Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling.

BACKGROUND: Preoperative chemoradiotherapy followed by surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas. Yet, predicting that patients will respond to treatment remains an unmet clinical challenge. EXPERIMENTAL DESIGN: Using laser-capture microdissection we isolated RNA from stroma and tumour glands from prospective pre-treatment samples (n = 15). Transcriptomic profiles were obtained hybridising PrimeView Affymetrix arrays. We modelled a carcinoma-associated fibroblast-specific genes filtering data using GSE39396. RESULTS: The analysis of differentially expressed genes of stroma/tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment; codifying mainly for extracellular matrix and ribosomal components. We built a carcinoma-associated fibroblast (CAF) specific classifier with genes showing changes in expression according to the tumour regression grade (FN1, COL3A1, COL1A1, MMP2 and IGFBP5). We assessed these five genes at the protein level by means of immunohistochemical staining in a patient's cohort (n = 38). For predictive purposes we used a leave-one-out cross-validated model with a positive predictive value (PPV) of 83.3%. Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the leave-one-out cross-validated regression model improved the classification performance with a PPV of 93.3%. An independent cohort was used for classifier validation (n = 36), achieving a PPV of 88.2%. In a multivariate analysis, the two-protein classifier proved to be the only independent predictor of response. CONCLUSION: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.

Tuberculosis in Anti-Tumour Necrosis Factor-treated Inflammatory Bowel Disease Patients After the Implementation of Preventive Measures: Compliance With Recommendations and Safety of Retreatment.

BACKGROUND AND AIMS: Despite having adopted preventive measures, tuberculosis (TB) may still occur in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNF). Data on the causes and characteristics of TB cases in this scenario are lacking. Our aim was to describe the characteristics of TB in anti-TNF-treated IBD patients after the publication of the Spanish TB prevention guidelines in IBD patients and to evaluate the safety of restarting anti-TNF after a TB diagnosis. METHODS: In this multicentre, retrospective, descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. RESULTS: We collected 50 TB cases in anti-TNF-treated IBD patients, 60% male, median age 37.3 years (interquartile range [IQR] 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated and 26% extrapulmonary. In 30 patients (60%), TB cases developed despite compliance with recommended preventive measures; *not performing 2-step TST (tuberculin skin test) was the main failure in compliance with recommendations. In 17 patients (34%) anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. CONCLUSIONS: Tuberculosis could still occur in anti-TNF-treated IBD patients despite compliance with recommended preventive measures. A significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.

Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a multicenter study.

BACKGROUND: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery. Around 50% of patients with proctocolectomy with ileal pouch-anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report efficacy of IFX in these patients. METHODS: A retrospective, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Short-term IFX efficacy was evaluated at week 8 and mid-term efficacy at weeks 26 and 52. Complete response was defined as cessation of diarrhea and urgency and partial response as marked clinical improvement but persisting symptoms. The modified Pouchitis Disease Activity Index (mPDAI) without endoscopy was calculated when available. RESULTS: Thirty-three consecutive UC patients with chronic refractory pouchitis were included (18 male, mean age 45 years, range 21-67). At week 8, 21% patients achieved complete response and 63% showed partial clinical response. At weeks 26 and 52, 33% and 27% achieved complete response and 33% and 18% showed partial clinical response, respectively. Thirteen patients (39%) withdrew treatment (four for lack of efficacy, four for loss of response and five for adverse events). None of the potential factors analyzed had an influence on response to IFX. CONCLUSIONS: IFX was effective in the short- and mid-term in patients with chronic refractory pouchitis. However, medication had to be discontinued in a high number of patients.

Incidence of adult form of autoimmune hepatitis in Valencia (Spain).

BACKGROUND AND STUDY AIMS: There is little information on the incidence of autoimmune hepatitis (AIH) because on many occasions the disease can progress asymptomatically, different diagnostic criteria have been proposed during the last 20 years, and many epidemiological studies are based on retrospective clinical series. The aim of this study was to determine the incidence of AIH in the province of Valencia, Spain, during the year 2003. PATIENTS AND METHODS: The Services of Gastroenterology of eight acute-care reference hospitals in the province of Valencia, Spain, covering 1,774,736 inhabitants over 14 years of age, participated in a prospective study. All newly diagnosed patients with AIH between January 1, 2003 and December 31, 2003 were eligible. The diagnosis was based on criteria of the International Autoimmune Hepatitis Group revised in 1999. RESULTS: There were 19 new cases of AIH, 18 females and 1 male [mean (SD) age of 54.3 (11.2) years, range 23-73]. Incidence peaked in the 45-54 year age group. Eighteen cases were classified as AIH type 1 and one case as AIH type 2. The incidence rate of AIH for the year 2003 in people older than 14 years of age was 1.07 new cases per 100,000 inhabitants, with 1.96 cases per 100,000 inhabitants in females and 0.12 cases per 100,000 inhabitants in males. CONCLUSIONS: The 2003 annual incidence of AIH in Valencia, Spain, was similar to that reported in other European countries. AIH occurred more frequently in women and in the 45-54 year age group, type 1 being the most common.

