EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma.

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

New celecoxib multiparticulate systems to improve glioblastoma treatment.

Treatment of malignant gliomas consists of resection followed by radiotherapy and chemotherapy. Celecoxib (CXB), a selective COX-2 inhibitor, is able to control inflammation and pain, to improve the efficacy of radiotherapy, and to inhibit at high doses the growth of cancer cells. Two new delivery systems for CXB are developed: microspheres (MPs) for implantation in the brain after partial/complete removal of the tumor, and nanoparticles (NPs) for their potential to cross the blood brain barrier and deliver CXB into the CNS. Cell culture assays performed in PC12, SKN-AS and U373-MG cells demonstrate the antiproliferative affects of CXB, with EC50 values of 99.81 µM and 82.4 µM in U373-MG and SKN-AS cells. Encapsulation efficacy of CXB in formulation MP2 (20% CXB) was 74.6 ± 2.2% with a zero-order release rate of 47.8 µg/day/20mg microspheres for 34 days. Uncoated and polysorbate 80-coated CXB-NPs are prepared by nanoprecipitation. Mean sizes of uncoated and coated CXB-NPs were 173.6 ± 44.9 nm and 100.6 ± 62.1 nm. Cerebral cortex images showed a marked increase of fluorescence when the surfactant-coated NPs were administered to rats. These results suggest that both CXB formulations (MPs and NPs) are adequate systems to enhance the effects of chemotherapy in the treatment of malignant brain tumor.

Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen's ureteral reimplantation for vesicoureteral reflux: long-term results.

PURPOSE: To compare efficacy of Cohen's ureteral reimplantation and endoscopic treatment with Dx/HA in patients with primary VUR grades II, III and IV. METHODS: From April 2002 to June 2004, patients over 1 year old with VUR grade I, II, III or IV were included. Patients were randomized into two groups: endoscopic treatment (ET) or ureteral reimplantation (UR). In the ET group, an ultrasonography study was performed 24 h and 1 month after surgery, and two voiding cystourethrographies at 3 and 6 months post treatment. In the UR group, an ultrasonography study was done 7 days and 1 month after surgery and a micturial cystography 6 months post surgery. A postoperative nuclear direct cystogram was performed 5 years later in both groups. RESULTS: A total of 41 patients were included in this study: in ET 22 patients with 35 refluxing ureters and in UR 19 patients with 32 refluxing ureters. The VUR grades in ET were: 16 grade II, 16 grade III and 3 grade IV; and in UR: 15 grade II, 12 grade III and 5 grade IV. VUR was resolved in 91% (32/35) of ET (28% of ureters needed a second injection), and in 100% of UR group. Five years after the procedure, VUR was still resolved in 30/32 of ET and 32/32 of UR. CONCLUSION: Short- and long-term follow up shows that multiple endoscopic treatment of VUR grades II, III and IV with Dx/HA is as effective as ureteral reimplantation.

Clinical and microbiological features of a cystic fibrosis patient chronically colonized with Pandoraea sputorum identified by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry.

Clonal isolates identified as various nonfermentative Gram-negative bacilli over a 5-year period from sputum cultures of a 30-year-old cystic fibrosis patient were successfully reidentified as Pandoraea sputorum by combining 16S rRNA sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Decreased lung function improved after 1 year of azithromycin and inhaled 7%-hypertonic saline treatment.

[Treatment of hepatocellular carcinoma using precision transcatheter arterial chemoembolization (TACE): results of two years' experience in a general hospital]. / Quimioembolización de hepatocarcinoma mediante TACE-precisión: resultados al 2.° año en un hospital general.

OBJECTIVES: To present our experience in the use of microspheres preloaded with adriamycin (DC Bead(®)) in the transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma, in a two-year prospective multidisciplinary study in consecutive patients to evaluate the efficacy, safety, and tolerance of this procedure. MATERIAL AND METHODS: From May 2007 to January 2010, we performed 30 TACE procedures in 17 patients (3 women and 14 men; mean age, 68 years; age range, 56-85 years). We performed a mean of 1.76 procedures per patient using the precision TACE protocol. Outcomes were evaluated using the RECIST-EASL criteria by clinical, laboratory, CT, and MRI follow-up at 1, 3, 6, and 12 months. RESULTS: The procedure was considered an initial technical success in all cases. The total dose was delivered in seven cases; in the remaining cases, the total dose was not reached (mean dose, 80mg). An objective response was observed in 64.7% of patients: a complete response was observed in 29.41% and a partial response in 35.29%. Disease was stabilized in 23.52% and progressed in 11.76%. We observed two cases of abscess/necrosis and one of ischemic cholecystitis. There were no deaths or cases of liver failure related with the procedure. CONCLUSIONS: TACE using microspheres preloaded with adriamycin (DC Beads®) is safe and effective, given the low rate of complications, good tolerance in patients, and increased tumor response.

