SEOM clinical guidelines in early stage breast cancer (2018).

Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20-30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy.

Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma.

PURPOSE: Immunotherapy (IT) agents and BRAF inhibitors (BRAFi) are effective treatments for patients with advanced BRAF-mutant melanoma although the optimal sequence remains to be elucidated. The aim of this study was to compare the outcomes of two different cohorts of patients treated with BRAFi first, then IT or the reverse sequence. PATIENTS AND METHODS: This is a retrospective study on two groups of patients: a cohort was treated first with BRAFi followed by immunotherapy (BRAFi-IT) and the other cohort with the reverse sequence (IT-BRAFi). Baseline characteristics and clinical outcomes were compared between the two cohorts. RESULTS: A total of 25 patients were included in the study. Sixteen patients were given BRAFi-IT sequence and nine received IT-BRAFi sequence. No differences were observed in the characteristics of patients prior to each treatment between cohorts. Objective response rate (ORR) achieved by BRAFi were not different among groups. ORR achieved by IT was higher when administered after BRAFi (43.8 vs 0 %). Survival rates at 1-2 years were similar in both cohorts and median overall survival was not different for BRAFi-IT and IT-BRAFi (log rank test p = 0.97). CONCLUSIONS: No differences were observed in OS between the two cohorts. These results support the indistinct use of IT or BRAFi as initial treatment in patients with metastatic BRAF-mutant melanoma, although higher rate of response to IT was observed when administered after BRAFi. Prospective randomized clinical trials are needed on this issue.

Assignment of tumor subtype by genomic testing and pathologic-based approximations: implications on patient's management and therapy selection.

BACKGROUND: Breast cancer subtypes can be identified by genomic testing or pathology-based approximations. However, these classifications are not equivalent and the clinical relevance of both classifications needs to be fully explored. METHODS: Ninety-four patients were randomized to neoadjuvant single agent doxorubicin or docetaxel. Tumor subtype was assessed by pathology-based classification and by gene expression using the PAM50 plus the claudin-low predictor (CLP). Kappa Cohen's coefficient (κ) was used to test the agreement between methods. Multivariate Cox proportional hazards analyses were used to determine the significance of each methodology in the prediction of prognosis. Likelihood ratio statistics of both classifications were evaluated. RESULTS: The agreement between pathology-based classification and PAM50 was moderate [κ = 0.551, 95 % confidence interval (95 % CI) 0.467-0.641]. Tumor subtype assessed by both classifications were prognostic for overall survival (OS) and relapse-free survival (P < 0.05). However, PAM50 + CLP provided more prognostic information, in terms of OS, than the pathology-based classification (P < 0.05). Patients with triple negative tumors as well as basal-like tumors had worse OS when first treated with doxorubicin (HR = 5.98, 95 % CI 1.25-28.67, and HR = 5.02, 95 % CI 0.96-26.38, respectively). However, claudin-low tumors did not show significant differences in OS according to neoadjuvant treatment branch. Indeed, we found that claudin-low tumors treated with pre-operative doxorubicin had significantly better OS than basal-like tumors treated with neoadjuvant doxorubicin (adjusted HR = 0.16, 95 % CI 0.04-0.69, P = 0.014). CONCLUSIONS: The assignment of tumor subtype can differ depending on the methodology, which might have implications on patient's management and therapy selection.

[Medical research in Chile: quantitative indicators]. / La investigacion medica en Chile. Indicadores epistemometricos.

Diverse indicators were used to examine medical research in Chile. According to participation in Fondecyt projects, it was concluded that 420 persons were involved in medical sciences research and that 41.9% of them had no postgraduate title. During the eighties, there was a clear aging of the community dedicated to medical research. The scientific productivity was assessed through the inventory of publications in indexed journals. During the eighties, the number of articles in Clinical Medicine and Biomedical Sciences increased two-fold. The University of Chile published the greatest number of articles, followed by the Catholic University and, with a remarkable lower amount, other Universities. The impact of the published articles in Clinical Medicine and Biomedical Sciences was calculated from the citations that they generated from 1986 to 1988. Likewise, the articles registered in 1985 with the higher citation indexes were identified.

Increased superoxide production by polymorphonuclear leukocytes in systemic lupus erythematosus.

Normal and lupus PMN show an enhancement in superoxide production in vitro when stimulated with lupus serum. When N-formyl-methionyl-leucyl-phenylalanine (FMLP) was used, lupus PMN showed an O2- production of 2.1 nmol/min/10(7) cells, which is 5.2 times the response of normal PMN stimulated by FMLP. Our results show the existence of serum factors in SLE patients that can stimulate O2- production by PMN. Lupus neutrophils showed an increased response to membrane stimuli such as FMLP, capable of triggering the cell respiratory burst. Lupus neutrophils appeared more responsive to membrane stimuli. The serum and cellular factors seemed to indicate an increase rate of superoxide production by PMN in lupus patients, which could be relevant factors in the development of vasculitis and tissue damage.

[Overview of research in Chile by several epistemolometric indicators]. / Visión de la investigación en Chile a través de algunos indicadores epistemométricos.

Scientific productivity in Chile was studied examining a data bank constructed with the publications indexed by the Institute for Scientific Information during 1987 and 1988. The bank excludes meeting abstracts and contains the full title of the published paper, the list of authors, addresses, field, and the nature of collaboration between two or more institutions. The articles were classified in different fields and tabulated according to the institution from which they originated. Although biology remains to be the more productive subject (26.5%) followed by medical sciences (23.9%) and chemistry (12.3%), articles in mathematics and physics continued their increase as in previous years. Using the scientometric indicators published by Braun et al., the impact of the research originated in Chile in biology, physics and mathematics was compared to that attained in Argentina, Brazil, Mexico and Venezuela. The role of the chilean National Research Fund and the output of the financed research projects were also analyzed. The successful results obtained during the first years in which the National Research Fund has been involved in the support of the scientific activity in Chile, confirms the need to strengthen its budget, according to the goals stated in the National Plan for Science and Technology for Development.