[Factors influencing the decision to administer systemic corticosteroids in Crohn's disease]. / Factores que influyen en la decisión de administrar corticoides sistémicos en la enfermedad de Crohn.

INTRODUCTION: Crohn's disease shows periods of exacerbation and remission. Corticosteroids are the most frequently used drugs in exacerbations of disease activity. The objective of this study is to determine which clinical and laboratory parameters are associated with the therapeutic decision to administer corticosteroids during the course of the disease. MATERIAL AND METHOD: Two-hundred seven consecutive visits made by 62 patients with Crohn's disease were selected from a database. Data from visits in which corticosteroid administration was initiated (n = 65) were compared with those from visits in which this decision was not made (n = 142). Univariate and multivariate (logistic regression) analyses were performed. The results are expressed as odds ratio (OR) with 95% confidence interval (95% CI). RESULTS: In the univariate analysis statistically significant differences were found between groups in localization, maintenance treatment, Crohn's Disease Activity Index (CDAI) score, the presence of abdominal pain, mass, perianal disease, extraintestinal manifestations and all laboratory parameters (leukocytes, platelets, fibrinogen, erythrocyte sedimentation rate, C-reactive protein). In the multivariate analysis (with corticosteroid administration as the dependent variable) a statistically significant positive association was found between the decision to administer corticosteroids and mild (OR = 31.9; 95% CI, 6.6-154.1), moderate or severe (OR = 49.7; 95% CI, 6.1-401.3) CDAI, ileocolic localization (OR = 4.8; 95% CI, 1-22.1) and the presence of perianal disease (OR = 7.4; 95% CI, 1.5-35.9), while a negative association was found with maintenance treatment with immunosuppressant drugs (OR = 0.05; 95% CI, 0.30-0.008). The laboratory variables positively associated with corticosteroid administration were C-reactive protein and leukocyte count. CONCLUSION: The variable with greatest predictive value for corticosteroid prescription is the CDAI score, although other clinical and laboratory variables not included in this index are also associated with corticosteroid administration. There is a negative association between the use of immunosuppressive drugs and corticosteroid prescription.

[Dynamic ultrasonography in the diagnosis of gallbladder dysfunction: reliability of a simple method with easy clinical application]. / Ultrasonografía dinámica en el diagnóstico de la disfunción vesicular: fiabilidad de un método sencillo de fácil aplicación clínica.

AIMS: Although the results of dynamic ultrasonography (DUS) are similar to those of dynamic cholescintigraphy (DCS) in the study of gallbladder function, the methodology required for this technique is laborious and sometimes complex. The aim of this study was to investigate the reliability of a simple method of DUS to evaluate gallbladder function using DCS as a reference. PATIENTS AND METHODS: Gallbladder function was studied using DUS and DCS in 80 consecutive patients with clinical findings compatible with gallbladder dysfunction. For DUS the ellipsoid method was used with measurement of three gallbladder diameters (transversal, longitudinal and anteroposterior) in basal conditions and after applying a cholecystokinetic stimulus (meal test); gallbladder emptying of less than 50% was considered abnormal. In DCS intravenous cholecystokinin (CCK) (0.40 IDU/kg in 20 minutes) was used as stimulus and an ejection fraction < or = 40% was considered abnormal. RESULTS: In 15 patients (19%; 95% CI, 11-29%) abnormal gallbladder response was found using DUS. The ejection fraction in the entire group of patients studied was 48 26.2%. Ejection fraction was abnormal in 41 patients (51%; 95% IC, 40-63%) with a value of 25 8.5% and was normal in 39 patients (49%; 95% IC, 40-63%) with a value of 71.5 14.5%. The correlation coefficient between the values of gallbladder emptying calculated with DUS and the ejection fraction obtained with DCS was 0.199 (p = 0.079). When patients were divided according to gallbladder emptying measured by DUS and the ejection fraction obtained with DCS the concordance was very low (k = 0.065; EE = 0.085). CONCLUSIONS: DUS performed using a simple technique lacks diagnostic value in gallbladder dysfunction when DCS is taken as a reference test