EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

EZH2 is mutated in nearly 25% of follicular lymphoma (FL) cases. Little is known about how EZH2 affects patients' response to therapy. In this context, the aim of this study was to retrospectively analyze the frequency of mutations in EZH2 at diagnosis in tissue and ctDNA in patients with FL and to assess the patients' outcomes after receiving immunochemotherapy, depending on the EZH2 mutation status. Among the 154 patients included in the study, 27% had mutated EZH2 (46% with high-grade and 26% with low-grade FL). Of the mutated tissue samples, the mutation in ctDNA was identified in 44% of cases. EZH2 mutation in ctDNA was not identified in any patient unmutated in the tissue.Unmutated patients who received R-CHOP had significantly more relapses than patients who received R-Bendamustine (16/49 vs. 2/23, p = 0.040). Furthermore, our results show that patients with mutated EZH2 treated with R-CHOP vs. those treated with R-Bendamustine present a lower incidence of relapse (10% vs. 42% p = 0.09 at 4 years), a higher PFS (92% vs. 40% p = 0.039 at 4 years), and higher OS (100% vs. 78% p = 0.039 at 4 years). Based on these data, RCHOP could be a more suitable regimen for mutated patients, and R-bendamustine for unmutated patients. These findings could mean the first-time identification of a useful biomarker to guide upfront therapy in FL.

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.

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.

[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.

Outcomes of bile duct drainage by means of ERCP in geriatric patients / Resultados del drenaje de la vía biliar por CPRE en pacientes con edad geriátrica.

BACKGROUND AND OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) is usually the procedure of choice for relieving bile duct obstruction. a large number of patients undergoing this intervention are geriatric population (aged 75 years of age and older). Our aim was to assess the efficacy of ERCP in this group of patients as compared to younger ones. PATIENTS AND METHODS: A retrospective study. All patients in whom a therapeutic biliary endoscopy had been performed over a four-year period of time (2002-2005) were included. RESULTS: 178 geriatric patients and 159 younger ones underwent ERCP. No differences were found in successful biliary drainage (97.7 vs. 98.7%), complication number (11.8 vs. 14.4%), or mortality rate (1.1 vs. 0.6%). On the other hand, more common bile duct stones were found in geriatric patients (57.3 vs. 39.6%, p = 0.004), and also more self-expanding metal stents were employed to drain malignant obstructive jaundice (47 vs. 8%, p = 0.0035). In the youngest group, more ERCPs were repeated in the same patients (4 vs. 10%, p = 0.001). CONCLUSIONS: The geriatric population showed similar success and morbidity and mortality rates when compared to younger patients in draining their bile duct by means of ERCP. Common bile duct stones were more frequently found in geriatric patients. No patients needing an ERCP should be excluded only because of their age.

Evaluation of the environmental contamination at an abandoned mining site using multivariate statistical techniques--the Rodalquilar (Southern Spain) mining district.

Unsupervised and supervised pattern recognition techniques such as hierarchical cluster analysis, principal component analysis, factor analysis and linear discriminant analysis have been applied to water samples recollected in Rodalquilar mining district (Southern Spain) in order to identify different sources of environmental pollution caused by the abandoned mining industry. The effect of the mining activity on waters was monitored determining the concentration of eleven elements (Mn, Ba, Co, Cu, Zn, As, Cd, Sb, Hg, Au and Pb) by inductively coupled plasma mass spectrometry (ICP-MS). The Box-Cox transformation has been used to transform the data set in normal form in order to minimize the non-normal distribution of the geochemical data. The environmental impact is affected mainly by the mining activity developed in the zone, the acid drainage and finally by the chemical treatment used for the benefit of gold.

[Prevalence of modifiable risk factors in the nursing diagnosis of risk for sudden infant death syndrome]. / Prevalencia de factores de riesgo modificables en el diagnóstico de enfermería: riesgo del síndrome de la muerte súbita del lactante.

OBJECTIVE: To measure the prevalence of modifiable risk factors for the nursing diagnosis of risk of sudden infant death syndrome (RSIDS), and to establish the association between the prevalence found and the sociodemographic characteristics of the sample. MATERIAL AND METHODS: The sample was composed of 384 mothers (Spaniards, Moroccans and Ecuadorians). Data were collected in the maternity ward of Sta. M del Rosell Hospital in Cartagena (Murcia) from June to November 2007 through a questionnaire containing items on sociodemographic variables and questions about upbringing habits and practices, which are defined as modifiable risk factors by the NANDA-I taxonomy. In the statistical analysis, the Chi-square test was used for qualitative variables and Student's t-test and analysis of variance were used for quantitative variables. RESULTS: A total of 77.1% of newborns were diagnosed with RSIDS related to modifiable risk factors. Notable was the high prevalence of risk factors such as the choice of side-lying position to put the newborn to bed in 39.8% (153) and smoking during pregnancy in 25.7% (99). Statistically significant associations were found (p<0.001) between the diagnosis of RSIDS and the mother's nationality, educational level and household income. CONCLUSION: The high prevalence of some modifiable risk factors among newborns raises the need to provide more information about upbringing habits and practices for SIDS prevention, not only in Infant Nursing Consulting Rooms but also throughout pregnancy and in the first days of life of the newborn.

Randomized clinical trial of the effect of intravenous fluid administration on hormonal and renal dysfunction in patients with obstructive jaundice undergoing endoscopic drainage.

