Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers.

OBJECTIVES: Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy. METHODS: Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test. RESULTS: Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis. DISCUSSION: In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

Effectiveness and Safety of the Switch from Remicade® to CT-P13 in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: To evaluate the clinical outcomes in patients with IBD after switching from Remicade® to CT-P13 in comparison with patients who maintain Remicade®. METHODS: Patients under Remicade® who were in clinical remission with standard dosage at study entry were included. The 'switch cohort' [SC] comprised patients who made the switch from Remicade® to CT-P13, and the 'non-switch' cohort [NC] patients remained under Remicade®. RESULTS: A total of 476 patients were included: 199 [42%] in the SC and 277 [58%] in the NC. The median follow-up was 18 months in the SC and 23 months in the NC [p < 0.01]. Twenty-four out of 277 patients relapsed in the NC; the incidence of relapse was 5% per patient-year. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months in this group. Thirty-eight out of 199 patients relapsed in the SC; the incidence rate of relapse was 14% per patient-year. The cumulative incidence of relapse was 5% at 6 months and 28% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2-6). Thirteen percent of patients had adverse events in the NC, compared with 6% in the SC [p < 0.05]. CONCLUSIONS: Switching from Remicade® to CT-P13 might be associated with a higher risk of clinical relapse, although this fact was not supported in our study by an increase in objective markers of inflammation. The nocebo effect might have influenced this result. Switching from Remicade® to CT-P13 was safe.

Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Impact of a do-not-do intervention on 12 laboratory measurements. / Impacto de una intervención de «no hacer¼ en 12 determinaciones de laboratorio.

OBJECTIVES: In recent years, various scientific societies and healthcare organisations have created recommendations aimed at decreasing the use of healthcare interventions that have shown no efficacy or effectiveness. The aim of this study was to assess the impact of an intervention on 12 do-not-do recommendations regarding the laboratory in 7 hospital centres. METHODS: Before-after study conducted in 7 hospital centres of Cordoba and Jaen during 2015 and 2016. Based on the recommendations of existing scientific societies, a consensus was reached on various actions regarding laboratory measurements. We analysed the number and cost of measuring 6 tumour markers (carcinoembryonic antigen, prostate-specific antigen, carbohydrate antigen [CA] 15.3, CA125, CA19.9 and alpha-fetoprotein), thyrotropin, T3, T4, glycated haemoglobin, urea, ferritin and antigliadin antibodies, before and after implementing the consensus. RESULTS: Compared with the previous year, there were 55,902 fewer laboratory measurements (-19%) in 2016, with an overall savings of €82,100. The reduction in the number of measurements occurred mainly in plasma urea (-50.3%) and in the tumour markers CA125 (-16%), CA19.9 (-11.6%) and CA15.3 (-10.5%). The most pronounced savings were achieved in the measurements of urea (-€21,002), thyroid hormones (-€12,716) and thyrotropin (-€7,638). CONCLUSIONS: The adoption and consensus of do-not-do recommendations among healthcare levels resulted in a significant reduction in unnecessary measurements.

Extracolonic Cancer in Inflammatory Bowel Disease: Data from the GETECCU Eneida Registry.

OBJECTIVES: The objective of this study was (a) To know the prevalence and distribution of extracolonic cancer (EC) in patients with inflammatory bowel disease (IBD); (b) To estimate the incidence rate of EC; (c) To evaluate the association between EC and treatment with immunosuppressants and anti-tumor necrosis factor (TNF) agents. METHODS: This was an observational cohort study. INCLUSION CRITERIA: IBD and inclusion in the ENEIDA Project (a prospectively maintained registry) from GETECCU. EXCLUSION CRITERIA: Patients with EC before the diagnosis of IBD, lack of relevant data for this study, and previous treatment with immunosuppressants other than corticosteroids, thiopurines, methotrexate, or anti-TNF agents. The Kaplan-Meier method was used to evaluate the impact of several variables on the risk of EC, and any differences between survival curves were evaluated using the log-rank test. Stepwise multivariate Cox regression analysis was used to investigate factors potentially associated with the development of EC, including drugs for the treatment of IBD, during follow-up. RESULTS: A total of 11,011 patients met the inclusion criteria and were followed for a median of 98 months. Forty-eight percent of patients (5,303) had been exposed to immunosuppressants or anti-TNF drugs, 45.8% had been exposed to thiopurines, 4.7% to methotrexate, and 21.6% to anti-TNF drugs. The prevalence of EC was 3.6%. In the multivariate analysis, age (HR=1.05, 95% CI=1.04-1.06) and having smoked (hazards ratio (HR)=1.47, 95% confidence interval (CI)=1.10-1.80) were the only variables associated with a higher risk of EC. CONCLUSIONS: Neither immunosuppressants nor anti-TNF drugs seem to increase the risk of EC. Older age and smoking were associated with a higher prevalence of EC.

