P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance.

5-Fluorouracil (5-FU), together with other drugs such as oxaliplatin, is one of the most important pharmacological agents in the treatment of colorectal cancer. Although mitogen-activated protein kinases (MAPKs) have been extensively connected with resistance to platinum compounds, no role has been established in 5-FU resistance. Here we demonstrate that p38MAPK activation is a key determinant in the cellular response to 5-FU. Thus, inhibition of p38MAPKα by SB203580 compound or by short-hairpin RNA interference-specific knockdown correlates with a decrease in the 5-FU-associated apoptosis and chemical resistance in both HaCaT and HCT116 cells. Activation of p38MAPK by 5-FU was dependent on canonical MAP2K, MAPK kinase (MKK)-3 and MKK6. In addition, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) showed a redundancy of function for the final activation of p38MAPK. Resistance associated with p38MAPK inhibition correlates with an autophagic response that was mediated by a decrease in p53-driven apoptosis, without effect onto p53-dependent autophagy. Moreover, the results with colorectal cancer-derived cell lines with different p53 status and patterns of resistance to 5-FU suggest that de novo and acquired resistance was controlled by similar mechanisms. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the cellular response to 5-FU by controlling the balance between apoptosis and autophagy.

Colonic stenting as a bridge to surgery in malignant large-bowel obstruction: a report from two large multinational registries.

OBJECTIVES: To date, this is the largest prospective series in patients with malignant colorectal obstruction to evaluate the effectiveness and safety of colonic self-expanding metal stents (SEMSs) as an alternative to emergency surgery. SEMSs allow restoration of bowel transit and careful tumor staging in preparation for elective surgery, hence avoiding the high morbidity and mortality associated with emergency surgery and stoma creation. METHODS: This report is on the SEMS bridge-to-surgery subset enrolled in two multicenter international registries. Patients were treated per standard of practice, with documentation of clinical and procedural success, safety, and surgical outcomes. RESULTS: A total of 182 patients were enrolled with obstructive tumor in the left colon (85%), rectum (11%), or splenic flexure (4%). Of these patients, 86% had localized colorectal cancer without metastasis. Procedural success was 98% (177/181). Clinical success was 94% (141/150). Elective surgery was performed in 150 patients (9 stomas) and emergency surgery in 7 patients for treatment of a complication (3 stomas). The overall complication rate was 7.8% (13/167), including perforation in 3% (5/167), stent migration in 1.2% (2/167), bleeding in 0.6% (1/167), persistent colonic obstruction in 1.8% (3/167), and stent occlusion due to fecal impaction in 1.2% (2/167). One patient died from complications related to surgical management of a perforation. CONCLUSIONS: SEMSs provide an effective bridge to surgery treatment with an acceptable complication rate in patients with acute malignant colonic obstruction, restoring luminal patency and allowing elective surgery with primary anastomosis in most patients.

Use of fully covered self-expanding metal stents for the management of benign biliary conditions.

BACKGROUND AND AIM: biliary self-expanding metal stents (SEMS) have the advantage of being inserted undeployed with very small sizes and provide, when fully opened, large diameters for biliary drainage. However, their use in benign conditions has been very limited, mainly because of difficulty in their extraction. We present our initial experience with a fully covered SEMS (Wallflex) for the management of benign problems of the bile duct. PATIENTS AND METHODS: in a prospective study, stents of 8 mm in diameter and 4, 6 or 8 cm long were inserted by means of ERCP. These SEMS were chosen when according to medical judgement it was thought that diameters greater than 10 French (3.3 mm) were needed for proper biliary drainage. Stents were extracted also endoscopically, several months later when deemed clinically appropriate. RESULTS: twenty biliary SEMS were inserted. Reasons for insertion were: large intrahepatic biliary fistula after hydatid cyst surgery (1), perforation of the papillary area following endoscopic sphincterotomy (2), coaxial insertion to achieve patency in obstructed uncovered stents inserted in benign conditions (3), benign strictures (7), multiple and large common bile duct stones that could not be extracted because of tapering and stricturing of the distal common bile duct (7). In all cases, successful biliary drainage was achieved and there were no complications from insertion. Stents were easily extracted after a mean time of 132 days (36-270) in place. Complete resolution of biliary problems was obtained in 14 patients (70%). CONCLUSIONS: in our initial experience, the fully covered Wallflex biliary stent was removed without any complication after being in place in the common bile duct for a mean time of over four months. Therefore, it could be used in the management of benign biliary conditions.

