Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Dental arch size, biting force, bizygomatic width and face height in three Colombian ethnic groups / Tamaño del arco dental, fuerza de mordida, anchura bizigomatica y altura facial en tres grupos étnicos colombianos

The objective of this study was to describe transversal dimensions of the dental arches, bite force and facial index in three ethnic groups representative of Colombia. The sample size included 197 adolescents, 12 to 14 year old, 33% mestizo, 35% of African ancestry and 32% Amazon Indian; 50.3% male and 49.7% female. The comparative analysis to determine differences between ethnic groups was made by the Kruskal Wallis test and then the Principal Component Analysis was used to establish the pattern of measurements identifying ethnic characteristics. All measurements showed statistically significant differences among ethnic groups except facial height (p=0.157). It was evidenced that Amazon indian have a higher bite force (p <0.05) than the other twoethnic groups. Regarding dental arch transversal dimensions, Amazon Indian have a higher arch transversal width with a length average of 44.1 mm. This length was greater than mestizo adolescents (M=36.7 mm) and Afroamerican (M=38.3 mm). In conclusion, the amazon Ticuna Indian ethnia has a significantly higher bite force, higher dental arch transversal width and higher bizygomatic width than the other two ethnic groups considered.

El objetivo fue describir las dimensiones transversales de los arcos dentales, la fuerza de mordida y el índice facial en tres grupos étnicos de Colombia. El tamaño de la muestra fue de 197 adolescentes, de 12 a 14 años; 33% mestizos, 35% de ascendencia africana y 32% indio amazónico; 50,3% hombres y 49,7% mujeres. El análisis comparativo para determinar las diferencias entre los grupos étnicos se hizo mediante la prueba de Kruskal Wallis y luego el Componente Principal de Análisis se utilizó para establecer el patrón de las mediciones para identificar las características étnicas. Todas las mediciones mostraron diferencias estadísticamente significativas entre los grupos étnicos, excepto la altura facial (p=0,157). Se evidencia que el indio amazónico tiene una mayor fuerza de mordida (p<0,05) que los otros dos grupos étnicos. En cuanto a las dimensiones transversales del arco dental, el indio amazónico se caracterizó por tener un mayor ancho, con una longitud media de 44,1 mm. Esta longitud es mayor que en los adolescentes mestizos (M=36,7 mm) y afroamericanos (M=38,3 mm). En conclusión, la etnia india amazónica Ticuna tiene una fuerza de mordida significativamente mayor, así como mayor ancho del arco dental transversal y ancho bicigomático que los otros dos grupos étnicos considerados.

Impact of human leukocyte antigen molecules E, F, and G on the outcome of transplantation.

BACKGROUND: HLA class I molecules are divided into classic (Ia) and nonclassic (Ib). Nonclassic HLA molecules (E, F, and G) have acquired relevance owing to their immunomodulatory properties and possible repercussions for induction of tolerance in organ transplantation. The objective of this study was to identify the impact of these molecules on transplant success or failure. METHODS: A systematic review of literature was performed with the use of MeSH terms in Pubmed. Clinical trials, randomized clinical trials, case-control studies, and reviews from the past 15 years were included. RESULTS: HLA-E*0103/E*0103 genotype is associated with lower risk of graft-versus-host disease, decreased mortality, and greater disease-free survival after bone marrow transplantation. There were no significant associations between HLA-F and clinical outcomes in any of the studies. Elevated serum levels of HLA-G were associated with a lower incidence of rejection in hepatic and renal transplantation during the 1st year and lower T-cell response after bone marrow, liver, and kidney transplantation. Detection of mRNA of HLA-G1 was also associated with less graft rejection. CONCLUSIONS: Current literature suggests that nonclassic HLA Ib molecules play an important role in immunotolerance in organ transplantation; however, more studies are required to predict outcomes related to specific genotypes.

Analysis of dental arch dimensions in three Colombian ethnic groups / Análisis de las dimensiones del arco dental en tres grupos étnicos colombianos

The purpose of this study was to compare dental arch transversal and anteroposterior dimensions in three ethnic groups from Colombia. A digital caliper was used to take 16 transversal and two sagittal measurements, 9 for the upper jaw and 9 for the lower jaw. The sagittal measure determining arch length was drawn from a mesial line traced from first right permanent molar to first left permanent molar, and a perpendicular line from the point of contact between central incisive teeth, both for the upper and lower jaw. The dimensions of upper dental arch in the three ethnic groups showed differences in intercanine distance, as well as between premolar and between molar teeth. The same differences were found for lower dental arches. The populations evaluated show distinctive characteristics in dental arch dimensions, thus the mestizo population had narrow arches while the natives had wide arches.