High-density dependence but low impact on selected reproduction parameters of Brucella suis biovar 2 in wild boar hunting estates from South-Western Spain.

Porcine brucellosis is a disease caused by Brucella suis, which is characterized by reproductive disorders in pigs. The number of cases of swine brucellosis has risen in many European countries, likely because of the presence of a wild reservoir of B. suis in wild boar. This study aimed at evaluating factors that may influence the probability of infection with Brucella spp. in wild boar and at assessing the impact of a previous contact with Brucella spp. on reproductive parameters of wild boar. Two hundred and four wild boar living in Extremadura (south-western Spain) were studied. The presence of anti-Brucella antibodies was determined using an indirect ELISA, while the presence of living bacteria in genital organs was evaluated through microbiological cultures. Sex, age, density of wild boar in summer and presence of outdoor pigs were selected as possible risk factors for being seropositive for Brucella spp. in wild boar. In addition, reproductive parameters such as breeding status or potential fertility in females and testis weight in males were estimated and related to the presence of anti-Brucella antibodies. A total of 121 animals were seropositive, resulting in a prevalence of 59.3% (95% CI). In addition, seven isolates of B. suis biovar 2 were obtained. Wild boar density in summer, as well as age and sex, was proposed as factors to explain the probability of Brucella seroconversion, although wild boar density in summer was the key factor. Current measures of reproductive parameters were not influenced by a previous contact with Brucella spp. Isolation of B. suis confirms that wild boar could represent a risk to domestic pig health in the study area. Wild boar density seems to have a great influence in the probability of infections with B. suis and suggests that density management could be useful to control Brucella infection in wild boar.

Outbreak of swine erysipelas in a semi-intensive wild boar farm in Spain.

Swine erysipelas (SE) is a disease caused by the bacterium Erysipelothrix rhusiopathiae and is one of the best-known and most serious diseases affecting domestic pigs. However, few studies exist concerning the susceptibility of wild boars to this disease and the role of this species as a reservoir. This study investigates and describes an outbreak of SE that occurred on a semi-intensive wild boar breeding farm housing 40 boars in Extremadura (SW Spain) on 11-18 February 2010. Seven animals died, of which four were examined post-mortem. Of these, three (two females and one male) were approximately 3 months old, and one was 1 year old (male). Lesions were consistent with acute septicaemia, consisting of cutaneous erythema/cyanosis and petechial haemorrhages in kidneys, urinary bladder, lungs and meninges. The 1-year-old male also had proliferative polyarthritis. Histopathology confirmed the presence of disseminated intravascular coagulation and vasculitis. Additionally, a bilateral acute panuveitis with concurrent necrotizing vasculitis and diffuse corneal oedema, neither of which have been described before in this disease, were found in the 3-month-old male boar. E. rhusiopathiae was isolated from all four animals in pure cultures from several tissues. Of these four animals, antibodies against E. rhusiopathiae, using an indirect ELISA test, were only detected in the 1-year-old male boar with polyarthritis. Posteriorly, of nine live adults tested for antibodies, four (including an adult male with polyarthritis) were positive.

Comparação da secreção de citocinas (IL-4, IL-5, IL-6, IL-10) entre pacientes com nefropatia da IgA e deficiência de IgA / Comparison of the cytokine secretion (IL-4, IL-5, IL-6, IL-10) among patients with IgA nephropathy and IgA deficiency