[Interventional radiology for bile duct stones]. / Litiasis de las vías biliares en manos del radiólogo intervencionista.

OBJECTIVE: This article describes our experience in the percutaneous technique of expelling bile duct calculi into the duodenum by dilating the papilla with a balloon catheter. MATERIAL AND METHODS: We prospectively studied 365 patients (173 men, 192 women; mean age, 75 years; range 26-98) with bile duct calculi (single=213, multiple=152). In 102 cases, residual stones were percutaneously expelled into the duodenum via an indwelling T-tube; in 263 cases, primary (non-residual) stones were expelled from the hepatic or cystic duct through the common bile duct into the duodenum. The technique consisted of dilating the papilla with an angioplasty catheter and expelling the stone into the duodenum with an occlusion balloon; prior mechanical fragmentation was performed in only 48 cases. Percutaneous biliary drainage to the exterior was maintained for 2 to 8 days. RESULTS: The procedure was successful on the first attempt in 91.5% of cases and in 94.3% after the second attempt. The procedure failed in 16 cases, mainly due to the large size of the calculi. Residual lithiasis was resolved in 99% of cases and primary (non-residual) lithiasis was resolved in 91%. There were 23 major complications including 6 cases with poor clinical outcome and death (mortality at 30 days was 1.6%). CONCLUSIONS: Percutaneous anterograde evacuation of bile duct stones by dilating the papilla with an angioplasty catheter and expelling the stones with an occlusion balloon is effective, nontraumatic, and safe; this procedure maintains the anatomic and functional integrity of the sphincter. When performed by an experienced interventional radiologist, it is a viable alternative to choledochotomy.

[A pilot study of endoscopic experimental transgastric peritoneoscopy and endoscopic gastrorrhaphy in a canine model.]. / Estudio piloto de endoscopia experimental:peritoneoscopia transgástrica y gastrorrafiaendoscópica en modelo canino.

BACKGROUND AND AIMS: Natural Orifice Translumenal Endoscopic Surgery (NOTES) is an experimental technique with potential advantages compared to laparoscopic surgery. Trans gastric peritoneoscopy (TP) is a NOTES technique. The aim of this study was to perform TP, to evaluate feasibility and technical limitations in a survival model. MATERIALS AND METHODS: The following procedures were performed in 4 anesthetized dogs using a single channel video gastroscope: Gastrotomy with needle-knife puncture followed with extension of the incision with a pull-type sphincterotome,pneumoperitoneum with the endoscope,peritoneoscopy and gastrorrhapy using hemoclips and endoloops. RESULTS: All the procedures were accomplished successfully with a mean duration of 80 minutes. Gastrotomy induced minor bleeding.Peritoneal cavity was accessed safely and peritoneoscopy was accomplished without incidents.Retroflexed maneuvers were mandatory to visualize upper abdomen and overinflation oftenly occurred. The closure of the gastric wall incision was successfully obtained. All the animals made an uncomplicated recovery after 7 days. CONCLUSIONS: TP is technically feasible and safe in a canine model. This study highlights several technical limitations and confirms the need for technological development.

Stenting as first option for endovascular treatment of malignant superior vena cava syndrome.

OBJECTIVE: Endoprostheses were inserted in cancer patients with superior vena cava syndrome to assess their effectiveness as first-choice, initial treatment for relief of symptoms. SUBJECTS AND METHODS: Wallstent prostheses (n = 73) of various lengths (5-14 cm; median, 7 cm) and diameters (10-16 mm; median, 16 mm) were inserted in 52 cancer patients (51 men, 1 woman; age range, 44-78 years; mean, 63 years) who were diagnosed and confirmed by cavography or phlebography as having superior vena cava syndrome. A single stent was sufficient in 37 patients, two stents were required in 11, three stents in two, and four stents in another two patients. Contraindications for the procedure were severe cardiopathy or coagulopathy. RESULTS: Resolution of symptoms was achieved in all patients within 72 hr. At follow-up, six obstructions, one partial migration to the right atrium, two incorrect placements, and four stent "shortenings" were noted. All were successfully resolved by repeated stenting. Symptom-free survival ranged from 2 days to 17 months (mean, 6.4 months). At the time of this writing, eight patients are alive and have patent stents. The rest have died from their cancer. CONCLUSION: The Wallstent vascular endoprosthesis is an effective initial treatment in superior vena cava syndrome of neoplastic origin. Morbidity and complications are minimal. Clinical relief of symptoms is rapid; therefore, the Wallstent endoprosthesis is highly recommended as the first choice for palliative treatment of superior vena cava syndrome, especially because the clinical decision for subsequent chemotherapy or radiotherapy or surgery is not in any way prejudiced.

Differential 5-HT-mediated regulation of stress-induced activation of proopiomelanocortin (POMC) gene expression in the anterior and intermediate lobe of the pituitary in male rats.

