p38ß (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models.

BACKGROUND AND PURPOSE: Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental models. However, the molecular mechanism implicated in gemcitabine-associated radiosensitivity remains unknown. MATERIALS AND METHODS: The human sarcoma cell lines A673 and HT1080, and a mouse cell line derived from a 3-methylcholanthrene induced sarcoma were used as experimental models. Modulation of p38MAPKs was performed by pharmacological approaches (SB203580) and genetic interference using lentiviral vectors coding for specific shRNAs. Viability was assessed by MTT. Gene expression was evaluated by western blot and RT-qPCR. Induction of apoptosis was monitored by caspase 3/7 activity. Response to ionizing radiation was evaluated by clonogenic assays. RESULTS: Our data demonstrate that chemical inhibition of p38MAPK signalling pathway blocks gemcitabine radiosensitizing potential. Genetic interference of MAPK14 (p38α), the most abundantly expressed and best characterized p38MAPK, despite promoting resistance to gemcitabine, it does not affect its radiosensitizing potential. Interestingly, specific knockdown of MAPK11 (p38ß) induces a total loss of the radiosensitivity associated to gemcitabine, as well as a marked increase in the resistance to the drug. CONCLUSION: The present work identifies p38ß as a major determinant of the radiosensitizing potential of gemcitabine without implication of p38α, suggesting that p38ß status should be analysed in those cases in which gemcitabine is combined with ionizing radiation.

P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy.

Targeting cell cycle has become one of the major challenges in cancer therapy, being Palbociclib, a CDK4/6 inhibitor, an excellent example. Recently, it has been reported that Palbociclib could be a novel radiosensitizer agent. In an attempt to clarify the molecular basis of this effect we have used cell lines from colorectal (HT29, HCT116) lung (A549, H1299) and breast cancer (MCF-7). Our results indicate that the presence of a p53 wild type is strictly required for Palbociclib to exert its radiosensitizing effect, independently of the inhibitory effect exerted on CDK4/6. In fact, abrogation of p53 in cells with functional p53 blocks the radiosensitizing effect of Palbociclib. Moreover, no radiosensitizing effect is observed in cells with non-functional p53, but restoration of p53 function promotes radiosensitivity associated to Palbociclib. Furthermore, the presence of Palbociclib blocks the transcriptional activity of p53 in an ATM-dependent-fashion after ionizing radiation exposure, as the blockage of p21/WAF1 expression demonstrates. These observations are a proof of concept for a more selective therapy, based on the combination of CDK4/6 inhibition and radiotherapy, which would only benefit to those patients with a functional p53 pathway.

Value of 99mTc-MIBI scintimammography in women with impalpable breast lesions seen on mammography.

OBJECTIVE: To find out if 99mTc-methoxyisobutylisonitrile scintimammography (MIBI) is useful in the evaluation of impalpable breast lesions in women referred for biopsy after mammography screening. DESIGN: Observational and prospective study. SETTING: Radiological screening campaign in Spain. PATIENTS: 36 patients referred between September 1997 and June 1998 (37 biopsies) with impalpable breast lesions referred consecutively from a screening campaign. Ages ranged from 50 to 64 years. INTERVENTIONS: Mammography, ultrasound, MIBI, and wire-guided biopsy. MAIN OUTCOME MEASURES AND RESULTS: Mean values for sensitivity, specificity, positive predictive value, and negative predictive value for scintimammography were 78.9, 72.2, 75, and 76.5 respectively (p = 0.002). The logistic regression analysis showed that 99mTc-MIBI scintimammography result predicted (p = 0.003) the risk of breast cancer in this group of patients (odds ratio: 9.75), particularly infiltrating ductal carcinoma. CONCLUSIONS: MIBI scintimammography in patients referred for biopsy after mammography screening does not so much rule out cancer as confirm the diagnosis. Its practical benefit would be not so much avoiding biopsy for these patients as aiding in planning the radicality of their excision.

[Influence of menopausal status in homocysteine plasma levels]. / Influencia de la menopausia en la concentración plasmática de homocisteína.

