Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

BACKGROUND: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. METHODS: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). RESULTS: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. CONCLUSION: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. CLINICAL TRIAL NUMBER: NCT02288936 (PREMIERE trial).

Usefulness of manometry to select patients with anal fissure for controlled anal dilatation.

AIM: To evaluate the use of anorectal manometry to select patients for controlled anal dilatation. METHODOLOGY: A prospective study was performed using anorectal manometry on all patients with chronic anal fissure who did not have a good response to conservative treatment. Those with increased anal resting pressure were treated with controlled anal dilatation using a two valved anuscope. A second anorectal manometry was indicated after controlled anal dilatation. RESULTS: 19 patients without anorectal pathology (Healthy Control Group) and 57 patients with chronic anal fissure were included in this study. Controlled anal dilatation was performed on 27 patients, maximum resting pressure 122 ± 19 mmHg. In the controlled anal dilatation group the healing rate was 92.5%, mean maximum resting pressure post-controlled anal dilatation was 91 ± 30 mmHg. We found one case of transitory anal incontinence (3.7%). None of the patients had anal incontinence at 18 months of the follow-up. In the remaining 30 patients non selected for controlled anal dilatation (chronic anal fissure control group), a proportion of 53.3% recurrences were registered after conservative treatment. CONCLUSIONS: Anal healing of chronic anal fissure and a significant decrease in maximum resting pressure recorded by manometry confirms the success of this procedure. The manometric evaluation of the maximum resting pressure is useful in the selection of chronic anal fissure patients for controlled anal dilatation. The efficacy of dilatation to treat chronic anal fissure in patients with raised anal sphincter pressure was high and complications were rare.

Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c-CCR2-CX3CR1- counterparts, are expanded in inflammatory bowel disease.

Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45+HLA-DR+CD14+CD64+) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11chighCCR2+CX3CR1+ cells, a phenotype also shared by circulating CD14+ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11c-CCR2-CX3CR1- phenotype. CD11chigh monocyte-like cells produced IL-1ß, both in resting conditions and after LPS stimulation, while CD11c- Mϕ-like cells produced IL-10. CD11chigh pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c- Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14+ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11chighCCR2+CX3CR1+) into tolerogenic tissue-resident (CD11c-CCR2-CX3CR1-) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c- Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11chigh monocyte-like cells.

Characterization and follow-up of esophagogastric junction outflow obstruction detected by high resolution manometry.

BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is a newly described diagnostic entity growing in importance due to the use of high resolution manometry (HRM). There is little knowledge regarding its incidence, etiopathogeny, long-term evolution, and most suitable treatment. Our objective was to increase the awareness of EGJOO to optimize the management of these patients. METHODS: We conducted a historical (retrospective and prospective) study of patients diagnosed with EGJOO using HRM combined with multichannel intraluminal impedance, comparing their manometric and impedance characteristics with those of a control group. Symptoms, etiology of obstruction, acid exposure, clinical course (and its associated factors), and response to treatment were also evaluated in the EGJOO group. KEY RESULTS: Forty-four subjects were included (28 patients and 16 controls). Esophagogastric junction outflow obstruction patients presented incomplete esophageal transit more frequently than controls. Patients with structural obstruction had dysphagia more frequently than patients with functional obstruction, and different manometric, impedance, and pH-metric patterns. Over one-third of the EGJOO patients presented a spontaneous resolution of symptoms without EGJOO treatment. In the multivariate analysis, the variables associated with this spontaneous symptomatic resolution included typical symptoms of gastro-esophageal reflux disease or epigastralgia as the main symptom and resting or basal pressure of the upper esophageal sphincter <50 mmHg. CONCLUSIONS & INFERENCES: The majority of EGJOO patients presented intact peristalsis which may compensate for the lack of EGJ relaxation. In the EGJOO patients presenting favorable factors associated with a spontaneous resolution of symptoms, invasive treatments should be considered with special caution. Structural etiologies are more amenable to management, while the remainder may improve without intervention.

Leiomyosarcoma of the pulmonary veins with extension to the left atrium.

A leiomyosarcoma of the right pulmonary vein in a 43-year-old woman extended to the right atrial wall and compromised the posterior mitral leaflet. Successful surgical treatment was accomplished with a right pneumonectomy, partial resection of the left atrial wall, and mitral valve replacement under cardiopulmonary bypass. Six months later a mediastinal recurrence with extension to the left hemithorax was treated with resection and postoperative radiotherapy.

Prevalence of Helicobacter pylori infection-associated histologic chronic gastritis in the Spanish population.