Utilización de prótesis metálicas autoexpandibles totalmente recubiertas en procesos biliares benignos / No disponible

Introducción y objetivo: las prótesis metálicas autoexpandibles biliares (PMAB) tienen la ventaja de introducirse plegadas con calibres muy pequeños y proporcionar, al abrirse completamente, diámetros grandes para el drenaje biliar. Su utilización en procesos benignos ha estado muy limitada, fundamentalmente por la dificultad en su extracción. Presentamos nuestra experiencia inicial con una PMAB totalmente recubierta (Wallflex) para tratar patología benigna de la vía biliar. Pacientes y métodos: en un estudio descriptivo prospectivo se insertaron por CPRE prótesis de 8 mm de diámetro y 4, 6 u 8 cm de longitud, cuando se consideró que para el drenaje biliar eran precisos diámetros superiores a 10 french (3,3 mm). Las prótesis se retiraron también por endoscopia varios meses después según se consideró oportuno clínicamente. Resultados: se insertaron 20 PMAB. Los motivos fueron: gran fístula biliar intrahepática tras cirugía de quiste hidatídico (1), perforación del área papilar por esfinterotomía endoscópica (2), recanalización de prótesis no recubiertas insertadas en procesos benignos (3), estenosis benignas (7), coledocolitiasis múltiples y de gran tamaño con afilamiento-estenosis del colédoco distal que no pudieron extraerse (7). En todos los casos se logró un drenaje biliar satisfactorio y no se produjeron complicaciones por la inserción. Las prótesis se extrajeron con facilidad a los 132 días de media (36-270). La resolución completa de los procesos se obtuvo en 14 pacientes (70%). Conclusiones: en nuestra experiencia inicial, la prótesis Wallflex biliar totalmente recubierta pudo extraerse sin complicaciones tras permanecer en el colédoco hasta una media de más de cuatro meses, por lo que podría utilizarse en el tratamiento de procesos biliares benignos(AU)

Background and aim: biliary self-expanding metal stents (SEMS) have the advantage of being inserted undeployed with very small sizes and provide, when fully opened, large diameters for biliary drainage. However, their use in benign conditions has been very limited, mainly because of difficulty in their extraction. We present our initial experience with a fully covered SEMS (Wallflex) for the management of benign problems of the bile duct. Patients and methods: in a prospective study, stents of 8 mm in diameter and 4, 6 or 8 cm long were inserted by means of ERCP. These SEMS were chosen when according to medical judgement it was thought that diameters greater than 10 French (3.3 mm) were needed for proper biliary drainage. Stents were extracted also endoscopically, several months later when deemed clinically appropriate. Results: twenty biliary SEMS were inserted. Reasons for insertion were: large intrahepatic biliary fistula after hydatid cyst surgery (1), perforation of the papillary area following endoscopic sphincterotomy (2), coaxial insertion to achieve patency in obstructed uncovered stents inserted in benign conditions (3), benign strictures (7), multiple and large common bile duct stones that could not be extracted because of tapering and stricturing of the distal common bile duct (7). In all cases, successful biliary drainage was achieved and there were no complications from insertion. Stents were easily extracted after a mean time of 132 days (36- 270) in place. Complete resolution of biliary problems was obtained in 14 patients (70%). Conclusions: in our initial experience, the fully covered Wallflex biliary stent was removed without any complication after being in place in the common bile duct for a mean time of over four months. Therefore, it could be used in the management of benign biliary conditions(AU)

Biliary sphincterotomy dilation for the extraction of difficult common bile duct stones.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy (BS) is the usual method for extracting common bile duct stones. However, following BS and by means of extraction balloons and Dormia baskets a complete bile duct clearance cannot be achieved in all cases. We present a study on the impact that hydrostatic balloon dilation of a previous BS (BSD) may have in the extraction rate of choledocholithiasis. PATIENTS AND METHODS: A prospective study which included 91 consecutive patients diagnosed with choledocholithiasis who underwent ERCP. For stone removal, extraction balloons and Dormia baskets were used, and when necessary BSD was employed. RESULTS: Complete bile duct clearance was achieved in 86/91 (94.5%) patients. BSD was used in 30 (33%) cases. In these cases, extraction was complete in 29/30 (97%); 23 (76%) patients in the BSD group had anatomic difficulties or bleeding disorders. The most frequently used hydrostatic balloon diameter was 15 mm (60%). There were 7 (7.6%) complications: two self-limited hemorrhage episodes in the BSD group and one episode of cholangitis, one of pancreatitis, and three of bleeding in the group in which BSD was not used. CONCLUSIONS: BSD is a very valuable tool for extracting common bile duct stones. In our experience, there has been an increase in the extraction rate from 73% (Rev Esp Enferm Dig 2002; 94: 340-50) to 94.5% (p = 0.0001, OR 0.1, CI 0.05-0.45), with no increase in complications.

