Evolución y resultados del tratamiento neoadyuvante en cáncer de mama durante un periodo de 10 años / Progress and oncological outcome of neoadjuvant therapy in breast cancer patients during a 10-year period

Introducción: el cáncer de mama es la neoplasia más frecuente en mujeres españolas. Los continuos avances en su tratamiento han contribuido a mejorar de forma progresiva la supervivencia en estadios precoces. Entre los avances durante los últimos años, hay que destacar el tratamiento neoadyuvante.Material y métodoshemos valorado la evolución temporal de las indicaciones y los resultados del tratamiento neoadyuvante del cáncer de mama durante un periodo de 10 años. Para ello, se han analizado las características clínicas, la respuesta completa patológica (RCp), la supervivencia global (SG) y libre de progresión (SLP) de todos los pacientes con cáncer de mama tratados con neoadyuvancia entre el 1 de enero de 2007 y el 31 de diciembre de 2016.Resultadosse han tratado 212 pacientes con cáncer de mama. A lo largo de los 10 años hemos observado un progresivo aumento en el número de pacientes tratadas con neoadyuvancia, en la edad de los pacientes incluidos (p < 0,001), en los casos de menopausia (p = 0,029), de casos triple negativo y HER2 positivo. También, hemos observado un aumento en el número de casos en los que se ha realizado cirugía conservadora y biopsia selectiva del ganglio centinela.Conclusionesel tratamiento neoadyuvante se utiliza cada vez más en las pacientes con cáncer de mama, sobre todo en los subtipos de mal pronóstico (triple negativo y HER2). La incorporación de nuevos fármacos y el tratamiento de estadios más precoces está contribuyendo a la mejora de las tasas de RCp y las cirugías conservadoras. (AU)

Introduction: Breast cancer is the most frequent tumor in Spanish women. Continuous advances in the treatment of this neoplasm, have contributed to progressively improve survival in early stages. In the last years, neoadjuvant treatment has evolved and changes have occurred in the treatment indication and in the results.Material and methodsWe have assessed the temporal evolution of indications and results of neoadjuvant therapy in breast cancer over a 10-year period. We have analyzed the clinical characteristics, the complete pathological response (CRp), overall survival (OS) and progression-free survival (PFS) of all patients with breast cancer treated with neoadjuvant therapy between January 1st 2007 and December 31st 2016.ResultsDuring the study period, 212 patients were treated.  Throughout the 10-year period, we observed that increasingly older patients had been treated (p < 0.001), a greater number of menopausal patients (p = 0.029), a greater number of triple negative and HER2 positive cases. In addition, a larger number of conservative surgeries and sentinel lymph node biopsies had been performed.ConclusionsNeoadjuvant therapy is increasing in patients with breast cancer, especially in subtypes with poor prognosis (triple negative and HER2). The emerging new drugs and treatment in earlier stages has increased the rate of pCR and breast conserving surgery. (AU)

A Multicenter Analysis of the Outcome of Cancer Patients with Neutropenia and COVID-19 Optionally Treated with Granulocyte-Colony Stimulating Factor (G-CSF): A Comparative Analysis.

BACKGROUND: Approximately 15% of patients infected by SARS-CoV-2 develop a distress syndrome secondary to a host hyperinflammatory response induced by a cytokine storm. Myelosuppression is associated with a higher risk of infections and mortality. There are data to support methods of management for neutropenia and COVID-19. We present a multicenter experience during the first COVID-19 outbreak in neutropenic cancer patients infected by SARS-CoV-2. METHODS: Clinical retrospective data were collected from neutropenic cancer patients with COVID-19. Comorbidities, tumor type, stage, treatment, neutropenia severity, G-CSF, COVID-19 parameters, and mortality were analyzed. A bivariate analysis of the impact on mortality was carried out. Additionally, we performed a multivariable logistic regression to predict respiratory failure and death. RESULTS: Among the 943 cancer patients screened, 83 patients (11.3%) simultaneously had neutropenia and an infection with COVID-19. The lungs (26%) and breasts (22%) were the primary locations affected, and most patients had advanced disease (67%). In the logistic model, as adjusted covariates, sex, age, treatment (palliative vs. curative), tumor type, and the lowest level of neutrophils were used. A significant effect was obtained for the number of days of G-CSF treatment (OR = 1.4, 95% CI [1,1,03,92], p-value = 0.01). CONCLUSIONS: Our findings suggest that a prolonged G-CSF treatment could be disadvantageous for these cancer patients with infections by COVID-19, with a higher probability of worse outcome.

