Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study.

BACKGROUND: We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients. METHODS: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. RESULTS: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment. CONCLUSION: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit. TRIAL REGISTRATION: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

SEOM clinical practice guideline: management and prevention of febrile neutropenia in adults with solid tumors (2018)

Febrile neutropenia (FN) is a common dose-limiting toxicity of chemotherapy, with a profound impact on the evolution of patients with cancer, due to the potential development of serious complications, mortality, delays, and decrease in treatment intensity. This article seeks to present an updated clinical guideline, with recommendations regarding the diagnosis, prevention, and treatment of febrile neutropenia in adults with solid tumors. The aspects covered include how to properly approach the risk of microbial resistances, epidemiological aspects, considerations about the initial empirical approach adapted to the risk, special situations, and prevention of complications. A decision-making algorithm is included for use in the emergency department based on a new, validated tool, the Clinical Index of Stable Febrile Neutropenia, which can be used in patients with solid tumors who appear stable in the initial phase of neutropenic infections, and can help detect those at high risk for complications in whom early discharge must be avoided

No disponible

SEOM clinical practice guideline: management and prevention of febrile neutropenia in adults with solid tumors (2018).

Febrile neutropenia (FN) is a common dose-limiting toxicity of chemotherapy, with a profound impact on the evolution of patients with cancer, due to the potential development of serious complications, mortality, delays, and decrease in treatment intensity. This article seeks to present an updated clinical guideline, with recommendations regarding the diagnosis, prevention, and treatment of febrile neutropenia in adults with solid tumors. The aspects covered include how to properly approach the risk of microbial resistances, epidemiological aspects, considerations about the initial empirical approach adapted to the risk, special situations, and prevention of complications. A decision-making algorithm is included for use in the emergency department based on a new, validated tool, the Clinical Index of Stable Febrile Neutropenia, which can be used in patients with solid tumors who appear stable in the initial phase of neutropenic infections, and can help detect those at high risk for complications in whom early discharge must be avoided.

SEOM guidelines on hydroelectrolytic disorders

Hydroelectrolytic disorders are one of the most common metabolic complications in cancer patients. Although often metabolic alterations affecting various ions are part of the manifestations of the oncological disease, even in the form of paraneoplastic syndrome, we must not forget that very often, these disorders could be caused by various drugs, including some of the antineoplastic agents most frequently used, such as platin derivatives or some biologics. These guidelines review major management of diagnosis, evaluation and treatment of the most common alterations of sodium, calcium, magnesium and potassium in cancer patients. Aside from life-sustaining treatments, we have reviewed the role of specific drug treatments aimed at correcting some of these disorders, such as intravenous bisphosphonates for hypercalcemia or V2 receptor antagonists in the management of syndrome of inappropriate antidiuretic hormone secretion-related hyponatremia (AU)

No disponible

SEOM guidelines on hydroelectrolytic disorders.

Hydroelectrolytic disorders are one of the most common metabolic complications in cancer patients. Although often metabolic alterations affecting various ions are part of the manifestations of the oncological disease, even in the form of paraneoplastic syndrome, we must not forget that very often, these disorders could be caused by various drugs, including some of the antineoplastic agents most frequently used, such as platin derivatives or some biologics. These guidelines review major management of diagnosis, evaluation and treatment of the most common alterations of sodium, calcium, magnesium and potassium in cancer patients. Aside from life-sustaining treatments, we have reviewed the role of specific drug treatments aimed at correcting some of these disorders, such as intravenous bisphosphonates for hypercalcemia or V2 receptor antagonists in the management of syndrome of inappropriate antidiuretic hormone secretion-related hyponatremia.

Protocolo de manejo de pancreatitis aguda. Hospital Universitario San Ignacio (HUSI) Bogotá / Acute Pancreatitis Protocol, Hospital Universitario San Ignacio (HUSI), Bogotá

La pancreatitis aguda es la inflamación aguda del páncreas con grado variable de compromiso de los tejidos regionales y diferente grado de compromiso sistémico. Se utilizan como definiciones las establecidas en el consenso de Atlanta (anexo 1). B. Diagnóstico 1. Historia clínica. Se presenta dolor en hemiabdomen superior, usualmente serio y acompañado de grados variables de vómito, náuseas y fiebre. Son importantes los antecedentes personales y familiares. 2. En el examen físico siempre se deben incluir el peso, la talla, el índice de masa corporal (IMC), la temperatura, la saturación de oxígeno (SAO2), la frecuencia cardiaca, la frecuencia respiratoria y la tensión arterial.