BACKGROUND: Some studies have found that postmenopausal women have increased plasma homocysteine levels while others do not. The aim of this study was to know if homocysteine levels are increased in Spanish postmenopausal women. PATIENTS AND METHODS: In 100 postmenopausal women (age: mean [SD] 56 [6] years) homocysteine, creatinine, folic acid, vitamin B12 and lipoproteins were determined. Controls were 50 premenopausal women (age: 29 [6] years), 50 men with similar age to postmenopausal women, and 50 men with similar age to premenopausal women. All the subjects of the study were healthy. RESULTS: Homocysteine concentrations were higher in postmenopausal compared with premenopausal women (8.6 [2.1]; 95% confidence interval [CI], 8.2-9.1 vs 7.7 [1.6]; 95% CI, 7.2-8.1 micromol/l; p < 0.05), but were not different between both men groups. Hyperhomocysteinemia was found in 9 postmenopausal but in any premenopausal women (9% vs 0%; p = 0.03). Low density lipoprotein cholesterol values were higher (155 [32]; 95% CI, 148-161 vs 111 [32]; 95% CI, 101-120 mg/dl; p < 0.05), and high density lipoprotein cholesterol lower (54 [12]; 95% CI, 52-57 vs 64 [18]; 95% CI, 59-69 mg/dl; p < 0.05) in postmenopausal than premenopausal women. In postmenopausal women homocysteine levels were negatively associated with folic acid and positively associated with creatinine levels, but there was not association with age, vitamin B12 serum levels and lipoproteins. CONCLUSION: In postmenopausal women increased homocysteine concentrations, together with hypercholesterolemia, could contribute to the raise of their cardiovascular risk.

Fistulectomía radial y cierre primario en el tratamiento de la fístula periareolar recidivante / Radial fistulectomy and primary closure in the treatment of recurrent periareolar fistula

Objetivo. La fístula periareolar recidivante es un proceso inflamatorio crónico cuya patogenia y tratamiento siguen siendo controvertidos. El objetivo del estudio fue evaluar la efectividad de la fistulectomía radial con cierre primario, bajo anestesia local y en régimen ambulatorio, en esta enfermedad. Material y métodos. Realizamos un estudio sobre 12 pacientes (nueve mujeres y tres hombres) evaluados consecutivamente desde 1996. Cuando la enfermedad se detectó en fase de absceso se realizó drenaje simple. Establecida la fístula, la cirugía definitiva consistió en la escisión radial de todo el trayecto con cierre primario bajo anestesia local en régimen ambulatorio. El período de seguimiento medio fue de 1,8 años (rango: 0,5-3 años).Resultados. Todas las pacientes fueron dadas de alta el día de la intervención y no se produjeron consultas distintas de las programadas al alta. Como complicación destaca una infección de la herida quirúrgica que remitió con drenaje y tratamiento antibiótico. No se han detectado recidivas en el período estudiado. Conclusiones. El procedimiento es realizable bajo anestesia local y en régimen de cirugía ambulatoria; la tasa de infección de herida es muy baja; la técnica resulta sencilla y fácilmente reproducible por cualquier cirujano, y la tasa de recidiva resultaría muy baja en comparación con otras técnicas publicadas (AU)

Pancreaticoduodenectomy due to cancer in the elderly.

The elderly have traditionally been excluded from pancreaticoduodenectomy due to the high morbimortality of this procedure. Six cases of pancreaticoduodenectomy) 5 cephalic and 1 total) for periampullary tumors in patients over 70 are reported. There was no mortality. We conclude that, in selected cases, pancreaticoduodenectomy can be performed safely in the elderly.

Choledochoduodenostomy and sphincterotomy in the treatment of choledocholithiasis.