El propósito de éste estudio fue comparar las dimensiones transversal y anteroposterior del arco dental en tres grupos étnicos de Colombia. Se utilizó un calibrador digital para tomar 16 medidas transversales y dos sagitales, 9 maxilares y 9 mandibulares. La medida sagital para determinar la longitud del arco se elaboró a partir de una línea trazada desde mesial primera molar derecho permanente al primer molar izquierdo permanente, y una línea perpendicular desde el punto de contacto entre los incisivos centrales, tanto para el maxilar y mandíbula. Las dimensiones del arco dental maxilar en los tres grupos étnicos mostraron diferencias en la distancia intercanina, así como entre premolares y molares. Las mismas diferencias se encontraron en la mandíbula. Las poblaciones evaluadas presentan características distintivas en las dimensiones del arco dental, por lo que la población mestiza tuvo arcos estrechos, mientras que los nativos tuvieron arcos anchos.

Perfil de ácidos graxos do leite de cabras leiteiras alimentadas com dieta contendo dois níveis de óleo de arroz / Production and milk composition of dairy goats receiving two levels of rice bran oil in the diet

Foram testados os efeitos de dois níveis de extrato etéreo à base de óleo de arroz no concentrado em 30 cabras Saanen durante a fase inicial de lactação. A alimentação baseou-se na relação 60% de volumoso (feno de alfafa) e 40% de concentrado comercial com dois níveis de extrato etéreo (3% e 5%). As variáveis estudadas foram a quantificação e qualificação do perfil de ácidos graxos do leite total e frente ao tempo de lactação. O acréscimo de óleo de arroz na dieta diminuiu (P<0,05) a concentração de ácidos graxos saturados e aumentou (P<0,05) a concentração de ácidos graxos poli-insaturados no leite caprino. O ácido linoleico conjugado (ALC) também é afetado positivamente pelo acréscimo de óleo de arroz na dieta. A inclusão de óleo de arroz nos níveis de 3% e 5% da matéria seca, na dieta de cabras leiteiras da raça Saanen, influencia o perfil de ácidos graxos do leite, com ênfase no ALC, até a 11ª semana de lactação.

The effects of two levels of ether extract based on rice oil concentrate in 30 Saanen goats during early lactation were evaluated. The feeding was based on the ratio of 60% forage (alfalfa hay) and 40% commercial concentrate with two levels of lipids (3% and 5%). The variables were the quantification and qualification of the fatty acid profile of whole milk and forward to the time of lactation. The addition of rice bran oil in the diet decreased significantly (P<0.05) the concentration of saturated fatty acids and increased (P<0.05) the concentration of polyunsaturated fatty acids in goats' milk. The linoleic acid was also positively affected by the addition of rice bran oil in the diet. The inclusion of rice bran oil at levels of 3% and 5% of dry matter in the diet of Saanen dairy goats influences the fatty acid profile of milk, with emphasis on linoleic acid until the 11th week of lactation.

Biotipo morfológico facial en tres grupos étnicos colombianos: una nueva clasificación por medio del índice facial / Facial biotype in three Colombian ethnic groups: a new classification by facial index

El objetivo de este estudio es evaluar el índice facial de tres poblaciones colombianas y proponer un nuevo método para identificar los biotipos morfológicos faciales teniendo en cuenta el tipo de ascendencia. Para esto, se tomaron las medidas de Nasion a Gnation y la distancia Bicigomática con un calibrador digital en tres grupos étnicos diferentes: 63 niños de la población Ticuna (Amazonas), 68 niños del municipio de Puerto Tejada (Cauca) y 65 niños del municipio de Santiago de Cali (Valle). Por medio de la prueba post hoc T2 de Tamhane se determinó que las poblaciones son distintas y que el índice morfológico facial tradicional no discriminaba esas diferencias. Por tal razón se utilizó el método estadístico de conglomerados difusos con el fin de determinar el número de grupos o biotipos para cada tipo de ascendencia. Se concluyó, que las poblaciones mestizas y afro-descendientes tienen similitudes por lo cual se agruparon juntas y el algoritmo c-medias generó cuatro biotipos característicos, mientras que para la población indígena Ticuna (Amazonas) solo se generaron tres biotipos.

The aim of this study is evaluate the facial index of three Colombian populations and propose a new method to identifythe facial morphological biotypes taking into account the type of ascendancy. For this, measures were taken of Nasion to Gnation and bizygomatic distance with a digital caliper in three ethnic groups: 63 children from Ticuna population (Amazonas), 68 children from municipality of Puerto Tejada (Cauca) and 65 children from municipality Santiago de Cali (Valle). Through the post hoc Tamhane's T2 was determined that the populations are different and the facial morphological index did not discriminate these differences. We used the statistical method of fuzzy clusters to determine the number of groups or biotypes for each type of ascendancy. We concluded that mixed populations and African descent have similarities, therefore they were grouped together and the c-means algorithm generated four biotypes characteristic, while the indigenous population Ticuna (Amazon) only generated three biotypes.