BACKGROUND: Renal dysfunction in patients with biliary obstruction is associated with extracellular water depletion. This study examined the effect of preoperative saline infusion before biliary drainage on hormonal and renal functional derangements in patients with obstructive jaundice. METHODS: In a randomized study, 49 patients with malignant obstructive jaundice were investigated at baseline, on the day of drainage, and at 24 h, 72 h and 7 days after internal endoscopic biliary drainage. Patients were randomized to receive (n = 22) or not to receive (n = 27) 3000 ml normal saline intravenously for 24 h before drainage. Variables analysed included extracellular water volume, creatinine clearance, and serum levels of aldosterone, renin, atrial natriuretic peptide (ANP), vasopressin and albumin. RESULTS: Preoperative saline infusion produced a rise in creatinine clearance, diuresis, ANP concentration and extracellular water volume but this did not translate into better recovery of renal function after operation. Drainage produced a fall in creatinine clearance in all patients, but hormonal and renal function had recovered by 2 days after restoration of bile flow, independently of preoperative hydration. CONCLUSION: Fluid administration expands the extracellular water compartment before drainage but fails to improve renal function after drainage. Definitive improvement in endocrine and renal function requires the restoration of bile flow into the duodenum.

Role of intrarenal endothelin 1, endothelin 3, and angiotensin II expression in chronic cyclosporin A nephrotoxicity in rats.

Endothelin 1 (Et1) is widely expressed in the kidney and is related to several functions and to pathological conditions with progression towards sclerosis. The function of endothelin 3 (Et3) at the renal level is debatable, but it could have an important regulatory function in the reabsorption of water through its action on tubular type B receptors. Angiotensin II has recently been implicated as the principal factor responsible for the progression of interstitial fibrosis induced by cyclosporin A (CsA). We investigated this relationship in vivo and analyzed the modifications induced by CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day of CsA for 28 and 56 days. Immunohistochemical methods and molecular analysis were used to study the expression of Et1 and Et3 and immunohistochemistry alone to determine the intrarenal expression of angiotensin II. Rats treated with CsA developed chronic nephrotoxicity lesions; semiquantitative analyses of hyaline arteriolopathy revealed that the passage of time affected the extent of this lesion and led to the diminution of the total glomerular area. Immunohistochemical results showed that chronic CsA treatment induced moderate secretion of Et1 and Et3 at tubular and glomerular levels and that the local expression of angiotensin II in the treatment groups was more evident than in control animals. Besides, the mRNA levels of preproEt3 showed a dramatic increase from 28 days after CsA treatment (control group 0.07+/-0.11 vs. CsA group 0.48+/-0.11, p<0.01), while the mRNA levels of preproEt1 increased from 56 days (control group 0.15+/-0.05 vs. CsA group 0.34+/-0.09, p< 0.05). At 28 days, renal lesions correlated strongly with the mRNA levels of Et3 (r>0.50, p<0.01). However, at 56 days, the key finding was the strong correlation of the most important analytical, histological, and immunohistochemical parameters of CsA nephrotoxicity with Et1 mRNA levels (r>0.50, p<0.01). These results support the hypothesis that the clinical and morphological phenomena linked with CsA nephrotoxicity are related to hypersecretion of endothelins and local expression of angiotensin II in the outer medulla and medullary rays; Et3 and angiotensin II are the first to act, followed subsequently by Et1.

Chronic cyclosporin A nephrotoxicity, P-glycoprotein overexpression, and relationships with intrarenal angiotensin II deposits.

P-glycoprotein (P-gp) expels hydrophobic substances from the cell, including chemotherapeutic agents and immunosuppressants such as cyclosporin A (CsA) and FK506. Exposure of cultured renal tubular cells to CsA induces P-gp overexpression in cell membranes. Angiotensin II has recently been implicated as the principal factor responsible for progression of interstitial fibrosis induced by CsA. To investigate the in vivo relationships between histological lesions, P-gp overexpression, and intrarenal angiotensin II deposits, we developed a model of chronic CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day CsA for 28 and 56 days and fed either a standard maintenance diet or a low-salt diet. Immunohistochemical methods were used to study the expression of P-gp in renal tubular cells and the appearance of intrarenal angiotensin II deposits. Rats treated with CsA developed chronic nephrotoxicity lesions that were more evident in the group fed the low-salt diet. Treatment with CsA induced overexpression of P-gp in tubular cells of the kidney that increased with time. We found that immunohistochemical expression of P-gp was slightly more severe in rats fed a low-salt diet. Intrarenal deposits of angiotensin II were more evident in rats treated with CsA; these deposits also increased with time. This finding was also more relevant in rats given the low-salt diet. The up-regulation of P-gp was inversely related to the incidence of hyaline arteriopathy (r = -0.65; P < 0.05), periglomerular (r = -0.58; P < 0.05) and peritubular fibrosis (r = -0.63; P < 0.05), and intrarenal angiotensin H deposits in animals with severe signs of nephrotoxicity (r = -0.65; P < 0.05). These results support the hypothesis that the role of P-gp as a detoxicant in renal cells may be related to mechanisms that control the cytoplasmic removal of both toxic metabolites from CsA and those originating from the catabolism of signal transduction proteins (methylcysteine esters), which are produced as a result of ras activation in presence of angiotensin II.