symptoms, combined with lower functioning, were also significantly associated with anxiety, depression, and distress. In the multivariate analysis, female sex and emotional distress were positively associated with an increased risk of depression; likewise, female sex, low social functioning, insomnia, and emotional distress were associated with anxiety. CONCLUSIONS: Emotional symptoms and QoL had a significant bidirectional effect on this study; this underscores the necessity to identify and treat anxiety, depression, and distress to improve psychological well-being and the QoL in LC patients.

A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population.

BACKGROUND: Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC. METHODS: A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes. RESULTS: EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1-2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79-15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92-15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55-5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7-15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18-3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49-5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22-4.80) p = 0.011 respectively]. CONCLUSION: EGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy.

Modifying factors of PD-L1 expression on tumor cells in advanced non-small-cell lung cancer.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression predicts immunotherapy utility in nononcogenic addictive lung adenocarcinoma (ADC). However, its reproducibility and reliability may be compromised outside clinical trials. This study aimed to evaluate factors associated with PD-L1 expression in lung ADC. METHODS: This observational study assessed 547 tumor samples with advanced lung ADC from January 2016 to December 2020 in a single cancer institution. Tumor samples were stained by at least one approved PD-L1 clone, SP263 (Ventana) or 22C3 (Dako), and stratified in tumor proportion score (TPS) <1%, 1-49%, or ≥50%. RESULTS: Of all the tumor samples, positive PD-L1 staining was higher in poorly differentiated tumors (67.3% vs. 32.7%, p < 0.001). Analytical factors associated with a PD-L1 high expression (TPS ≥ 50%) were the SP263 clone (19.6% vs. 8.2%, p < 0.001), time of archival tumor tissue <12 months (15.3% vs. 3.8%, p = 0.024), whenever the analysis was performed in the most recent years (2019-2020) (19.0% vs. 8.3%, p < 0.001), and whenever the analysis was performed by pathologists in the academic setting (Instituto Nacional de Cancerologia, INCan) (19.9% vs. 11.9%, p = 0.001). In the molecular analysis, EGFR wild-type tumors had an increased proportion of PD-L1 positive and PD-L1 high cases (60.2% vs. 47.9%, p = 0.006 and 17.4% vs.8.5%, p = 0.004). A moderate correlation (r = 0.69) in the PD-L1 TPS% was observed between the two different settings (INCan vs. external laboratories). CONCLUSION: Clinicopathological factors were associated with an increased PD-L1 positivity rate. These differences were significant in the PD-L1 high group and associated with the academic setting, the SPS263 clone, time of archival tumor tissue <12 months, and a more recent period in the PD-L1 analysis.

Comparison of Optimisation Algorithms for Centralised Anaerobic Co-Digestion in a Real River Basin Case Study in Catalonia.

Anaerobic digestion (AnD) is a process that allows the conversion of organic waste into a source of energy such as biogas, introducing sustainability and circular economy in waste treatment. AnD is an intricate process because of multiple parameters involved, and its complexity increases when the wastes are from different types of generators. In this case, a key point to achieve good performance is optimisation methods. Currently, many tools have been developed to optimise a single AnD plant. However, the study of a network of AnD plants and multiple waste generators, all in different locations, remains unexplored. This novel approach requires the use of optimisation methodologies with the capacity to deal with a highly complex combinatorial problem. This paper proposes and compares the use of three evolutionary algorithms: ant colony optimisation (ACO), genetic algorithm (GA) and particle swarm optimisation (PSO), which are especially suited for this type of application. The algorithms successfully solve the problem, using an objective function that includes terms related to quality and logistics. Their application to a real case study in Catalonia (Spain) shows their usefulness (ACO and GA to achieve maximum biogas production and PSO for safer operation conditions) for AnD facilities.

Clinical Impact of the COVID-19 Pandemic in Mexican Patients with Thoracic Malignancies.