Significance of cytomegalovirus prophylaxis strategies and development of cancer in kidney transplant recipients.

Cytomegalovirus (CMV) infection is one of the most common complications among kidney transplant recipients; two approaches preventing this complication are currently available: universal prophylaxis (UP) and pre-emptive therapy (PT). Despite some differences, similar effectiveness and safety have been proven in several studies for both strategies. However, Spinner et al compared both treatments in 115 renal transplant recipients showing deaths were more likely to occur in patients who received UP. Most of these deaths (2/4 cases) occurred because malignancies developed. This finding is paradoxical because CMV is considered a potentially oncogenic virus and, therefore, UP (a longer therapy compared with the PT) should not be linked with the emergence of a greater number of tumors. New evidence suggests that changes in host immune response triggered by CMV infection may have a mitigating effect on the development of tumors. It is now known CMV infection produces a clonal expansion of gamma delta T lymphocytes which can elicit an aggressive response against neoplastic cells. Currently, UP is the therapy most frequently used in Colombian transplant centers; however, doses administered vary depending on several clinical and laboratory factors. There are no clinical cohorts treated with PT. Reviewing the impact of different length dosing schemes is important for creating an immune response affecting malignancy development in kidney transplant recipients.

Plasma nitrate accumulation during the development of pacing-induced dilated cardiac myopathy in conscious dogs is due to renal impairment.

Heart failure is associated with an increase in plasma nitrate and nitrite (NOx). To date there is still some controversy regarding the causes of nitrate accumulation during the development of heart failure. The goal of this study was to analyze the underlying mechanisms that cause accumulation of plasma nitrates during the development of heart failure in dogs. Dogs were chronically instrumented for measurement of hemodynamics and renal function. Hearts were paced initially at 210 bpm for 3 weeks and then at 240 until the development of heart failure. Hemodynamics, renal function, renal blood flow, arterial blood gases, hemoglobin, plasma and urine NOx levels, and creatinine levels were measured weekly. Heart failure was assessed by hemodynamic alterations, physical signs such as lethargy, ascites, cachexia, and postmortem evidence of cardiac hypertrophy. LVSP (from 127 +/- 3 to 106 +/- 3 mmHg), LV dP/dt (from 2658 +/- 173 to 1439 +/- 217 mmHg/s), MAP (from 101 +/- 1.9 to 83 +/- 1.8 mmHg) fell, whereas LVEDP tripled (from 6.4 +/- 0.9 to 20 +/- 2.6 mmHg), and heart rate rose (from 101 +/- 4.2 to 117 +/- 6.3 bpm), all changes P < 0.05. RBF (from 146 +/- 10 to 96 +/- 9.9 ml/min), urine output (V) (from 0.26 +/- 0.02 to 0.16 +/- 0.02 ml/min), GFR (from 63 +/- 1.8 to 49 +/- 2 ml/min), and Na excretion (from 45 +/- 4.5 to 14 +/- 4.6 microEq/min) all decreased (P < 0.05), whereas RVR increased (from 0.68 +/- 0.05 to 0.94 +/- 0.1 mmHg/ml/min). These changes took place during a rise in plasma NOx (from 3.7 +/- 0.5 to 16+/-3.3 microM), a decrease in urine NOx (from 33 +/- 9.9 to 8.1 +/- 4.9 microM), and a concurrent increase in NOx reabsorption (from 221 +/- 31 to 818 +/- 166 nmol/min). There was a direct correlation between the increase in plasma NOx levels and an increase in filtered load (r(2) = 0.97, P = 0.02), a negative correlation between NOx levels and NOx excretion (r(2) = 0.65 P < 0.09), and a direct correlation between plasma NOx levels and NOx reabsorption (r(2) = 0.97, P = 0.02). These results indicate that elevated plasma NOx during heart failure are most likely the result of an impairment of the renal function and not increased NOx production. Furthermore, without knowing changes in renal function the measurement of plasma NOx in and of itself is a meaningless index of NO formation.

[Inhibition of invasion and multiplication of Toxoplasma gondii in human colonic epithelial cells by a monoclonal antibody against protein SAG2]. / Inhibición de la invasión y multiplicación de Toxoplasma gondii en células epiteliales de colon humano por un anticuerpo monoclonal contra la proteína SAG2.

By an bromodeoxyuridine (BrdU) incorporation assay, it was proved hat an IgG 1 subclass, murine monoclonal antibody to surface protein SAG2 of Toxoplasma gondii is capable of reducing the invasion and multiplication of the parasites in highly differentiated mucine secretory HT29-18N2 line cells from a human colon adenocarcinoma. This result shows the importance of surface protein SAG2 of T.gondii in invasion and further multiplication of parasites in the host cell.