Inhibition of mouth skeletal muscle relaxation by flavonoids of Cistus ladanifer L.: a plant defense mechanism against herbivores.

Cistus ladanifer exudate is a potent inhibitor of the sarcoplasmic reticulum Ca2+-ATPase (Ca2+-pump) of rabbit skeletal muscle, a well-established model for active transport that plays a leading role in skeletal muscle relaxation. The low concentration of exudate needed to produce 50% of the maximum inhibition of the sarcoplasmic reticulum Ca2+-ATPase activity, 40-60 microg/ml, suggests that eating only a few milligrams of C. ladanifer leaves can impair the relaxation of the mouth skeletal muscle of herbivores, as the exudate reaches up to 140 mg/g of dry leaves in summer season. The flavonoid fraction of the exudate accounts fully for the functional impairment of the sarcoplasmic reticulum produced by the exudate (up to a dose of 250-300 microg/ml). The flavonoids present in this exudate impair the skeletal muscle sarcoplasmic reticulum function at two different levels: (i) by inhibition of the Ca2+-ATPase activity, and (ii) by decreasing the steady state ATP-dependent Ca2+-accumulation. Among the exudate flavonoids, apigenin and 3,7-di-O-methyl kaempferol are the most potent inhibitors of the skeletal muscle sarcoplasmic reticulum. We conclude that the flavonoids of this exudate can elicit an avoidance reaction of the herbivores eating C. ladanifer leaves through impairment of mouth skeletal muscle relaxation.

Herniorrafia inguinal: diez años de seguimiento / Inguinal herniorraphy: ten years follow-up

La hernia inguinal constituye una de las patologias que con más frecuencia recibe tratamiento quirurgico a nivel mundial, y a pesar de ello no hay consenso universal en cuanto al tipo de cirugia ideal. Entre las principales medidas de calidad de la hemiorrafia se encuentran los indices de recurrencia, que en series personales o de centros especializados se ha reportado entre 1 y 2 por ciento, pero que no ha sido reproducible en centros docentes por cirujanos con diferente nivel de experiencia y en forma no estandarizada, donde se han reportado cifras hasta del 15 por ciento. En el siguiente trabajo, se presenta la experiencia de diez años con la cirugia de hernia inguinal por via anterior en el Hospital Universitario San Ignacio, cuyos resultados buscan establecer conductas futuras más efectivas en el manejo de estos pacientes. Se encontro una tasa inaceptablemente alta de recurrencia a largo plazo (16 por ciento) con el uso del reparo a la cintilla iliopubica, lo cual planteó la busqueda de alternativas quirurgicas mas seguras en los pacientes con hernias inguinales indirectas y orificio profundo debilitado, los cuales constituyen su principal indicacion. Asimismo, la baja morbilidad y mortalidad de la tecnica de McVAY, unidas a una recurrencia del 7 por ciento, la hacen una altemativa segura y eficaz. en el reparo de cualquier tipo de hernia inguinal no complicada por via anterior.

The content of glycogen phosphorylase and glycogen in preparations of sarcoplasmic reticulum-glycogenolytic complex is enhanced in diabetic rat skeletal muscle.

AIMS/HYPOTHESIS: We have examined the effect of diabetes and pharmacological insulin treatment on the content of glycogen phosphorylase and glycogen associated with the sarcoplasmic reticulum-glycogenolytic complex from rat skeletal muscle. METHODS: Diabetes was induced in rats by streptozotocin injection. Enzymatic activities were measured using spectrophotometric methods. Glycogen phosphorylase was determined measuring the pyridoxal-5' -phosphate content and using polyacrylamide gel electrophoresis. Glycogen content was measured by enzymatic and the phenol sulfuric methods. RESULTS: The content of glycogen phosphorylase associated with the sarcoplasmic reticulum glycogenolytic complex gradually arises after diabetes induction. The content of glycogen phosphorylase was restored to a control value by pharmacological insulin treatment. In addition, the content of glycogen in preparations of sarcoplasmic reticulum-glycogenolytic complex of diabetic animals was also increased, whereas the content of glycogen in total muscle of diabetic rats was similar to that of the control rats. The absolute and relative amount of glycogen associated with sarcoplasmic reticulum seemed to increase in diabetic animals. These effects on the compartmentalisation of glycogen were suppressed by insulin treatment. Additionally, the rate of conversion of glycogen phosphorylase b to a, an index of the phosphorylase kinase activity, was 50 % lower in diabetic rats, increasing the dephosphorylated form of glycogen phosphorylase and, as a consequence, its association with sarcoplasmic reticulum membranes. CONCLUSION/INTERPRETATION: These results suggest that under diabetic conditions, both glycogen phosphorylase and a small percentage of muscle glycogen are relocalized in the sarcoplasmic reticulum-glycogenolytic complex.