BACKGROUND: Accumulated evidence indicates that patients with lung cancer are a vulnerable population throughout the pandemic. Limited information is available in Latin America regarding the impact of the pandemic on medical care. The goal of this study was to describe the clinical and social effect of COVID-19 on patients with thoracic cancer and to ascertain outcomes in those with a confirmed diagnosis. MATERIALS AND METHODS: This cohort study included patients with thoracic neoplasms within a single institution between March 1, 2020, and February 28, 2021. All variables of interest were extracted from electronic medical records. During this period, the Depression Anxiety and Stress Scale 21 (DASS-2) was applied to evaluate and identify more common psychological disorders. RESULTS: The mean age for the total cohort (n = 548) was 61.5 ± 12.9 years; non-small cell lung cancer was the most frequent neoplasm (86.9%), advanced stages predominated (80%), and most patients were under active therapy (82.8%). Any change in treatment was reported in 23.9% of patients, of which 78.6% were due to the COVID-19 pandemic. Treatment delays (≥7 days) were the most frequent modifications in 41.9% of cases, followed by treatment suspension at 37.4%. Patients without treatment changes had a more prolonged progression-free survival and overall survival (hazard ratio [HR] 0.21, p < .001 and HR 0.28, p < .001, respectively). The mean DASS-21 score was 10.45 in 144 evaluated patients, with women being more affected than men (11.41 vs. 9.08, p < .001). Anxiety was reported in 30.5% of cases, followed by depression and distress in equal proportions (18%). Depressed and stressed patients had higher odds of experiencing delays in treatment than patients without depression (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.53-13.23, p = .006 and OR 3.18, 95% CI 1.2-10.06, p = .006, respectively). CONCLUSION: Treatment adjustments in patients with thoracic malignancies often occurred to avoid COVID-19 contagion with detrimental effects on survival. Psychological disorders could have a role in adherence to the original treatment regimen. IMPLICATIONS FOR PRACTICE: The pandemic has placed an enormous strain on health care systems globally. Patients with thoracic cancers represent a vulnerable population, with increased morbidity and mortality rates. In Mexico, treatment modifications were common during the pandemic, and those who experienced delays had worse survival outcomes. Most treatment modifications were related to a patient decision rather than a lockdown of health care facilities in which mental health impairment plays an essential role. Moreover, the high case fatality rate highlights the importance of improving medical care access. Likewise, to develop strategies facing future threats that may compromise health care systems in non-developed countries.

Impact of detecting plasma EGFR mutations with ultrasensitive liquid biopsy in outcomes of NSCLC patients treated with first- or second-generation EGFR-TKIs.

BACKGROUND: Few trials have evaluated the utility of liquid biopsies to detect epidermal growth factor receptor mutations (EGFRm) at the time of response evaluation and its association with the clinical characteristics and outcomes of non-small-cell lung cancer (NSCLC) patients. OBJECTIVE: This study aimed to evaluate, in a real-world clinical setting, the prevalence of plasma EGFRm and its association with the clinical characteristics, response and survival outcomes of NSCLC patients under treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). METHODS: This observational study enrolled advanced or metastatic NSCLC patients, with confirmed tumor EGFRm, receiving treatment with first- or second-generation EGFR-TKIs. Blood samples for the detection of plasma EGFRm were collected at the time of response evaluation and processed using the Target Selector™ assay. The main outcomes were the detection rate of plasma EGFRm, median Progression-Free Survival (PFS) and Overall Survival (OS) according to plasma EGFR mutational status. RESULTS: Of 84 patients, 50 (59.5%) had an EGFRm detected in plasma. After a median follow-up of 21.1 months, 63 patients (75%) had disease progression. The detection rate of plasma EGFRm was significantly higher in patients with disease progression than in patients with partial response or stable disease (68.3% versus 33.3%; P< 0.01). PFS and OS were significantly longer in patients without plasma EGFRm than among patients with plasma EGFRm (14.3 months [95% CI, 9.25-19.39] vs 11.0 months [95% CI, 8.61-13.46]; P= 0.034) and (67.8 months [95% CI, 39.80-95.94] vs 32.0 months [95% CI, 17.12-46.93]; P= 0.006), respectively. A positive finding in LB was associated with the presence of ⩾ 3 more metastatic sites (P= 0.028), elevated serum carcinoembryonic (CEA) at disease progression (P= 0.015), and an increase in CEA with respect to baseline levels (P= 0.038). CONCLUSIONS: In NSCLC patients receiving EGFR-TKIs, the detection of plasma EGFRm at the time of tumor response evaluation is associated with poor clinical outcomes.