Analysis of circulating tumour DNA to identify patients with epidermal growth factor receptor-positive non-small cell lung cancer who might benefit from sequential tyrosine kinase inhibitor treatment.

BACKGROUND: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach. PATIENTS AND METHODS: A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR). RESULTS: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases. CONCLUSIONS: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.

Comprehensive cross-platform comparison of methods for non-invasive EGFR mutation testing: results of the RING observational trial.

Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next-generation sequencing (NGS)-based methods, three high-sensitivity PCR-based platforms, and two FDA-approved methods were compared using 72 plasma samples, from EGFR-mutant non-small-cell lung cancer (NSCLC) patients progressing on a first-line tyrosine kinase inhibitor (TKI). NGS platforms as well as high-sensitivity PCR-based methodologies showed excellent agreement for EGFR-sensitizing mutations (K = 0.80-0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86-0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false-positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.

Benefit of primary percutaneous coronary interventions in the elderly with ST segment elevation myocardial infarction.

OBJECTIVE: Primary percutaneous coronary intervention (P-PCI) has demonstrated its efficacy in patients with ST segment elevation myocardial infarction (STEMI). However, patients with STEMI ≥75 years receive less P-PCI than younger patients despite their higher in-hospital morbimortality. The objective of this analysis was to determine the effectiveness of P-PCI in patients with STEMI ≥75 years. METHODS: We included 979 patients with STEMI ≥75 years, from the ATención HOspitalaria del Síndrome coronario study, a registry of 8142 consecutive patients with acute coronary syndrome admitted at 31 Spanish hospitals in 2014-2016. We calculated a propensity score (PS) for the indication of P-PCI. Patients that received or not P-PCI were matched by PS. Using logistic regression, we compared the effectiveness of performing P-PCI versus non-performance for the composite primary event, which included death, reinfarction, acute pulmonary oedema or cardiogenic shock during hospitalisation. RESULTS: Of the included patients, 81.5 % received P-PCI. The matching provided two groups of 169 patients with and without P-PCI. Compared with its non-performance, P-PCI presented a composite event OR adjusted by PS of 0.55 (95% CI 0.34 to 0.89). CONCLUSIONS: Receiving a P-PCI was significantly associated with a reduced risk of major intrahospital complications in patients with STEMI aged 75 years or older.

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics.

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28- CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28- CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28- CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.

Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy.

The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T-cell proliferative dysfunctionality could be reverted by PD-1/LAG-3 co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.

Sarcoma sinovial pericárdico primario: un reto clínico / Primary pericardial synovial sarcoma. A clinical challenge

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A propósito de la desensibilización rápida al ácido acetilsalicílico de pacientes con cardiopatía isquémica. Respuesta / About rapid aspirin desensitization in coronary artery disease patients. Response

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Desensibilización rápida al ácido acetilsalicílico de pacientes con cardiopatía isquémica: experiencia de un centro / Rapid desensitization to aspirin in patients with coronary artery disease: A single center experience

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Quality of Life in Spanish advanced non-small-cell lung cancer patients: determinants of global QL and survival analyses.

PURPOSE: This paper studies the Quality of Life (QL) of Spanish advanced non-small-cell lung cancer (NSCLC) patients receiving platinum-doublet chemotherapy, compares our results with those from studies from other cultural areas, and identifies factors associated with global QL and survival prognostic variables. METHODS: EORTC QLQ-C30 and QLQ-LC13 questionnaires were completed three times by 39 patients along treatment and follow-up. Univariate and multivariate logistic regression analyses were performed to study global QL determinants (≤50 points considered low global-QL score). Analyses of prognostic variables for death were performed (Cox proportional hazards models). RESULTS: QL mean scores in the whole sample were moderately high, with limitations (>30) in physical, role, social functioning, emotional areas, fatigue, pain, neuropathy and global QL. Differences with studies from other cultural areas were mainly found in the lower score for dyspnoea (≥15 points). There were no significant differences in QL scores between the first and second assessments. In six areas, the third assessment was lower than the first and second: fatigue, hair loss (>20 points); physical, social functioning, neuropathy (10-20 points); emotional functioning (5-10 points). The best model to explain the chances of low QL includes, as explanatory variables, high emotional functioning as protective factor and fatigue as risk factor (R(2) = 0.70). Eight QL areas (four pain-related) and performance status showed a statistically significant association with survival. CONCLUSION: Patients adapted well to their disease and treatments. Platinum-doublet can be administered in advanced NSCLC patients. Our QL data are in line with those from other cultural areas.

Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial.

PURPOSE: Although many studies have confirmed the synergic effects of combining chemotherapy (CT) and radiotherapy (RT), clinical data evaluating safety and efficacy of erlotinib in combination with RT in locally advanced non-small-cell lung cancer (NSCLC) are limited. The aim of this study was to determine the feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to the standard three-dimensional conformal thoracic RT in patients with unresectable or locally advanced NSCLC who are not candidates for receiving standard CT. PATIENTS AND METHODS: Feasibility and tolerability, assessed by evaluating adverse events (AEs), and effectiveness, by calculating progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and objective response rate (ORR), were analyzed in 30 patients receiving RT alone and 60 receiving RT and erlotinib. RESULTS: Erlotinib with RT showed an extended CSS and a higher rate of complete responses compared with RT alone. No differences between groups were found regarding OS, PFS, and ORR. AEs were significantly higher in the combined treatment, which mainly included cutaneous toxicity, dyspnea, fatigue, hyporexia, diarrhea, and infection. Erlotinib did not increase the toxicity produced by RT. CONCLUSION: The combination of erlotinib with RT produced, in our study, a scarce clinical benefit in the treatment of unresectable or locally advanced NSCLC, limited to complete responses and longer CSS rate compared with RT alone. Increased toxicity events were associated with combined therapy, which mainly included cutaneous toxicity. In our opinion, further studies in molecularly unselected lung cancer patients treated with EGFR TKIs and RT are not indicated. The use of biomarkers for the identification of patients that are most likely to benefit from this treatment is an essential next step in the research of this condition.

Determinants of patient satisfaction with care in a Spanish oncology day hospital and its relationship with quality of life.

OBJECTIVE: This study evaluates satisfaction with care (SC) in cancer patients treated at a Spanish day hospital to identify SC determinants and assess the relationship between SC and quality of life. METHODS: One hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Cancer Outpatient Satisfaction with Care questionnaire for chemotherapy (OUT-PATSAT35 CT), the Oberst patients' perception of care quality and satisfaction scales, and an item on intention to recommend the hospital. Frequencies in the SC instruments, Spearman correlations between each scale of the OUT-PATSAT35 CT and overall satisfaction and between the subscales of OUT-PATSAT35 CT and of QLQ-C30 were calculated, and the determinants of patients' SC were calculated through multivariate regression models. RESULTS: Satisfaction with care was high: mean scores were >70 in all OUT-PATSAT35 CT areas except doctor availability and environment. These scores were in line with the other SC instruments. Correlation with overall satisfaction was high and statistically significant (p < 0.01) for all subscales, especially for the nurses domain, which also had higher SC scores. Correlations between the EORTC QLQ-C30 and the OUT-PATSAT35 CT were low (≤ 0.35). Younger patients and those with breast cancer showed significantly lower satisfaction in most subscales. Unmarried patients and patients that had undergone surgery reported lower satisfaction only in specific subscales. CONCLUSIONS: Satisfaction with care among cancer patients treated at the day hospital is high. Nurses play a key and successful role. Age and tumour location revealed stronger relationships with SC. Correlations between SC and quality of life indicate that these concepts are complementary.

The cancer outpatient satisfaction with care questionnaire for chemotherapy, OUT-PATSAT35 CT: a validation study for Spanish patients.

