Plasma levels of trastuzumab in gastric cancer: Case report.

Introduction The use of trastuzumab with a fluoropyrimidine and platinum compound is currently the standard first-line treatment of patients with metastatic HER2-positive gastric cancer, but it appears that serum levels of trastuzumab determine the clinical effectiveness of this treatment, affecting progression-free survival and overall survival. Case report We report the case of a patient with metastatic HER2-positivegastric cancer, receiving XELOX (fluoropyrimidine and oxaliplatin) plus trastuzumab at standard doses, who presented sub-therapeutic serum levels during the first two treatment cycles and rapid disease progression (progression-free survival = 5.6 months). Discussion This case reveals a possible cause of poor effectiveness of trastuzumab treatment for metastatic gastric cancer in some patients, namely low circulating levels of the drug. It highlights the importance of monitoring as a possible tool for individual dose adjustment to optimize this therapy.

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Sepsis de repetición en un paciente con gammapatía monoclonal de significado incierto / Several episodes of bacterial infections in a patient with monoclonal gammapathy of undetermined significance

No disponible

Zinc, copper, manganese, and iron in chronic alcoholic liver disease.

Ethanol consumption and/or liver damage may alter liver content of several trace elements, as iron, zinc, copper, and manganese. This alteration may play a role on ongoing liver fibrogenesis. Based on these facts we have determined liver, serum, and urinary Mn, Cu, Zn, and Fe levels in a group of alcoholic cirrhotics and noncirrhotics with normal renal function, comparing them with those of controls. We have observed low liver zinc and high liver copper--this last in relation with histomorphometrically determined total amount of liver fibrosis--and manganese contents in cirrhotics, together with increased excretion of zinc and iron and decreased excretion of manganese. Zinc, iron, and copper excretion kept a relation with data of severity of cirrhosis, including mortality in the case of urinary copper, independently of the use of diuretics. Thus, liver copper and urinary iron, zinc, and copper excretion seem to be related with data of severity of chronic alcoholic liver disease. Low urinary manganese excretion may play a role on liver manganese overload.

[Chronic liver disease exacerbated during alpha-interferon treatment]. / Hepatopatía crónica exacerbada tras tratamiento con alpha-interferón.

A 27 year old male patient was referred to our clinical unit because of marked elevation of serum bilirubin (up to 15.3 mg/dl), ASAT (563 U/l) and ALAT (845 U/l) were detected after institution of therapy with alpha interferon. The patient had been previously treated because of persistent slight elevation of serum transaminases, serological markers of hepatitis B virus and hepatitis C virus being both negative. Liver histology was consistent with chronic active hepatitis. Antinuclear, anti smooth muscle and antimitochondrial autoantibodies were all negative, although anti smooth muscle antibodies became positive (1/40) after interferon therapy. The drug was withdrawn, prednisone was instituted, and transaminases and bilirubin values returned to normality.

Alcoholic withdrawal syndrome and seizures.

A study of 72 alcoholics, hospitalized for alcohol withdrawal syndrome, was undertaken to determine the incidence of seizures, their relationship with other withdrawal symptoms, the presence of brain atrophy and the relationship of this last with withdrawal intensity severity. Sixty-seven (93%) were male and the mean age was 44.9 +/- 1.3 (mean +/- SEM) years. Thirty-three (46%) of the 72 patients had seizures at admission, 10 of these developed minor withdrawal symptoms, in 18 delirium tremens ensued and 5 showed no symptoms of withdrawal. Thirty-nine (54%) had withdrawal syndrome without seizures. Twenty-one of these developed minor withdrawal syndrome and 18 delirium tremens. Seizures showed no relationship with the other withdrawal manifestations, and in all the cases preceded them. Our findings also show that alcoholics with seizures due to withdrawal are more prone to suffer seizures in their future withdrawal episodes, and that alcoholics who suffer morning withdrawal symptoms are prone to develop delirium tremens. In 46 patients a CT scan was performed. Though the alcoholics showed ventricular and sulcal enlargement, brain atrophy was similar when the seizure and non-seizure groups or those with and without delirium tremens were compared. However, cortical and ventricular atrophy were related to the existence of previous episodes of withdrawal syndrome [corrected].

Functional decline and nutritional status in a hospitalized geriatric population: sequential study.

We analyzed the relations between nutritional status and several measures of the ability to perform the normal activities of daily living (ADL) in a long-term institutionalized geriatric population and also studied whether changes in this ability, as found ten months later, were associated with changes in the nutritional status. Nutritional status was assessed using objective anthropometric measurements (triceps skinfold, mid upper-arm circumference, midarm muscle area [AMA], midarm fat area [AFA]) and subjective clinical features (temporal muscle atrophy [TMA] and Bichat's fat atrophy [BFA]). The capacity to perform ADL was analyzed considering ability to eat and to walk, dental status, and mental performance status. Patients with total absence or loss of more than 50% of the teeth showed less AMA and AFA and greater degrees of TMA and BFA; the same happened with regard to deterioration of mental performance status. Those patients fed through a nasogastric tube showed less AFA and serum albumin and also a greater degree of TMA and BFA. Patients unable to walk without aid showed less AMA and AFA. Patients whose capacity to walk improved or whose mental performance status ameliorated showed an increase of their AMA, whereas AFA slightly decreased in those patients whose abilities to eat and to walk deteriorated. Long-term hospitalization in our center led to improvement and to deterioration of ADL in approximately the same number of patients, and similar changes were seen in the nutritional measures.