Biliary sphincterotomy dilation for the extraction of difficult common bile duct stones

Background and aim: endoscopic retrograde cholangiopancreatography(ERCP) with biliary sphincterotomy (BS) is the usualmethod for extracting common bile duct stones. However, followingBS and by means of extraction balloons and Dormia baskets acomplete bile duct clearance cannot be achieved in all cases. Wepresent a study on the impact that hydrostatic balloon dilation of aprevious BS (BSD) may have in the extraction rate of choledocholithiasis.Patients and methods: a prospective study which included 91consecutive patients diagnosed with choledocholithiasis who underwentERCP. For stone removal, extraction balloons and Dormia basketswere used, and when necessary BSD was employed.Results: complete bile duct clearance was achieved in 86/91(94.5%) patients. BSD was used in 30 (33%) cases. In these cases,extraction was complete in 29/30 (97%); 23 (76%) patients in theBSD group had anatomic difficulties or bleeding disorders. Themost frequently used hydrostatic balloon diameter was 15 mm(60%). There were 7 (7.6%) complications: two self-limited hemorrhageepisodes in the BSD group and one episode of cholangitis,one of pancreatitis, and three of bleeding in the group inwhich BSD was not used.Conclusions: BSD is a very valuable tool for extracting commonbile duct stones. In our experience, there has been an increasein the extraction rate from 73% (Rev Esp Enferm Dig2002; 94: 340-50) to 94.5% (p = 0.0001, OR 0.1, CI 0.05-0.45), with no increase in complications(AU)

[Palliative management of malignant gastric outlet obstruction with endoscopically inserted self-expanding metal stents].

AIM AND BACKGROUND: the insertion of self-expanding metal stents to palliate malignant gastric outlet obstruction is a minimally invasive procedure that is being increasingly used. We discuss experience with this technique in a level-II hospital in the Spanish National Health System. PATIENTS AND METHODS: a retrospective five-year study (2003-2007) was conducted in 23 patients who underwent 27 procedures aimed at resolving malignant gastric outlet obstruction (mean, 0.45 procedures per month) using endoscopically inserted noncovered stents (Wallstent and Wallflex). RESULTS: insertion was technically feasible in all 27 (100%) attempts, with satisfactory clinical results in 25 cases (92.5%). Endoscopy alone was used 10 times (37%), and both endoscopy and fluoroscopy on 17 (63%) occasions. After stent insertion, one patient was intervened for treatment, and a patient with an unsuccessful prosthesis received a palliative surgical bypass. Four stents became obstructed by tumoral ingrowth, and patency was reestablished by inserting a new stent. Obstructive jaundice caused by stents covering the papilla of Vater occurred in three cases. There were no other complications or mortality due to the procedure. Mean survival was 104 days (range 28-400, SD +/- 94). CONCLUSIONS: in our experience endoscopic insertion of self-expanding metal stents appears to be a safe and efficient palliative method for malignant gastric outlet obstruction, and can be performed successfully in a center with our characteristics.

Ictericia por coledocolitiasis diagnosticada mediante una radiografía simple de abdomen / No disponible

No disponible

Long-term follow-up of patients with small-bowel angiodysplasia on capsule endoscopy. Determinants of a higher clinical impact and rebleeding rate.

BACKGROUND: the clinical impact of small-bowel angiodysplasia has not been defined. We present a prospective study to determine the features of individuals with a higher risk of rebleeding or a worse clinical outcome. PATIENTS AND METHODS: thirty patients with angiodysplasia found on CE were included and followed for 12 months. Angiodysplasia were classified by their size as small ( 10 mm). We also studied angiodysplasia lesion numbers in each patient. Rebleeding was defined as a hemoglobin drop of more than 2 g/dl in the absence of melena or hematochezia in the case of occult GI bleeding, or with any or both manifestations. RESULTS: a therapeutic procedure was carried out in 13 patients (43.4%). Individuals with large angiodysplasia had higher transfusion requirements, a higher proportion of therapeutic procedure performed after CE, lower hemoglobin concentration, and a lower rebleeding rate. Patients with ten or more angiodysplasia lesions had also higher transfusion requirements and lower hemoglobin levels, but we found no differences in the number of therapeutic procedures or rebleeding rate between both groups. On follow up rebleeding was detected in 5 patients (16.7%), all of them with small angiodysplasias. Rebleeding was more frequent in patients who did not receive further interventions (23.53 vs. 7.69%; p = 0.037). CONCLUSIONS: angiodysplasia size >or= 10 mm determines a worse clinical impact and more possibilities of receiving a therapeutic procedure. Our findings support that patients with large lesions would benefit from therapeutic interventions with a reduction in rebleeding rate.