Objetivo: A nefropatia primária da IgA (NIgA) e adeficiência de IgA (DIgA) constituem as formas maiscomuns de glomerulonefrite e de deficiência primáriade anticorpos, respectivamente, despertando interesseespecial o fato de ambas envolverem distúrbios contrastantes da produção da IgA. O objetivo deste trabalho foi comparar os níveis de citocinas possivelmente implicadas na produção da IgA (IL-4, IL-5, IL-6, IL-10) em pacientes com NIgA ou DIgA. Casuística e Métodos: Foram estudados 18 pacientes com NIgA (hematúria microscópica e proteinúria persistente ou intermitente e biópsia renal percutânea com depósito de IgA em mesângio glomerular detectado por imunofluorescência), sendo nove do gênero masculino e nove do feminino, com média de idade de 33,2 anos; 17 pacientes com DIgA (níveis séricos de IgA menores do que 7 mg/dL e níveis normais ou elevados de IgG e IgM), sendo 13 do gênero masculino e quatro do feminino, com média de idade de 25,5 anos; dez voluntários sadios (dois do gênero masculino e oito do feminino com média de idade de 30,7 anos). As citocinas foram quantificadas por método imunoenzimático em sobrenadante de cultura de PMBC após 48 horas de estímulo com fitohemaglutinina . Resultados: Foram observados: 1) níveis elevadosde IL-5 e de IL-10 e baixos de IL-6 em pacientes com NIgA em relação aos pacientes com DIgA e controlessadios; 2) níveis semelhantes de IL-4 em ambos gruposde pacientes e mais elevados na NIgA em comparaçãoaos controles sadios; 3) níveis similares de todasas citocinas testadas em pacientes com DIgA e controlessadios. Conclusões: Os níveis elevados de IL-5 encontrados na NIgA reforçam a importância desta citocina na síntese de IgA, cujos níveis séricos estão aumentados em aproximadamente 50 per cent dos casos; os níveis elevados de IL-4 e IL-5 encontrados nestes pacientes sugerem que estas duas citocinas possam estar envolvidas na glicosilação da IgA e seu conseqüente depósito em mesângio renal; os níveis elevados de IL-10 e baixos de IL-6 observados em pacientes com NIgA reforçam a hipótese de que a IL-10 esteja implicada na síntese da IgA em humanos e sugerem que esta citocina possa desempenhar um papel regulador sobre a produção deIL-6.

[Hypotony maculopathy diagnosed by optical coherence tomography]. / Maculopatía hipotónica diagnosticada por tomografía de coherencia óptica.

CASE REPORT: A 40 year-old man with advanced pigmentary glaucoma in the left eye underwent trabeculectomy. In the immediate postoperative period, visual acuity decreased with no alterations noted on examination of the fundus or on angiofluoresceingraphy. Through optical coherence tomography, we were able to make a diagnosis of hypotonic maculopathy and treatment was immediately started. DISCUSSION: Hypotony maculopathy is one of the most feared complications of filtering eye surgery. In some cases, optical coherence tomography can be useful to confirm its diagnosis non invasively.

[Follow-up of macrotrabeculectomy in glaucoma]. / Estudio del seguimiento de la macrotrabeculectomía en el glaucoma.

PURPOSE: In this study we report the preliminary results of macrotrabeculectomy in our hospital. METHOD: Fifty-nine eyes of 41 patients with open-angle glaucoma underwent macrotrabeculectomy from Sept. 1994 through Sept. 1995 and were retrospectively analysed. Intraocular pressure control was defined as a decrease of postoperative IOP lower than 21 mm Hg or a decrease of at least 20% of initial IOP if this was lower than 21 mm Hg. Disc/cup ratio control was assumed when the progression was under 0.2. Disease control was defined when IOP, disc/cup ratio and visual field were controlled. RESULTS: IOP control was obtained in 93.22% of patients at 2 years and in 91.19% at 3 and 4 years. Disease control was achieved in 88.14% at 2 years and 84.3% at 3 and 4 years (Kapplan-Meier survival analysis). CONCLUSION: Macrotrabeculectomy is a safe and effective technique to control IOP and glaucomatous disease.

Interpretation of artificial neural networks by means of fuzzy rules.

This paper presents an extension of the method presented by Benitez et al (1997) for extracting fuzzy rules from an artificial neural network (ANN) that express exactly its behavior. The extraction process provides an interpretation of the ANN in terms of fuzzy rules. The fuzzy rules presented are in accordance with the domain of the input variables. These rules use a new operator in the antecedent. The properties and intuitive meaning of this operator are studied. Next, the role of the biases in the fuzzy rule-based systems is analyzed. Several examples are presented to comment on the obtained fuzzy rule-based systems. Finally, the interpretation of ANNs with two or more hidden layers is also studied.

