Algunos aspectos del compromiso cutáneo por el cáncer de mama: revisión de la literatura a propósito de tres casos / Cutaneous metastasis of breast cancer: three clinical cases and a review of the literature

Las metástasis cutáneas son infrecuentes, reportándose en la literatura rangos entre 0,6 por ciento y 10 por ciento. El cáncer de mama es la neoplasia más común en las mujeres con metástasis cutáneas. La presencia de éstas constituye un signo de enfermedad avanzada y es indicadora de mal pronóstico. Las lesiones pueden tener distintos patrones clínicos: tipo nodular, erisipeloide, alopecia y carcinoma telangiectásico. En el presente artículo se realiza un análisis retrospectivo de tres casos clínicos atendidos en nuestro centro y una revisión de la literatura.

Cutaneous metastases are unusual; their frequency in the literature ranges from 0.6 percent to 10 percent. Breast cancer is the most common cancer in women with cutaneous metastases. They are perceived as a sign of advanced disease and are regarded as a serious prognostic indicator. The lesions may present in distinct clinical forms: nodular pattern, erysipelas like presentations, alopecia and carcinoma telangiectaticum. In this article we analyzed three clinical cases that were seen in our center and a review of the literature.

[Infections in patients with Systemic Lupus Erythematosus]. / Infecciones en pacientes con lupus eritematoso sistémico.

Despite the availability of newer therapeutic interventions to improve clinical outcome in patients with Systemic Lupus Erythematosus (SLE), the incidence of infections as a cause of morbidity and mortality has not changed over the past 30 years. SLE itself increases the risk of infection, due to genetic (complement deficiencies) and acquired factors such as functional asplenia (humoral immunodepression) and the use of immunosuppressive drugs. These medications increase the risk of opportunistic infections that are associated with an altered cellular immune response. The main etiologic infectious agents in SLE patients are common bacterial pathogens, especially capsulated ones. The most common sites are lung, skin, bladder, brain and systemic infections. The main risk factor for infection is the history of a previous one. The clinical approach to SLE patients with suspected infectious diseases must consider the possibility of a flare up of the underlying disease, posing an additional problem to the clinician.

Hematoma esofágico espontáneo: caso clínico / Spontaneous esophageal hematoma: case report

Hematoma of the esophagus is a rare condition. We report the case of an 86 year old man, treated with aspirin. He was admitted by hematemesis, hemodynamically stable. Upper digestive tract endoscopy revealed a big esophageal hematoma: Contrast enhanced computed tomography of the chest confirmed the diagnosis. Clinical outcome was good without complications, with conservative medical management.

El hematoma esofágico es una condición poco frecuente. Presentamos el caso de un hombre de 86 años, en tratamiento con aspirina, que ingresa por cuadro hematemesis, con hemodinamia estable. Se realiza endoscopia digestiva alta que revela gran hematoma esofágico; tomografía computada de tórax con contraste confirma el diagnóstico. La evolución clínica fue satisfactoria sin complicaciones, con manejo médico conservador.

Infecciones en pacientes con lupus eritematoso sistémico / Infections in patients with systemic lupus erythematosus

Despite the availability of newer therapeutic interventions to improve clinical outcome in patients with Systemic Lupus Erythematosus (SLE), the incidence of infections as a cause of morbidity and mortality has not changed over the past 30 years. SLE itself increases the risk of infection, due to genetic (complement deficiencies) and acquired factors such as functional asplenia (humoral immunodepression) and the use of immunosuppressive drugs. These medications increase the risk of opportunistic infections that are associated with an altered cellular immune response. The main etiologic infectious agents in SLE patients are common bacterial pathogens, especially capsulated ones. The most common sites are lung, skin, bladder, brain and systemic infections. The main risk factor for infection is the history of a previous one. The clinical approach to SLE patients with suspected infectious diseases must consider the possibility of a flare up of the underlying disease, posing an additional problem to the clinician.

[Tuberculous meningitis in adults: review of 53 cases]. / Meningitis tuberculosa en adultos: análisis de 53 casos.