The purpose of the present study was to examine the role of 5-hydroxytryptamine (5-HT) neurons in mediating the effects of stress on proopiomelanocortin (POMC) gene expression in the anterior and intermediate lobes of the pituitary gland. To this aim, the effects of 5-HT depletion induced by administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 200 microg/rat; i.c.v.; 7 days) were investigated on POMC mRNA levels in the anterior and intermediate lobe of control and restraint-stressed rats. Three hours after brief exposure to diethyl ether (2 min) followed by 60 min of restraint stress increased POMC mRNA levels in the anterior and intermediate lobe of the pituitary. 5,7-DHT neurotoxic lesion, which resulted in a marked depletion of 5-HT (below the level of sensitivity of the neurochemical assay, 6 pg/sample) but not of dopamine or norepinephrine concentrations in the periventricular nucleus of the hypothalamus, had no effect on basal POMC mRNA levels in the anterior or intermediate lobe of the pituitary. However, 5-HT depletion further increased POMC mRNA levels in the anterior pituitary and completely blocked POMC mRNA level enhancement induced in the intermediate lobe of stressed rats. These results suggest a possible inhibitory 5-HT tone on POMC gene expression in the anterior pituitary and a stimulatory 5-HT tone in the intermediate lobe of the pituitary under these experimental conditions of stress. It appears, therefore, that 5-HT exerts a differential regulation of stress-induced activation of POMC gene expression in the anterior and intermediate lobes of the pituitary in male rats.

Treatment of superior and inferior vena cava syndromes of malignant cause with Wallstent catheter placed percutaneously.

Superior vena cava syndrome (SVCS) and inferior vena cava syndrome (IVCS) represent a severe symptomatic complication of some malignant tumors. Although radiation therapy and chemotherapy are elective, symptomatic relief takes 7-10 days to be achieved, and poor symptomatic benefit can be obtained in relapsed or resistant tumors. We report on a palliative approach using Wallstent catheters placed percutaneously in a series of 16 patients. Results obtained in relief of symptoms were excellent (complete response of cephalea, jugular enlargement, and collateral circulation achieved in 100% [16/16] of patients; complete response of edema obtained in 93% [15/16] of patients). Achievement of symptomatic response was obtained for all symptoms during the first 24 h poststenting, except for edema and dyspnea. Mean duration of patency of the stents was 6.4 months (range 2-17 months). Rates of morbidity and complications were very low. Dyspnea was a quite resistant symptom, and only four of 13 patients (31%) obtained complete response, while partial improvement was obtained in the other nine (79%). However, placement of the stents does not preclude the use of radiation therapy or chemotherapy. We think that these results and those from other studies warrant larger multicentric trials.

[Nephrolithiasis in children]. / Litiasis renal en el niño.

We reevaluated the medical records of 112 children with urolithiasis. The prevalence of this condition was 1/4.500 children admitted to our hospital. The mean age was 8.2 years and 54.4% of the afflicted patients were males. Fifty percent of the patients studied had a family history of urolithiasis. The two most frequent etiologies were urinary tract infections and metabolic disorders (hypercalciuria states, distal renal tubular acidosis and cystinuria). The etiology of the urolithiasis was unknown in 15% of our patients. The levels of magnesium and citrate, inhibitors of crystallization, were moderately low in some of the cases in which it was determined. Fifty percent of the children with urolithiasis showed urinary or renal complications. The extracorporeal lithotripsy was an effective treatment of urolithiasis in the patients in which it was performed. The recurrence rate was 8%. In one third of the urolithiasis associated with urinary infections and/or urinary tract malformations we found chronic pyelonephritis.

[Primary tumors of the parotid. An anatomicoclinical review]. / Tumores primarios de parótida. Revisión anatomoclínica.

It was studied 54 cases of tumors of parotid treated in the Hospital Universitario of Granada from 1978 to 1989. It was also studied the patient age and sex, the year and month of disease arise, the tumors stages at diagnosis, the different treatments followed and the histological classification. Finally the results are discussed.

[Schoenlein-Henoch nephropathy in childhood. Clinical and histologic study of 31 cases]. / Nefropatía de Schönlein-Henoch en la infancia. Estudio clínico e histológico de 31 casos.

A series of 31 cases of children affected by nephropathy, out of a total of 120 presenting with Schönlein-Henoch syndrome, observed in a period of seven years is reviewed. 87% of the patients evidenced renal involvement in the first month of disease. The manifestations of nephropathy were: Isolated hematuria. Hematuria-proteinuria less than 40 mg/m2/h. Nephrotic syndrome. Hematuria-nephrotic syndrome. Hematuria-nephrotic syndrome renal insufficiency. Biopsy was performed in 13 cases (41.9%). With regard to the ISKDC rules, the histological classification was: type I, one patient; type II, three patients; type III, seven patients; type V, one patient; type VI, one patient. Evolution was favorable in 30 cases, independently of treatment applied, and a complete remission was obtained in all of them.