[Neutrophil-dependent inflammatory reactions in systemic lupus erythematosus]. / Reacciones inflamatorias neutrofilo-dependientes en Lupus Eritematoso Sistémico.

We studied the possible role of polymorphonuclear neutrophil (PMN) aggregation in Systemic Lupus Erythematosus (SLE) by the capacity of sera from 32 lupus patients to induce in vitro normal PMN aggregation. Neutrophil aggregating activity (NAA) in this group was significantly greater than that found in 8 inactive SLE patients and in 8 controls. In patients with SLE, there was a positive correlation between disease severity and the quantitative measure of NAA. High levels of NAA were particularly characteristic of central nervous system SLE. These data suggest that the formation of intravascular leukoaggregates may contribute to morbidity in SLE. Normal PMN increase their spontaneous superoxide anion production (0.21 nmol/min 10(7) PMN) when stimulated with sera from SLE patients. Lupus PMN also show an enhancement of 100% in superoxide production in vitro when stimulated with lupus sera. When N formyl methionine leucyl phenylalanine (FMLP) was used, lupus PMN showed an O2-production of 2.1 nmol/min 10(7) which is 5-fold the response of normal PMN stimulated by FMLP. Our results show the existence of seric factors in SLE patients that can stimulate O2-production by PMN. Lupus neutrophils show an increased response to membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive to membrane stimuli. The seric and the cellular factors seem to indicate an increased rate of superoxide production by PMN in SLE patients, which can be relevant to vasculitis and tissue damage.

Reacciones inflamatorias neutrofilo-dependientes en Lupus Eritematoso Sistémico. / [Neutrophil-dependent inflammatory reactions in systemic lupus erythematosus]

We studied the possible role of polymorphonuclear neutrophil (PMN) aggregation in Systemic Lupus Erythematosus (SLE) by the capacity of sera from 32 lupus patients to induce in vitro normal PMN aggregation. Neutrophil aggregating activity (NAA) in this group was significantly greater than that found in 8 inactive SLE patients and in 8 controls. In patients with SLE, there was a positive correlation between disease severity and the quantitative measure of NAA. High levels of NAA were particularly characteristic of central nervous system SLE. These data suggest that the formation of intravascular leukoaggregates may contribute to morbidity in SLE. Normal PMN increase their spontaneous superoxide anion production (0.21 nmol/min 10(7) PMN) when stimulated with sera from SLE patients. Lupus PMN also show an enhancement of 100

in superoxide production in vitro when stimulated with lupus sera. When N formyl methionine leucyl phenylalanine (FMLP) was used, lupus PMN showed an O2-production of 2.1 nmol/min 10(7) which is 5-fold the response of normal PMN stimulated by FMLP. Our results show the existence of seric factors in SLE patients that can stimulate O2-production by PMN. Lupus neutrophils show an increased response to membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive to membrane stimuli. The seric and the cellular factors seem to indicate an increased rate of superoxide production by PMN in SLE patients, which can be relevant to vasculitis and tissue damage.

Cyclophosphamide modulates arachidonic acid metabolism by peritoneal macrophages.

The treatment of mice with a single dose of cyclophosphamide (Cy) (200 mg/kg) enhanced the chemiluminescence (CL) response of peritoneal macrophages (PM) triggered with opsonized zymosan (OpZ). The enhanced CL response could not be attributed to the stimulation of the cyanide-insensitive respiratory burst, since neither superoxide anion release nor immune complex-triggered cytotoxicity, an oxygen-dependent lytic mechanism, were increased in Cy-PM. Then, products of the oxidative metabolism of arachidonic acid were measured. It was found that Cy-PM exhibited increased release of prostaglandin E2 and leukotriene C4 in response to OpZ when compared with resident PM. In contrast, similar levels of thromboxane B2 production were observed in both populations. The activation of macrophage arachidonic acid metabolism reported here may contribute to the immunomodulating action of Cy.

Neutrophil-mediated cytotoxicity triggered by immune complexes: the role of reactive oxygen metabolites.

Normal human neutrophils triggered by precipitating immune complexes (IC), soluble IC (sIC) or heat-aggregated IgG (HAIgG) displayed low levels of cytotoxicity towards nonsensitized target cells. Catalase, but not heated catalase, completely impaired this nonspecific cytotoxicity (NSC), suggesting a key role for hydrogen peroxide (H2O2) in the lysis of target cells. Superoxide dismutase (SOD) and certain HO. and 1O2 scavengers were unable to exert significant effects. Three haem-enzyme inhibitors, sodium azide, sodium cyanide and 3-amino-1,2,4-triazole did not decrease neutrophil NSC, but markedly enhanced it. This data suggest that the mechanism involved was not dependent upon myeloperoxidase (MPO). The analysis of neutrophil-mediated ADCC indicates that oxygen-dependent but MPO-independent mechanisms appeared to be operative in this system. It was also found that the microfilament disrupting agents, cytochalasin B (CB) and dihydrocytochalasin B (dhCB), as well as the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), significantly enhanced NSC. In contrast, these compounds partially inhibited ADCC. This cytotoxic system provides a suitable model to study events that may occur during the course of immune complex diseases and also permits the evaluation of alternative lytic mechanisms triggered through neutrophil Fc gamma receptors.