Tuberculous Meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. The clinical spectrum is broad and may be non-specific making early diagnosis difficult. This increases the incidence of mortality. We describe the clinical characteristics of patients with TBM in Dr. Lucio Córdova's Infectious Disease Hospital in Santiago, Chile, between 1995 and 2002. We review 53 adult cases of TBM, with a median age of 39 years. At admission 66% of the patients had some mental status deterioration, and the classic triad of symptoms of meningeal irritation was present only in 30%. The cerebrospinal fluid (CSF) examination showed increased protein level, low glucose level and lymphocytic pleocytosis in most. Thirty percent of the patients were coinfected with HIV. The mortality in the later group was greater than in the TBM population as a whole (31 vs 17%). TBM is still a present diagnostic problem, in spite of the new diagnostic methods. A high index of suspicion is required in order to make an early diagnosis.

Meningitis tuberculosa en adultos: análisis de 53 casos / Tuberculous meningitis in adults: review of 53 cases

La meningitis tuberculosa (MTBC) es la forma más grave de tuberculosis extrapulmonar. El amplio espectro del cuadro clínico y su poca especificidad dificultan su diagnóstico precoz, relacionándose directamente con mayor letalidad. El objetivo de este estudio es analizar las características clínicas de los pacientes con diagnóstico de MTBC en el Hospital de Enfermedades Infecciosas Dr. Lucio Córdova, de Santiago, Chile, entre 1995 y 2002. Se estudiaron 53 casos de MTBC en adultos, con una edad mediana de 39 años. Al ingreso 66 por ciento de los pacientes presentaba algún grado de compromiso de conciencia, pero sólo 30 por ciento la tríada sintomática clásica. El LCR mostró aumento de proteínas, glucosa baja y linfocitosis, en la mayoría de los casos. Treinta por ciento de los pacientes presentó co-infección con VIH; la letalidad en este grupo de pacientes fue mayor, 31 vs 17 por ciento del total de la muestra. La MTBC continúa siendo una enfermedad vigente. El diagnóstico de certeza precoz de esta patología no es posible con los métodos actuales, por lo que la sospecha clínica es importante.

Anemia hemolítica autoinmune en paciente infectado por virus de inmunodeficiencia humana y enfermedad de Castleman / Autoimmnune hemolytic anemia in AIDS-HIV patient

We present a case of a 41 years old C3 phase AIDS patient on antiretroviral therapy for 5 years, who developed a severe hemolytic anemia refractory to usual treatment, which progressed to death. Anemia in AIDS patients is a common finding (60-80%); however hemolytic anemia is unusual and when it is present, it is generally mild; severe anemia is associated with bad prognosis. The etiology of hemolytic anemia in HIV patients is due to multiple causes, the one mediated by autoantibodies against the red cell, usually IgG, being most common. The antibodies most frequently detected are against U or i antigen. Drug-related hemolysis, in glucose 6-phosphate dehydrogenase (G-6PD)-deficient patients, may also occur. A third mechanism of hemolysis is related to microangiopathy secondary to bacterial sepsis or hemolytic uremic syndrome (HUS). Some reports associate haemolytic anemia and Castleman´s disease, a lymphoproliferative disease with localized widespread adenopathy, fever, autoimmune manifestations and recurring infections.

Se presenta un paciente con SIDA etapa C3, 41 años de edad, en tratamiento antiretroviral durante 5 años, que cursó con linfoadenopatías generalizadas y anemia hemolítica severa refractaria a tratamiento, con progresión hacia la muerte. La anemia en pacientes con SIDA es un hallazgo común (60-80%). Sin embargo, la anemia hemolítica es poco frecuente y generalmente de escasa magnitud, pero si es severa se relaciona con mal pronóstico. La etiología de la anemia hemolítica en pacientes VIH es múltiple siendo más común la mediada por autoanticuerpos contra antígenos del eritrocito, en su mayoría IgG. Los más frecuentes son dirigidos contra antígeno U e i. Otra causa frecuente es la inducida por fármacos, en pacientes con déficit de G-6PD. Un tercer mecanismo de hemólisis es el producido por microangiopatía secundaria a sepsis bacteriana o síndrome hemolítico urémico. Algunas publicaciones asocian anemia hemolítica y enfermedad de Castleman, desorden linfoproliferativo que se puede presentar clínicamente como una masa localizada o una alteración sistémica con linfoadenopatías, fiebre, manifestaciones autoinmunes e infecciones recurrentes.

Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency.

Serum concentrations of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), the low molecular weight form of IGF binding protein (IGFBP-1), insulin, C-peptide and GH were determined in six healthy subjects and four patients with GH deficiency during 30 min of moderate physical exercise on the cycle ergometer. The load corresponded to 60% of individual maximal oxygen uptake. IGF-1 and IGF-2 were determined by radioimmunoassays developed with antibodies isolated from immunized hens eggyolk after separation by automated acid gel filtration of serum samples prior to assay. Significant increases in the serum concentrations (mean +/- SEM) of IGF-1 (157 +/- 24 to 196 +/- 29 micrograms l-1, P less than 0.05) and IGF-2 (451 +/- 37 to 678 +/- 85 micrograms l-1, P less than 0.01) were seen in the healthy subjects after 10 min of exercise. The mean percentage increase was 26 +/- 5% for IGF-1 and 50 +/- 11% for IGF-2. No relation to the GH release was found. In GH-deficient patients the mean IGF-2 concentration rose 48 +/- 17% from basal 216 +/- 63 micrograms l-1 to a peak concentration of 324 +/- 115 micrograms l-1 (P less than 0.01) after 30 min, while the 38 +/- 20% rise of IGF-1 from basal 36 +/- 13 micrograms l-1 to a peak concentration of 55 +/- 27 micrograms l-1 was not significant. The serum IGFBP-1 concentration did not change during exercise, while insulin and C-peptide concentrations, as well as blood glucose, decreased in both healthy subjects and GH-deficient patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of IGF-II levels in human serum using the erythroleukemia cell line K562.

A homologous radioreceptor assay (RRA) has been developed for Insulin-like Growth Factor II (IGF II) using the human erythroleukemia cell line K562. These cells have binding sites for insulin and IGF-II but not for Insulin-like Growth Factor I (IGF I). All samples were dissociated and separated from binding proteins by gel filtration at acidic pH. In healthy adults the mean serum level of radioreceptor assayable IGF II (RRA-IGF II) and 95% confidence limits were 965 ng/ml and 717-1299 ng/ml, respectively. The mean level in GH deficient patients was significantly lower (p less than 0.001) compared with healthy subjects whereas no change was found in patients with acromegaly and uremia. Slightly lowered levels of RRA-IGF II were found in one patient with a tumor induced hypoglycemia.

An effective method for the separation of insulin-like growth factors 1 and 2 during the purification process.

The separation of human insulin-like growth factors hIGF-1 and hIGF-2 was greatly improved by an additional purification step using the cation exchanger Mono-S (FPLC) compared to previous studies. Cross-reactions between hIGF-1 and hIGF-2 were strongly reduced. The more highly purified hIGF-1 had a cross-reaction of less than 1% in the RIA for hIGF-2, and was equivalent to recombinant hIGF-1. The pure hIGF-2 had a cross-reaction of less than 1% in the RIA for hIGF-1. In the human placental hIGF-2 radioreceptor assay, the hIGF-1 polypeptide completed less than 1% with hIGF-2 when the type 1 IGF receptor was blocked with insulin.

The specificity of the human IGF-2 receptor.

The specificity of the type 2 insulinlike growth factor (IGF) receptor is evaluated in human placenta membranes and the human cell line K562. K562 cells have type 2 but not type 1 IGF receptors. Native IGF-2 isolated from human plasma and synthetic IGF-2 were equipotent in competing with labeled IGF-2 in both systems. Pure IGF-1 isolated from plasma, synthetic IGF-1 and recombinant IGF-1 could not crossreact with the type 2 IGF receptor in concentrations up to 1 microgram/ml in both systems. Studies on placenta membrane were done in the presence of 300 ug/ml insulin to block the type 1 IGF receptors. It is concluded that IGF-1, as well as insulin, cannot crossreact with the human type 2 IGF receptor.

Regulation of insulin-like growth factor II receptors by growth hormone and insulin in rat adipocytes.