Clinical and prognostic value of serum procollagen levels in chronic alcoholic liver disease.

Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells, including Ito cells, transitional cells, myofibroblasts and hepatocytes. Synthesis of collagen fibrils follows a complex metabolic pathway with intermediate products such as type III procollagen (III-PC). Serum levels of III-PC may reflect the activity of the fibrogenetic process. We analysed the relationship between the serum levels of III-PC (N-terminal peptide) and diverse clinical, biochemical and histological parameters of 77 alcoholic patients (27 cirrhotics), comparing them with those of 15 age- and sex-matched controls. A highly significant difference was obtained between controls and patients (P less than 0.0001), but no differences were observed between cirrhotics and non-cirrhotics. Serum III-PC significantly correlated with clinical and biochemical data of liver function derangement (prothrombin activity, serum albumin, bilirubin, gynecomastia, ascites, encephalopathy, edema, splenomegaly); with the duration of ethanol addiction and with MCV. Sixty patients were followed up for a period ranging between 3 and 1056 days (mean = 356 days); 9 of them died. Patients with III-PC levels above 38 ng/ml had a significantly higher mortality (P = 0.006) than those with levels under 38 (log rank test). Thus, serum III-PC may be a useful tool in the clinical evaluation and prognostic assessment of patients with chronic alcoholic liver disease.

[Changes of liver enzymes during severe infections]. / Alteración de las enzimas hepáticas en el curso de infecciones graves.

To establish the prevalence of liver enzyme alterations in the course of serious infections of diverse origin, 112 patients were studied retrospectively for the levels of GOT, GPT, LDH, GGT, alkaline phosphatase (FA) and bilirubin (BIL). Cases in which the values might be altered due to causes other than the infectious process were previously excluded. The prevalence of affectation of each of the parameters was the following: GGT, 39.1%; LDH, 33.3%; FAL, 30.1%; GOT, 29.5%; GPT, 24.8%; BIL, 18.3%. Seventy percent had at least one of these values changed. No significant differences were found in the incidence or intensity of the analytic alterations in function of the origin of the of infection, which suggests that these modification are nonspecific. Bilirubin levels were found to be significantly higher in the patients who died. On realizing the linear correlation analysis between the diverse parameters studied, a good correlation was found between them, suggesting a common pathogenetic mechanism.

Hepatocyte and nuclear areas and fatty infiltration of the liver in chronic alcoholic liver disease.

In 117 patients affected by chronic alcoholic liver disease, we have histomorphometrically determined hepatocyte and nuclear areas, total amount of fat and total amount of fibrosis, comparing them with the following clinical and biochemical parameters: ascites, encephalopathy, jaundice, spiders, collateral circulation, splenomegaly, prothrombin activity, serum albumin, gammaglobulin, bilirubin, ASAT, ALAT, GGT, leukocyte and platelet count, and daily consumption of ethanol. Both hepatocyte and nuclear areas closely correlated with most of the parameters indicative of hepatic function derangement, whereas fat amount correlated with them inversely, but positively with the daily consumption of ethanol. The degree of fibrosis was greater in patients with a worse hepatic function, and there was a direct relationship between the degree of fibrosis and hepatocyte and nuclear areas, and an inverse one between the degree of fibrosis and the total amount of fat.

Computerized liver imaging: relationship with quantitatively estimated histological parameters in liver cirrhosis.

In liver cirrhosis, increased splenic uptake of radiocolloid, causing the liver-to-spleen (L/S) ratio to decrease, is a characteristic finding, especially during advanced illness. Histologically, advanced liver cirrhosis shows progressive replacement of hepatic parenchyma by fibrous tracts, making it possible to quantify both image and histological parameters. On this basis, the authors performed this study in 39 alcoholic cirrhotic patients in order to determine the relationship between the L/S ratio and right-to-left hepatic lobe ratio (RL/LL) and the degree of fibrosis, fat droplet area, total fat amount, and hepatocyte area. The authors tested if it is possible to predict the degree of fibrosis on the basis of image features or on a combination of image and biochemical parameters, using multiple correlation studies. The degree of fibrosis correlates with the L/S ratio (r = -0.48). The degree of correlation improved using prothrombin, gamma globulin and L/S ratio (r = 0.656), but not enough to allow an accurate estimation of the degree of fibrosis on the basis of a combination of imaging and biochemical data. Neither RL/LL nor L/S ratios significantly correlated with fatty infiltration, fat droplet area, or hepatocyte enlargement. Thus, liver imaging is not useful in quantifying the main histological changes observed in alcoholic liver cirrhosis.

Effect of propylthiouracil on liver cell development in the male albino mouse: protective effect against ethanol-induced alterations.

The aim of the present study is to analyze whether the addition of propylthiouracil reverts the influence of ethanol on the development of periportal and pericentral hepatocytes and their nuclei in male albino mice. Propylthiouracil-treated animals showed decreased cellular and nuclear areas when compared with the control animals, except for the 180-day-old animals, whose pericentral cells and nuclei were greater than those of the controls and exhibited fatty infiltration. Pericentral hepatocytes and nuclei of the ethanol-fed animals showed an increase of their sizes, especially in 180-day-old animals. In contrast, hepatocyte and nuclear sizes of the animals treated with both propylthiouracil and ethanol were similar to those of the control group, suggesting a protective effect of propylthiouracil against the ethanol-induced alterations.