Over a 10-year period, 2610 patients underwent operation for biliary lithiasis. Exploratory choledochotomy was indicated in 591 patients (22.6 per cent). This was followed by simple choledochorrhaphy over a T tube in 240 patients (40.6 per cent), transduodenal sphincterotomy and choledochorrhaphy over a T tube in 126 (21.3 per cent), supraduodenal choledochoduodenostomy in 216 (36.5 per cent), and choledochoduodenostomy and transduodenal sphincterotomy in nine (1.5 per cent). Choledochoduodenostomy was performed if the bile duct was more than 12 mm in diameter. The indication for transduodenal sphincterotomy was the presence of a stone impacted in the papilla and/or papillary stenosis. Six patients developed abdominal abscess and three an external biliary fistula following choledochoduodenostomy. There were four abscesses and two episodes of acute pancreatitis in patients undergoing sphincterotomy. There was no difference in mortality rate between the two groups. After a mean follow-up of 5.6 years, 71.5 per cent of patients who underwent choledochoduodenostomy and 75.2 per cent of those who received transduodenal sphincterotomy were asymptomatic. The remainder suffered from dyspepsia, colicky pain or episodes of cholangitis. Nine patients underwent reoperation for residual calculi (six choledochoduodenostomies, three sphincterotomies).

Vagal system involvement in changes in small bowel motility during restraint stress: an experimental study in the dog.

Changes in small intestinal motility were studied during restraint stress in fasting animals and after food; the involvement of the vagal system in the pathophysiology of these changes was assessed. Small intestinal motility was recorded in 40 dogs using electromyography with monopolar electrodes and manometry with submucosal microballoons. Twenty animals underwent bilateral truncal vagotomy. Stress increased intestinal motility (percentage of slow waves followed by action potentials in 1 min), both in fasting conditions (P < 0.001) and post-prandially (P < 0.001). It also completely abolished the migrating motor complex-interdigestive myoelectric complex periodicity characteristic of the normal fasting pattern. In dogs subjected to vagotomy, restraint stress increased motility during fasting (P < 0.001) but decreased it after feeding (P < 0.01). Restraint stress thus increases small intestinal motility, both during fasting and after food. The vagal system is partially involved in this hypermotility response.

Long term results of surgical sphincterotomy in the treatment of choledocholithiasis.

The present article analyzes the indications for sphincterotomy in the Surgical Department of the University of Murcia, postoperative morbidity and mortality and the long term clinical situation of the patient after a follow-up period averaging 5.8 years. During a ten year period, a total of 2,610 patients underwent operation for biliary lithiasis, with exploratory choledochotomy indicated in 591 (22.6 percent). Surgical exploration of the bile duct finished with sphincterotomy in 135 (22.9 percent); 52 percent of these patients were less than 60 years old. The most frequent preoperative diagnosis was choledocholithiasis (33.3 percent) and cholelithiasis with crises of acute pancreatitis (30.3 percent). If we divide the ten years of the study into two five year periods, we noted a statistically significant decrease (p < 0.001) in the percentage of sphincterotomies compared with the number of choledochotomies performed during the second period. The rate of intra-abdominal complications was 5.1 percent; four intra-abdominal abscesses, one hemorrhaging at the level of the sphincterotomy and two instances of postoperative pancreatitis. Mortality in the series was 1.4 percent (two patients)--one with postoperative pancreatitis that developed torpidly and one with pulmonary embolism. Six years after the operation, 72.9 percent of the patients are still asymptomatic and the remaining patients have some type of symptoms--15.8 percent presented with dyspeptic syndrome; 2.0 percent had crises of colicky pain, and 5.9 percent required hospital admission for cholangitis. All of the patients with symptoms underwent endoscopy and ultrasonographic exploration of the bile duct. There were no pathologic findings in the biliary tree of patients who had dyspeptic syndrome or colicky pain, and all of the patients with cholangitis had a papillary stenosis and required endoscopic sphincterotomy or reoperation.

[Role of the vagal system in changes in small intestinal motility induced by psychological stress. Experimental study on dogs]. / Participación del sistema vagal en las alteraciones de la motilidad del intestino delgado inducidas por el stress psíquico. Estudio experimental en perros.

The objectives of the present study were: 1) to describe the modifications in motility of the small intestine in response to situations of psychic stress during fasting and postprandial periods. 2) To analyse the possible involvement of the vagal system in these modifications. For this we used a total of 40 dogs. The motility of the small intestine was recorded using electromyography techniques (monopolar electrodes) and manometric techniques (submucous microballons). The stress stimulus consisted in the complete body immobilization of the animal in plaster. We show that stress induced a significant increase in the intestinal motility index (percentage of show waves followed by the action potential) in the three locations of the intestine studied (duodenum, angle of Treitz and proximal part of the jejunum) during the fasting (p less than 0.001) and postprandial periods (p less than 0.001). Finally, we demonstrate that vagotomy prevents the effect of hypermotility causes by the psychic stress. We can conclude that psychic stress does indeed modify the normal motility of the small intestine, both in the fasting and postprandial periods, and the vagus is implicated in this hypermotility response.