Albúmina y proteina C reactiva como predictores tempranos de falla orgánica múltiple en pacientes traumatizados / Serum albumin and C-reactive protein as early predictors of multiple organ system failure on trauma

La falla organica multiple (FOM) sigue siendo la principal causa de mortalidad tardia en el trauma, y los esfuerzos actuales estan encaminados a la deteccion de elementos que puedan predecir en forma temprana cuales pacientes van a desarrollar este sindrome, para incluirlos en protocolos de investigacion en los que se empleen medidas terapeuticas agresivas que puedan modificar su pronostico. En el presente estudio se identifican como factores de prediccion la albumina serica y la proteina C reactiva, dos parámetros de facil determinacion, de amplia disponibilidad en la mayoria de hospitales y de bajo costo, los cuales serán de utilidad en la estratificacion de los pacientes severamente traumatizados que requieren un cuidado crítico más agresivo.

Extensión de la linfadenectomía para el tratamiento quirúrgico del adenocarcinoma gástrico en el Hospital Universitario San Ignacio: cohorte prospectiva con análisis de supervivencia / Extension of lymphadenectomy in the surgical treatment of adecarcinoma of the stomach

Introduccion: en 1992 se creo el Protocolo de Betania, para el diagnostico y tratamiento del cancer gastrico en Colombia. A partir de ese momenta, en el Hospital Universitario San Ignacio, el manejo de esta patologia se ha realizado siguiendo los parámetros de dicho protocolo. El siguiente estudio presenta los resultados de una cohorte prospectiva que incluyo todos los pacientes operados por cancer gastrico entre 1992 y 1998 en esta institucion. Materiales y metodos: cohorte prospectiva, observacional y descriptiva con analisis de supervivencia. Se incluyen todos los pacientes con diagnostico endoscopico e histologico de adenocarcinoma gastrico, operados en este hospital entre marzo de 1992 y diciembre de 1998. Se excluyeron del analisis los pacientes con tumores irresecables. Se analizaron entre otras las siguientes variables: demográficas, diagnostico endoscopico e histologico, estadificacion tumoral (TNM), tipo de cirugia, complicaciones posoperatorias y supervivencia. Resultados: entre marzo de 1992 y diciembre de 1998 se realizaron 137 procedimientos quirurgicos con diagnostico de cancer gastrico. 86 operaciones fueron consideradas con intencion curativa, 18 fueron paliativas y las 33 restantes laparotomias no terapeuticas. Estos ultimas 33 pacientes fueron excluidos del estudio. La supervivencia global actuarial fue de 54 por ciento a 5 anos. Las principales variables que determinaron la supervivencia fueron el numero de ganglios comprometidos y el estado tumoral. El nivel de diseccion ganglionar no tuvo impacto en la supervivencia y aumento significativamente la morbilidad. El tratamiento adyuvante con quimioterapia tampoco afecto la supervivencia. Conclusiones: los resultados del tratamiento quirurgico del cancer gastrico dependen del diagnostico temprano de la enfermedad, del compromiso ganglionar y no de la extension de la linfadenectomia.

Phosphorylated Ca2+-ATPase stable enough for structural studies.

The atomic structure of sarcoplasmic reticulum Ca(2+)-ATPase, in a Ca(2+)-bound conformation, has recently been elucidated (Toyoshima, C., Nakasako, M., Nomura, H. & Ogawa, H. (2000) Nature 405, 647-655). Important steps for further understanding the mechanism of ion pumps will be the atomic structural characterization of different key conformational intermediates of the transport cycle, including phosphorylated intermediates. Following our previous report (Champeil, P., Henao, F., Lacapère, J.-J. & McIntosh, D. B. (2000) J. Biol. Chem. 276, 5795-5803), we show here that it is possible to prepare a phosphorylated form of sarcoplasmic reticulum Ca(2+)-ATPase (labeled with fluorescein isothiocyanate) with a week-long stability both in membranes and in mixed lipid-detergent micelles. We show that this phosphorylated fluorescein isothiocyanate-ATPase can form two-dimensional arrays in membranes, similar to those that were used previously to reconstruct from cryoelectron microscopy images the three-dimensional structure of Ca(2+)-free unphosphorylated ATPase. The results also provide hope that crystals of phosphorylated Ca(2+)-ATPase suitable for x-ray crystallography will be achieved.