The acute and long-term effects of growth hormone (GH) on the binding of insulin-like growth factor II (IGF-II) were evaluated in adipose cells from hypophysectomized rats given replacement therapy with thyroxine and hydrocortisone and in cells from their sham-operated littermates. After the cells were incubated with insulin and/or GH, the recycling of IGF-II receptors was metabolically inhibited by treating the cells with KCN. IGF-II binding was 100 +/- 20% higher in cells from GH-deficient animals when compared with sham-operated controls. These GH-deficient cells also showed an increased sensitivity for insulin as compared with control cells (the EC50 for insulin was 0.06 ng/ml in GH-deficient cells and 0.3 ng/ml in control cells). However, the maximal incremental effect of insulin on IGF-II binding was reduced approximately 27% by hypophysectomy. GH added to the incubation medium increased the number of IGF-II binding sites by 100 +/- 18% in cells from hypophysectomized animals. This increase was rapidly induced (t1/2, approximately 10 min), but the time course was slower than that for the stimulatory effect of insulin. Half-maximal effect of GH on IGF-II binding was obtained at approximately equal to 10 ng/ml. Thus, GH added in vitro exerted a rapid insulin-like effect on the number of IGF-II receptors. GH also appears to play a regulating role for maintaining the cellular number of IGF-II receptors and, in addition, modulates the stimulatory effect of insulin on IGF-II binding.

Preferential association of the insulin-like growth factors I and II with metabolically inactive and active carrier-bound complexes in serum.

Ion-exchange chromatography of serum on DEAE-Sephadex A-50 using a stepwise NaCl gradient showed that complexes enriched with insulin-like growth factors I and II (IGF-I and IGF-II) could be preferentially eluted. A fraction eluted with 0.075 M-NaCl preferentially contained immunoreactive IGF-I with peak levels appearing in fractions of Mr approx. 110,000. The IGF-I-binding protein complex itself had low bioactivity as measured in a non-suppressible insulin-like (NSILA) bioassay. On conversion to free IGF-I by gel-permeation chromatography on Sephadex G-75 in 1% formic acid, however, the IGF-I did express its intrinsic NSILA bioactivity. In contrast, an IGF-II-enriched complex was eluted from the DEAE-Sephadex with 0.15 M-NaCl. Practically all of the recovered NSILA of the original serum was present in this fraction, in the Mr range 70,000-300,000 with a peak of 150,000. Chromatography on Sephadex G-75 in 1% formic acid separated this high-Mr NSILA into low-Mr (less than 15000) IGF-II and high-Mr acid-stable NSILA-P. The high-Mr IGF-II complex bound to concanavalin A-Sepharose, suggesting that it was a glycoprotein. The results confirm previous reports that a large portion of the NSILA of whole serum can be accounted for by a biologically active acid-dissociable complex. These data show for the first time that this active complex consists of an IGF-II-preferring binding protein. In direct contrast, the IGF-I-preferring complex does not express NSILA bioactivity until the IGF-I is liberated through acidification. The presence of a metabolically active IGF-II complex in serum raises questions as to its possible biological role in the adult.

Enhancement of insulin-like growth factor 2 receptors in glioblastoma.

The somatomedins (IGF-1/IGF-2) are a family of growth-promoting hormones which have been identified in the human central nervous system where their specific receptors are distributed. The present study identified somatomedin receptors in glioblastoma and compared them with those found in normal brain. A significant enhancement in the binding of 125I-IGF-2 but not 125I-IGF-1 to glioblastoma membranes was found. A fourfold increase in IGF-2 receptor concentration was observed. These findings indicate enhanced expression of the IGF-2 receptor in glioblastoma.

Specific binding of human growth hormone but not insulin-like growth factors by human adipocytes.

Binding of human GH (hGH) and insulin-like growth factors I and II (IGFI and II) to isolated human adipocytes from adult subjects was studied. Binding equilibrium for hGH at 24 degrees C was reached at 120 min and half-maximal specific binding at 6-8 ng/ml. Apparent Ka was 2.1 X 10(9) M-1 and Bmax 7.3 X 10(-11) M/10(6) cells. The human fat cell growth hormone receptor recognized neither bovine, ovine or rat GH nor human prolactin or placental lactogen. No specific receptors for human IGFII could be demonstrated. Thus, human adipocytes do not possess IGF receptors but have specific GH receptors which recognize hGH but not GH from lower species.