Neural networks with a continuous squashing function in the output are universal approximators.

In 1989 Hornik as well as Funahashi established that multilayer feedforward networks without the squashing function in the output layer are universal approximators. This result has been often used improperly because it has been applied to multilayer feedforward networks with the squashing function in the output layer. In this paper, we will prove that also this kind of neural networks are universal approximators, i.e. they are capable of approximating any Borel measurable function from one finite dimensional space into (0,1)" to any desired degree of accuracy, provided sufficiently many hidden units are available.

[Study of the corneal endothelium after glaucoma surgery]. / Estudio del endotelio corneal tras la cirugía del glaucoma.

PURPOSE: To analyze the changes suffered by corneal endothelium in patients who underwent a macrotrabeculectomy. METHODS: A prospective study was conducted on 35 patients who underwent a macrotrabeculectomy and 21 patients who did not undergo any surgical technique. All the patients suffered chronic open angle-glaucoma and we only studied patients between 65 and 75 years old. Central corneal endothelium was studied with a specular microscope before surgery and three months after it, analyzing endothelial density, coefficient of variation and hexagonal endothelial cells. RESULTS: The initial cellular count in the operated group was 2361.9 SD 400 and the final was 2211.9 SD 380 cells/mm(2). The decrease of cellular density was 150 cells/mm(2) (6.35%). In the not operated group the initial cellular count was 2313.4 SD 241 and the final was 2299.2 SD 241 cells/mm(2). A decrease of 14 cells/mm(2) was observed. This difference was statistically significant (p=0.035). No statistically significant differences were observed in coefficient of variation and hexagonal endothelial cells. CONCLUSIONS: A decrease of cellular count after three months of macrotrabeculectomy was observed and they are similar to previous studies with conventional trabeculectomies, clearly less than observed with mitomycin use. No statistically significant differences were observed in coefficient of variation and hexagonal endothelial cells.

[Pigment dispersion syndrome in a patient with megalocornea]. / Slndrome de dispersión pigmentaria en paciente con megalocórnea.

CASE REPORT: A case of a patient of 12 years old with megalocornea and bilateral pigment dispersion syndrome is reported. An ultrasound biomicroscopic study was performed with the UBM 840 (Zeiss-Humphrey, 50 MHz) and an iris concavity with an iridolenticular and iridozonular contact was observed. A new exam after pilocarpine instillation drops showed the resolution of the iris concavity, zonular and lenticular contact. DISCUSSION: The anterior chamber configuration of this patient analyzed with ultrasound biomicroscopy allowed us to understand the mechanism of the pigment dispersion syndrome.

Are artificial neural networks black boxes?

Artificial neural networks are efficient computing models which have shown their strengths in solving hard problems in artificial intelligence. They have also been shown to be universal approximators. Notwithstanding, one of the major criticisms is their being black boxes, since no satisfactory explanation of their behavior has been offered. In this paper, we provide such an interpretation of neural networks so that they will no longer be seen as black boxes. This is stated after establishing the equality between a certain class of neural nets and fuzzy rule-based systems. This interpretation is built with fuzzy rules using a new fuzzy logic operator which is defined after introducing the concept of f-duality. In addition, this interpretation offers an automated knowledge acquisition procedure.

[Priapism as the first manifestation of chronic granulocytic leukemia]. / Priapismo como primera manifestación de una leucemia granulocítica crónica.

We report a case of priapism in a patient with philadelphia positive chronic granulocytic leukemia. Combined medical and surgical therapy, including chemotherapy with hydroxyurea and multiple punctures of the corpora cavernosa respectively, effected a rapid detumescence and resolution of the priapism and control of the primary disease, although subsequent ability of erection was not fully restored.

[Prognostic value of fibrinogen measurement in acute pancreatitis]. / Valor pronóstico del fibrinógeno en las pancreatitis agudas.

To evaluate the utility of fibrinogen as a prognostic factor in acute pancreatitis (PA) it was measured within 48 hours of admission in 55 patients with acute pancreatitis studied prospectively. We found that patients with fibrinogen levels above 850 mg/dl. presented a serious evolution in 55.55% of cases as compared to 10.87% of those who had levels below this figure (p less than 0.01). We conclude that fibrinogen measurement can be useful in the early evaluation of the prognosis of acute pancreatitis.