A remarkably stable phosphorylated form of Ca2+-ATPase prepared from Ca2+-loaded and fluorescein isothiocyanate-labeled sarcoplasmic reticulum vesicles.

After the nucleotide binding domain in sarcoplasmic reticulum Ca2+-ATPase has been derivatized with fluorescein isothiocyanate at Lys-515, ATPase phosphorylation in the presence of a calcium gradient, with Ca2+ on the lumenal side but without Ca2+ on the cytosolic side, results in the formation of a species that exhibits exceptionally low probe fluorescence (Pick, U. (1981) FEBS Lett. 123, 131-136). We show here that, as long as the free calcium concentration on the cytosolic side is kept in the nanomolar range, this low fluorescence species is remarkably stable, even when the calcium gradient is subsequently dissipated by ionophore. This species is a Ca2+-free phosphorylated species. The kinetics of Ca2+ binding to it indicates that its transport sites are exposed to the cytosolic side of the membrane and retain a high affinity for Ca2+. Thus, in the ATPase catalytic cycle, an intrinsically transient phosphorylated species with transport sites occupied but not yet occluded must also have been stabilized by fluorescein isothiocyanate (FITC), possibly mimicking ADP. The low fluorescence mainly results from a change in FITC absorption. The Ca2+-free low fluorescence FITC-ATPase species remains stable after addition of thapsigargin in the absence or presence of decavanadate, or after solubilization with dodecylmaltoside. The remarkable stability of this phosphoenzyme species and the changes in FITC spectroscopic properties are discussed in terms of a putative FITC-mediated link between the nucleotide binding domain and the phosphorylation domain in Ca2+-ATPase, and the possible formation of a transition state-like conformation with a compact cytosolic head. These findings might open a path toward structural characterization of a stable phosphorylated form of Ca2+-ATPase for the first time, and thus to further insights into the pump's mechanism.

Herniorrafia preperitoneal: experiencia en el Hospital Universitario San Ignacio / Preperitoneal repair of inguinal hernia. Experience at San Ignacio University Hospital, Bogotá

Se presenta la experiencia del Hospital Universitario de San Ignacio (HUSI) en reparos herniarios por via preperitoneal, con una morbilidad y recurrencia dentro de los rangos publicados en la literatura. Se analizan los resultados de la cirugia en casos de hernias incarceradas, crurales y reproducidas que hasta el momento constituyen las principales indicaciones del procedimiento, el cual se proyecta hacia el futuro como una tecnica util y segura que permite su empleo en casi todos los tipos de defectos herniarios.

Plausible stoichiometry of the interacting nucleotide-binding sites in the Ca(2+)-ATPase from sarcoplasmic reticulum membranes.

The Ca(2+),Mg(2+)-ATPase from sarcoplasmic reticulum couples ATP hydrolysis to Ca(2+) transport toward the lumen of the muscular vesicular system. Combined structural and functional studies suggest that the Ca(2+) binding sites are formed by six amino acids of the same polypeptide and that cation translocation may take place through a channel inside a monomer of the ATPase. However, calorimetric, fluorescent, and kinetic studies suggest that the ATPase may assemble into functional oligomers of as yet unknown stoichiometry. We have addressed this question and attempted to determine the ATPase stoichiometry using a biophysical approach based on the analysis of the ATPase inhibition by fluorescein 5'-isothiocyanate in the presence of increasing ATP concentrations. For native SR membranes, our inhibition data are well described by a model consisting of two interacting nucleotide-binding sites per oligomer. This stoichiometry was disrupted in detergent C(12)E(8)-solubilized ATPase. Thus, these findings suggest that interacting nucleotide binding sites of the ATPase may appear as dimers, and imply that interactions of the globular cytoplasmic domains would play a modulatory role of the protein enzymatic activity.