Mitogenic response of human SH-SY5Y neuroblastoma cells to insulin-like growth factor I and II is dependent on the stage of differentiation.

Human insulin-like growth factor I and II (IGF-I and IGF-II) in concentrations of 1-30 ng/ml, were shown to stimulate ornithine decarboxylase activity and [3H]thymidine incorporation in human SH-SY5Y neuroblastoma cells. Proliferation of these cells was also stimulated by IGF-I and II when added to RPMI 1640 medium, fortified with selenium, hydrocortisone, transferrin, and beta-estradiol. Labeled IGF-I and II bound to SH-SY5Y cells. The cross-reaction pattern of IGF-I, IGF-II, and insulin in competing with the binding of labeled IGF-I and IGF-II, respectively, indicated that SH-SY5Y cells express both type I and type II IGF receptors. Treatment of SH-SY5Y cells for 4 d with 12-O-tetradecanoylphorbol-13-acetate (TPA), which resulted in morphological and functional differentiation and growth inhibition, abolished the mitogenic response to both IGF-I and II. Concomitantly, the binding of IGF-II disappeared almost totally, which offers a possible explanation for the reduced biological response to IGF-II after TPA treatment. In contrast, the IGF-I binding in TPA-treated cells was only reduced to approximately 70% of the binding to control cells. It is therefore not excluded that the IGF-I receptor could be uncoupled by TPA, with persistent binding capacity for IGF-I.

Purification of a high molecular weight somatomedin binding protein from human plasma.

The somatomedins insulin-like growth factor I and II (1,2) are in serum bound to high-molecular weight binding proteins (6,7,8). By use of a four step chromatographic procedure a somatomedin binding protein was isolated from outdated human plasma. Exclusion chromatography on Sephadex G-200 disclosed a molecular weight of 150 kDa. After lyophilization however, the binding activity was found in a lower molecular weight range of 35-45 kDa. A partial amino acid sequence analysis of the lyophilized material revealed a possible N-terminal sequence of Ala-Pro-Trp. This sequence is identical to the N-terminal sequence of the 35 kDa somatomedin binding protein previously isolated from human amniotic fluid (16).

The influence of purified somatomedins and insulin on foetal rat brain DNA synthesis in vitro.

The two main forms of somatomedins, termed insulin-like growth factor I and II (IGF-I and IGF-II), have been isolated from human plasma. Pure IGF-I or IGF-II was incubated with foetal rat brain cells and found to be equipotent in stimulating the [3H]thymidine incorporation into DNA, despite the fact that IGF-I not is present during foetal life.

Degradation of somatomedins by the thioredoxin system.

The insulin disulfide reducing thioredoxin system from E. coli was used to investigate a possible mechanism of degradation for the two somatomedins, insulin-like growth factor I and II (IGF-I and -II). The amounts of IGF-I and -II remaining after degradation were measured by use of human placenta radioreceptor assay. The results show that both IGF-I and -II were as sensitive to disulfide reduction as insulin.

Characterization of insulin-like growth factor II binding to human fibroblast monolayer cultures.

Two major somatomedin peptides have been isolated from human plasma, somatomedin-C/insulin-like growth factor I (SMC/IGF-I) and insulin-like growth factor II (IGF-II). Also, two types of SM/IGF receptors have been defined. Type I receptors have a higher affinity for SMC/IGF-I than IGF-II, and insulin binds to this receptor at high concentrations. Type II receptors have a higher affinity for IGF-II than SMC/IGF-I, and insulin does not bind to this receptor site. In this study, we characterized the binding of IGF-II to human monolayer fibroblast cultures, and the affinity and specificity of this binding. We also compared the binding of IGF-II to the binding of insulin and SMC/IGF-I to these cells. The receptors for IGF-II on normal human fibroblast monolayers fit the criteria for type II SM/IGF receptors, and there were more type II receptors on these cells than either insulin receptors or type I SM/IGF receptors. The type II receptors on human fibroblasts did not demonstrate autoregulation by homologous hormone, unlike the type I SM/IGF and insulin receptors. In addition, they were not changed by acute or chronic exposure to insulin. It is so far unclear what biological function IGF-II plays in vivo. This human fibroblast system will be a valuable experimental model for the study of IGF-II receptors and their relationship to the biological actions of IGF-II.