The aim of this study was to investigate the prevalence of Helicobacter pylori infection-associated chronic gastritis in an unselected Spanish population. Between November 1990 and May 1991, consecutive patients referred for upper gastrointestinal endoscopy due to severe upper abdominal complaints were studied. Only patients with chronic gastritis were included. Four biopsy specimens were taken (two for histologic examination, one for a rapid urease test, and one for culture of H. pylori). A total of 3094 patients from 17 Spanish Autonomic Communities 1817 men (58.7%) and 1277 women (41.3%) were studied by endoscopy. The mean age of the patients overall was 51.4 years. Of these 3094 patients, 1642 had symptomatic chronic gastritis. The prevalence of H. pylori infection in chronic gastritis patients in Spain was 85% (pooled data of the three methods above), and there was at a close correlation between severity of gastritis and H. pylori infection.

Significant increase in eradication rates of Helicobacter pylori infection with two consecutive dual therapies (omeprazole and amoxycillin or omeprazole and clarithromycin). A randomized study in 450 Spanish patients.

Helicobacter pylori infection is associated with peptic ulcer disease and chronic gastritis, and eradication of the microorganism markedly reduces the recurrence of peptic ulcer. However, a major problem is the choice of a treatment that is effective, has high eradication rate, and is well tolerated by patients. We evaluated the eradication of H. pylori infection in patients with chronic gastritis (CG), duodenal ulcer (DU), and gastric ulcer (GU) after two dual therapies (omeprazole with either amoxycillin or clarithromycin). Of 450 patients initially included in the study, 207 had CG, 187 DU and 56 GU, and all presented with H. pylori infection. Diagnosis was made from endoscope examination, biopsy samples, rapid urease test and 13C-urea breath test (UBT). H. pylori infection was considered to be present when two of the tests had positive results. All patients were randomized to one of two regimens: (A) omeprazole (20 mg b.i.d.) plus amoxycillin (750 mg t.i.d.) or (B) omeprazole (40 mg b.i.d.) plus clarithromycin (500 mg t.i.d.). The duration of each of the regimens was 2 weeks. Fifty-eight patients who showed H. pylori infection after the first treatment (27 with CG, 24 with DU, and 7 with GU) were allocated to a second therapy. H. pylori eradication was assessed by UBT, 6 weeks after the end of the therapies; positive values were those higher than 5 delta units. A second consecutive dual therapy of omeprazole plus an antibiotic (amoxycillin or clarithromycin) not used in the first therapy improved on the eradication rates obtained with the first regimen. The overall eradication rates were also higher, but no significant differences were found between amoxycillin and clarithromycin. The best results were obtained in those patients with GU.

[Is the carbohydrate antigen Ca 19.9 useful in the diagnosis of pancreatic carcinoma?]. / Es útil el antígeno carbohidratado Ca 19.9 en el diagnóstico de carcinoma pancreático?

OBJECTIVE: To determine the sensitivity and specificity of the tumor marker Ca 19.9 in subjects with suspected pancreatic cancer. MATERIAL AND METHODS: Levels of Ca 19.9 antigen were measured by enzymeimmunoassay during a 3 year period to 72 patients investigated for suspected pancreatic cancer. RESULTS: A threshold of 100 U/ml resulted in sensitivity of 94.7%, specificity of 39.6%, positive predictive value of 36% and negative predictive value of 95.4%. CONCLUSION: Levels of Ca 19.9 antigen > 100 U/ml are suggestive of malignancy in patients investigated for suspected pancreatic cancer.

Diagnostic and therapeutic approach to cholestatic liver disease.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.

[Serum immunoglobulin E levels in patient with fatty liver, whether associated with alcohol consumption or not]. / Niveles séricos de Inmunoglobulina E en pacientes con esteatosis hepática asociada o no al consumo de alcohol.

It has been reported that total Immunoglobulin E levels (IgE) are elevated in patients with liver damage (fatty liver), associated with alcohol consumption, but the mechanism responsible for this increase is not completely understood. The objective of this investigation was to determine serum concentrations of IgE in patients with fatty liver, associated or not with alcohol consumption. During the period of February-August 2000, a total of 756 patients attended the outpatient Gastroenterology Service of the University Central Hospital "Antonio María Pineda" in Barquisimeto, Venezuela. Of these, 150 were diagnosed as suffering from fatty liver, but only 63 patients fulfilled the inclusion criteria. The IgE was determined by Photoemission Immunometric Enzyme Immunoassay (High Resolution Amplified Chemoluminescence). IgE serum levels were higher in patients that consumed alcohol (low risk consumer, mean 586.42 +/- 779.74 UI/mL; consumer at risk, mean 329.31 +/- 358.13 UI/mL) in comparison with abstainers (mean 77.51 +/- 56.95 UI/mL) (p < 0.05). There was no relationship between IgE levels and the severity of hepatic steatosis. IgE may be considered a biochemical marker for fatty liver associated with alcohol consumption.

[Wilm's tumor in adults. Review of the literature on prognostic factors and treatment]. / Tumor de Wilms del adulto. Revisión de la literatura sobre factores pronósticos y tratamiento.