Traqueostomía percutánea / Percutaneous tracheostomy

La traqueostomia es un procedimiento realizado por el cirujano general de manera habitual a pacientes criticamente enfermos, hospitalizados en la Unidad de Cuidado Intensivo. En el mundo se venia efectuando la tecnica abierta convencional pero, a partir de 1985, se desarrolla la tecnica de traqueostomia percutanea, la cual alcanzo gran popularidad en todo el mundo debido a sus costos más bajos, al menor tiempo quirurgico y a la menor tasa de complicaciones. En el Hospital Universitario de San Ignacio se empezó a aplicar esta tecnica desde 1998 y para ello se diseño un estudio prospectivo de dos fases: la primera incluyo 8 pacientes a los cuales se les realizó el procedimiento en salas de cirugia; y la segunda incluyo otros 8 pacientes a los cuales se les realizó la traqueostomia percutanea en la Unidad de Cuidado Intensivo. Pudimos comprobar que la traqueostomia percutanea es un procedimiento seguro, rápido y eficaz.

Sepsis por cateter / Catheter sepsis

Con el advenimiento de las tecnicas de nutricion parenteral se hizo necesario el uso de cateteres venosos centrales. En el presente articulo se describen algunas de las complicaciones asociadas a su uso, se hace enfasis en la fisiopatologia, el diagnostico y la prevencion de una de las más serias, cual es la sepsis por cateter. Se presenta la experiencia del grupo de soporte metabolico y nutricional del departamento de cirugia del Hospital Universitario de San Ignacio, con un índice de infeccion de 3.2 por ciento, que se considera muy ajustado a nuestro tipo de pacientes.

Characterization of a protease-resistant domain of the cytosolic portion of sarcoplasmic reticulum Ca2+-ATPase. Nucleotide- and metal-binding sites.

Treatment of rabbit sarcoplasmic reticulum Ca2+-ATPase with a variety of proteases, including elastase, proteinase K, and endoproteinases Asp-N and Glu-C, results in accumulation of soluble fragments starting close to the ATPase phosphorylation site Asp351 and ending in the Lys605-Arg615 region, well before the conserved sequences generally described as constituting the "hinge" region of this P-type ATPase (residues 670-760). These fragments, designated as p29/30, presumably originate from a relatively compact domain of the cytoplasmic head of the ATPase. They retain two structural characteristics of intact Ca2+-ATPase as follows: high sensitivity of peptidic bond Arg505-Ala506 to trypsin cleavage, and high reactivity of lysine residue Lys515 toward the fluorescent label fluorescein 5'-isothiocyanate. Regarding functional properties, these fragments retain the ability to bind nucleotides, although with reduced affinity compared with intact Ca2+-ATPase. The fragments also bind Nd3+ ions, leaving open the possibility that these fragments could contain the metal-binding site(s) responsible for the inhibitory effect of lanthanide ions on ATPase activity. The p29/30 soluble domain, like similar proteolytic fragments that can be obtained from other P-type ATPases, may be useful for obtaining three-dimensional structural information on the cytosolic portion of these ATPases, with or without bound nucleotides. From our findings we infer that a real hinge region with conformational flexibility is located at the C-terminal boundary of p29/30 (rather than in the conserved region of residues 670-760); we also propose that the ATP-binding cleft is mainly located within the p29/30 domain, with the phosphorylation site strategically located at the N-terminal border of this domain.

Structural changes of the sarcoplasmic reticulum Ca(II)-ATPase nucleotide binding domain by pH and La(III).

The Ca(2+)-ATPase from sarcoplasmic reticulum couples the hydrolysis of one molecule of ATP to the transport of two Ca2+ ions in skeletal muscle fibers. Here, we study the accessibility of the fluorescein covalently attached to the Lys515 at the nucleotide binding domain of the ATPase to the small collisional quencher iodide at pH 6 and 8, as well as the effect of ligand binding (La3+, La(3+)-nucleotide, and Ca2+). Our results indicate that bound fluorescein is significantly more accessible at pH 6 than at pH 8, suggesting that pH modulates the structure of the nucleotide binding domain of the ATPase. This notion was further substantiated by the finding that La(3+)-nucleotide only interacted with the catalytic center at acidic pH. Notably, the differential accessibility of the nucleotide binding domain at acidic and basic pH cannot be rationalized in terms of the ATPase E1/E2 conformational equilibrium since a shift of the ATPase toward the E1 (plus Ca2+) or E2 (plus EGTA) did not affect the accessibility of fluorescein-labeled ATPase to the quencher. Taken together, these findings show the presence of structural flexibility in the FITC binding site and suggest a structural modulation of the Ca(2+)-ATPase nucleotide binding domain by pH and La3+ binding through long-range link-age mechanisms.