Brigatinib in ALK-positive non-small cell lung cancer: real-world data in the Latin American population (Bri-world extend CLICaP).

Background: Brigatinib has demonstrated its efficacy as first-line therapy and in further lines for ALK-positive non-small cell lung cancer (NSCLC) patients; however, real-world data in Latin America are scarce. Methods: From January 2018 to March 2020, 46 patients with advanced ALK-positive NSCLC received brigatinib as second or further line of therapy in Mexico and Colombia. The primary end point was progression-free survival (PFS); secondary end point was time to treatment discontinuation (TTD). Results: At a median follow-up of 9.3 months, the median PFS was 15.2 months (95% CI: 11.6-18.8), and TTD was 18.46 months (95% CI: 9.54-27.38). The estimated overall survival at 12 months was 80%. Safety profile was consistent with previously published data. Conclusion: Brigatinib is an effective treatment for previously treated ALK-positive NSCLC patients in a real-world setting.

Recommendations for detection, prioritization, and treatment of thoracic oncology patients during the COVID-19 pandemic: the THOCOoP cooperative group.

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.

Isochrones as Indicators of the Influence of Traffic in Public Health: A Visual Simulation Application in Ávila, Spain.

It is well known that excessive rescue times after traffic accidents negatively affect the health of those injured. There is a need to quantitatively measure the impact of unexpected events like ambulance availability, weather, floating population and congestion in those rescue times. A family of indicators based on isochrones is disguised and proposed to understand the risk of the whole population as the probability of not being assisted on time. Indicators of health risk for local towns are also defined. The indicators are calculated using a simulation model and visualized in web format. The framework of analysis is validated using Ávila (Spain) and the problem of the optimal deployment of ambulances as a test-bench.

Toward early diagnosis of lung cancer.

Our long term research goal is to develop a fully automated, image-based diagnostic system for early diagnosis of pulmonary nodules that may lead to lung cancer. In this paper, we focus on generating new probabilistic models for the estimated growth rate of the detected lung nodules from Low Dose Computed Tomography (LDCT). We propose a new methodology for 3D LDCT data registration which is non-rigid and involves two steps: (i) global target-to-prototype alignment of one scan to another using the learned prior appearance model followed by (ii) local alignment in order to correct for intricate relative deformations. Visual appearance of these chest images is described using a Markov-Gibbs random field (MGRF) model with multiple pairwise interaction. An affine transformation that globally registers a target to a prototype is estimated by the gradient ascent-based maximization of a special Gibbs energy function. To handle local deformations, we displace each voxel of the target over evolving closed equi-spaced surfaces (iso-surfaces) to closely match the prototype. The evolution of the iso-surfaces is guided by a speed function in the directions that minimize distances between the corresponding voxel pairs on the iso-surfaces in both the data sets. Preliminary results show that the proposed accurate registration could lead to precise diagnosis and identification of the development of the detected pulmonary nodules.

A novel 3D joint Markov-Gibbs model for extracting blood vessels from PC-MRA images.

New techniques for more accurate segmentation of a 3D cerebrovascular system from phase contrast (PC) magnetic resonance angiography (MRA) data are proposed. In this paper, we describe PC-MRA images and desired maps of regions by a joint Markov-Gibbs random field model (MGRF) of independent image signals and interdependent region labels but focus on most accurate model identification. To better specify region borders, each empirical distribution of signals is precisely approximated by a Linear Combination of Discrete Gaussians (LCDG) with positive and negative components. We modified the conventional Expectation-Maximization (EM) algorithm to deal with the LCDG. The initial segmentation based on the LCDG-models is then iteratively refined using a MGRF model with analytically estimated potentials. Experiments with both the phantoms and real data sets confirm high accuracy of the proposed approach.

[How to reduce the incidence of traumatic phlebitis]. / Flebitis traumáticas. Cómo disminuir su incidencia.

The authors carried out an analytic study on 2572 patients to reduce the occurrence of phlebitis having a traumatic cause. The authors conclude that the use of extensions after three way valves, or infusion systems and a venous catheter, considerably reduces the risk of traumatic phlebitis occurring. Furthermore, their use reduces 1. the bother patients incur, 2. the amount of work nursing professionals have derived by the appearance of traumatic phlebitis and 3. the cost of health care.