The incidence of adult Wilms' tumor is difficult to determine but the lesion is rare. The prognosis is poorer than in children, but in adults is often diagnosed at a higher clinical stage and with an unfavorable histologic type. There may be other reasons for the poor prognosis as well. A 33-year-old woman with metastatic disease (bilateral kidney tumors, pulmonary and multiples lymph nodes metastases) is described. Treatment with chemotherapy consisted of doxorubicin, ifosfamide and etoposide which resulted in complete remission that persisted for only three months. The factors that probably contributed to rapid progression included un favorable histology (predominant nodular blastematous elements which were anaplastic) and advanced disease. The precise histologic diagnosis was late precluding to plan the correct treatment.

Synchronous versus metachronous brain metastasis from testicular germ cell tumors (TGCT): an analysis from the Spanish Germ Cell Cancer Group data base.

BACKGROUND: Brain metastases of testicular germ cell tumor (TGCT) are a rare event. Prognostic is poor and there is not much evidence on optimal management of these patients. PATIENTS AND METHODS: A review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group data base from 1994 to 2012 was conducted. RESULTS: Thirty-three out of 6,200 cases (0.5 %). Nineteen patients (57 %) group 1: synchronous, 13 (40 %) group 2: metachronous and only one developed brain metastasis during cisplatin-based chemotherapy (excluded from the analysis). Median serum BHCG levels at initial diagnosis was higher in group 1, whereas elevated AFP serum levels were more common in group 2. Histology in the primary tumor: chorionic carcinoma for group 1 versus embryonal carcinoma for group 2. Mainly solitary brain metastasis in group 2 (54 versus 21 %, respectively). The median overall survival from the diagnosis of central nervous system involvement was 16 months for group 1 (CI 95 % 13.9-18) and 23 months (95 % CI 0-165) for group 2 (log rank p = 0.84). Long-term survivors were practically identical in the two groups (38.9 % group 1 versus 38.5 % group 2). Regardless of the timing of brain metastasis, those patients that achieved complete response to the treatment had better survival (log rank p 0.003). CONCLUSION: Although some distinctive clinical characteristics have been found between patients with synchronous versus metachronous brain metastasis from TGCT, the timing of brain metastasis did not seem to have prognostic influence, but due to the retrospective nature of the analysis and the results should be interpreted with caution.

Binding energy of hydrogenic impurities in quantum dots under intense laser radiation.

We calculate the binding energy of on- and off-center hydrogenic impurities in a parabolic quantum dot subjected to an intense high-frequency laser field. An exactly solvable model that replaces the actual Coulomb interaction with the donor by a non-local separable potential is introduced for calculating the binding energy. The separable potential allows us to solve the problem exactly and all calculations are carried out analytically. The action of the laser irradiation results in dressed Coulomb and confinement potentials. At low laser intensity the binding energy is found to decrease when the impurity is shifted away from the origin. At high laser intensity and strong confinement the opposite behavior is observed. We propose a simple one-dimensional model that explains the observed crossover.

Caracterización de trabajadores sexuales del área norte de Santiago portadoras de Chlamydia trachomatis / Characterization of sex workers in the northern area of Santiago with Chlamydia trachomatis

Marco Teórico: chlamydia trachomatis, agente bacteriano de infección de transmisión sexual (ITS) más frecuente en el mundo, se asocia a patología inflamatoria y neonatal, y a infertilidad. Las trabajadoras sexuales constituyen un grupo de alto riesgo para su contagio. Objetivo: Caracterizar trabajadoras sexuales portadoras de C. trachomatis del área norte de Santiago. Pacientes y Métodos: 36 trabajadoras sexuales con inmunofluorescencia directa positiva para C. trachomatis controladas en una Unidad de ITS. Se analizó en sus fichas clínicas: nivel educacional, uso de alcohol y drogas, tendencia sexual, ITS asociadas y uso de preservativo. Esta información se comparó con fichas clínicas de trabajadoras sexuales no portadoras. Resultados: No se encontraron diferencias estadísticamente significativas entre portadoras y no portadoras, a partir de la revisión de registros clínicos. Conclusión: El diagnóstico de infección de C. trachomatis y su adecuado control requieren de procedimientos estandarizados para su implementación en grupos de alto riesgo.

Background: chlamydia trachomatis, the most frequent bacterial agent of sexually transmited infections (STI) in the world, is associated with inflammatory and neonatal diseases, as well as with infertility. Sex workers are a high risk group. Objetive: To characterize sex workers in the northern area of Santiago, who are C. trachomatis carriers. Patients and Methods: 36 sex workers, whose direct immunofluorescence assays tested positive for C. trachomatis, attending a STI Unit. The following information was analyzed from their clinical records: educational level, alcohol and drugs use, sexual tendency, associated STIs and condom use. It was compared to the information from clinical records of non C. trachomatis carrier sex workers. Results: No statistically significant difference between carriers and noncarriers was found, regarding the aforementioned features, from the clinical records review. Conclusion: The diagnosis of C. trachomatis infection and its proper control require standardized proceedings to be implemented in high risk groups.