PURPOSE: The OUT-PATSAT35 CT questionnaire evaluates satisfaction with care expressed by cancer outpatients receiving chemotherapy. This study assesses the psychometric properties of the OUT-PATSAT35 CT when applied to a sample of Spanish patients. METHODS: One hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30, the OUT-PATSAT35 CT, the Oberst patients' perception of care quality and satisfaction scales (OS) and the item on intention to recommend the hospital (IR). Psychometric evaluation of the structure, reliability and validity of the questionnaire was conducted. RESULTS: Multitrait scaling analysis showed that 32 of 34 item-scale correlation coefficients met the standards for convergent validity and that many of them met the standards for discriminant validity. Cronbach's coefficients were good (0.78-0.97) for all scales except doctor availability and environment. Correlations between the QLQ-C30 and the OUT-PATSAT35 CT were low (≤0.40). Correlations between IR and the OUT-PATSAT35 CT were moderate, and correlations between this questionnaire and the OS were fairly low. Areas whose contents were more related had higher correlation coefficients (>0.50) and vice versa (<0.1). Male patients, elderly patients, those with higher education levels, those with higher scores in four OS and patients who had not received surgery showed higher satisfaction with care in several OUT-PATSAT35 CT areas. CONCLUSIONS: The OUT-PATSAT35 CT is a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the validation study conducted by the authors of the questionnaire and with the validation study for Spain of the OUT-PATSAT35 RT.

The EORTC information questionnaire, EORTC QLQ-INFO25. Validation study for Spanish patients.

INTRODUCTION: The EORTC QLQ-INFO25 evaluates the information received by cancer patients. This study assesses the psychometric properties of the QLQ-INFO25 when applied to a sample of Spanish patients. MATERIALS AND METHODS: A total of 169 patients with different cancers and stages of disease completed the EORTC QLQINFO25, the EORTC QLQ-C30 and the information scales of the inpatient satisfaction module EORTC IN-PATSAT32 on two occasions during the patients' treatment and follow- up period. Psychometric evaluation of the structure, reliability, validity and responsiveness to changes was conducted. Patient acceptability was assessed with a debriefing questionnaire. RESULTS: Multi-trait scaling confirmed the 4 multi-item scales (information about disease, medical tests, treatment and other services) and eight single items. All items met the standards for convergent validity and all except one met the standards of item discriminant validity. Internal consistency for all scales (α>0.70) and the whole questionnaire (α>0.90) was adequate in the three measurements, except information about the disease (0.67) and other services (0.68) in the first measurement, as was test-retest reliability (intraclass correlations >0.70). Correlations with related areas of IN-PATSAT32 (r>0.40) supported convergent validity. Divergent validity was confirmed through low correlations with EORTC QLQ-C30 scales (r<0.30). The EORTC QLQ-INFO-25 discriminated among groups based on gender, age, education, levels of anxiety and depression, treatment line, wish for information and satisfaction. One scale and an item showed changes over time. CONCLUSIONS: The EORTC QLQ-INFO 25 is a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the EORTC validation study.

The EORTC cancer outpatient satisfaction with care questionnaire in ambulatory radiotherapy: EORTC OUT-PATSAT35 RT. Validation study for Spanish patients.

OBJECTIVES: The EORTC OUT-PATSAT35 RT questionnaire evaluates the satisfaction with care (SC) expressed by cancer outpatients treated with radiotherapy. In this study we assess the psychometric properties of the OUT-PATSAT35 RT when applied to a sample of Spanish patients. METHODS: A total of 100 patients with different tumor sites completed the EORTC core questionnaire, QLQ-C30, the OUT-PATSAT35 RT, the Oberst patients' perception of care quality and satisfaction scale (OS) and the item on intention to recommend the hospital (IR). Psychometric evaluation of the structure, reliability and validity of the questionnaire was conducted. RESULTS: Multitrait-scaling analysis showed that 33 out of 34 item-scale correlation coefficients met the standards for convergent validity and that many of them met the standards for discriminant validity. Cronbach's coefficients were good (0.70-0.97) for all scales except environment. Correlations between the areas of the QLQ-C30 and OUT-PATSAT35 RT were generally low (<0.40). Correlations between the OS and the IR were moderate with the EORTC OUT-PATSAT35 RT. Areas whose contents were more related had higher correlation coefficients (>0.50), and vice versa (<0.20). Patients with higher scores on the OS and the IR, patients who had more visits to the doctor and patients who had a better performance status showed higher SC levels in 12, 8 and 1 OUT-PATSAT35 RT areas, respectively. CONCLUSIONS: The OUT-PATSAT35 RT appears to be a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the validation study conducted by the authors of the questionnaire.