Long-term results of choledochoduodenostomy in the treatment of choledocholithiasis: assessment of 225 cases.

During a 10-year period 2610 patients were operated on for biliary lithiasis; in 225 (8.6 per cent) cases the operation concluded with a choledochoduodenostomy. The commonest preoperative diagnosis (62.2 per cent) in these 225 patients was choledocholithiasis; 30 patients had previously had a cholecystectomy. After choledochoduodenostomy, 4.0 per cent of patients had an intra-abdominal complication; six patients developed an intra-abdominal abscess and three developed an external biliary fistula. Four patients (1.8 per cent) died, three from pulmonary complications and one from a biliary fistula. After a mean follow-up period of 4.6 years, 71.5 per cent of patients were asymptomatic. The remainder suffered from dyspepsia (15.1 per cent), colicky pain (8.7 per cent) or episodes of cholangitis (4.7 per cent). Endoscopy in the symptomatic patients allowed the following conclusions: (a) no patient with dyspepsia had a problem at the anastomosis; (b) 27 per cent of those with colic had anastomotic stenosis or the sump syndrome; and (c) all patients with cholangitis had anastomotic stenosis and residual calculi.

[Surgical treatment of gastric cancer. Evaluation of results in 313 consecutive cases]. / Tratamiento quirúrgico del cáncer gástrico. Valoración de resultados en 313 casos consecutivos.

The results of 313 gastric adenocarcinomas, treated by the same surgical team during 10 years have been evaluated retrospectively. The pathological characteristics, operability (88.8%) and resectability (69.8%) rates, surgical technique and morbility and mortality rates are analyzed. The causes of late mortality, total five-year survival, depending on the stage of the tumors, and survival in relation to treatment are reported.

Changes in small intestinal motility in acute physical stress--an experimental study.

The objectives of the present study were: 1) to describe the modifications in motility of the small intestine in response to situations of acute physical stress during fasting and post-prandial periods. 2) To analyse the possible involvement of the adrenergic and beta-endorphinergic systems in these modifications. For this we used a total of 60 dogs. The motility of the small intestine was recorded using electromyography techniques (monopolar electrodes) and manometric techniques (submucous microballoons). Plasma levels of beta-endorphin and catecholamines were determined before and after the stimulus. We show that physical stress applied in phases I or II of the fasting period induced a significant increase in the percentage of slow waves followed by the action potential for 1 minute in the three locations of the intestine studied (duodenum, angle of Treitz and proximal part of the jejunum), lasting from 8 to 12 minutes (p less than 0.001). When it is applied during the early post-prandial period it is responsible for a significant decrease in the percentage of slow waves followed by the action potential for 1 minute for a period of 6 to 11 minutes (p less than 0.001). The administration of adrenergic blockers prevents the effect of hypomotility caused by acute physical stress (p less than 0.001), whereas the administration of naloxone favors this hypomotility effect (p less than 0.001). Acute physical stress, on being applied during the late post-prandial period increases the percentage of slow waves followed by the action potential for 1 minute for a period of 8 minutes (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Nutritional status of the children population in the Annobon island (Republic of Equatorial Guinea)]. / Estado nutricional de la población infantil en la isla de Annobon (República de Guinea Ecuatorial).

The prevalence of protein energetic malnutrition in the island of Annobon is very high. A summary of the nutritional state of the Annobonese children would show that 36% of them suffered from protein energetic malnutrition at the time of the study, and that 41% had prior exposure to such malnutrition. The group of children with low weight for their age, and short stature, is the one aged 13 to 24 months. Apart from the results of the nutritional study, mention is made of environmental factors (resources and eating habits), which influence the results obtained. That which is considered a priority in child health in Equatorial Guinea is pointed out.