Analysis of survival and prognostic factors in treatment of hepatocellular carcinoma in Spanish patients with drug-eluting bead transarterial chemoembolization.

BACKGROUND AND AIM: Drug-eluting bead transarterial chemoembolization (DEB-TACE) improves the survival of patients with hepatocellular carcinoma (HCC), intermediate stage [i.e. Barcelona Clinic Liver Cancer-B (BCLC-B)]. The aim of our study was to analyse the overall survival (OS) and prognostic factors of patients with HCC treated with DEB-TACE. PATIENTS AND METHODS: Patients' clinical course was recorded from January 2005 to July 2014. The median OS was obtained by the Kaplan-Meier method and compared using the log-rank test. The prognosis factors associated with OS were determined by a multivariate Cox regression analysis and the accuracy of the OS prediction was determined by calculation of the assessment for retreatment with TACE score (ART score). RESULTS: A cohort of 147 consecutive patients treated with DEB-TACE was included. Median age of the patients was 73.4 years. Overall, 68.7% were men, and all had cirrhosis, with 68.8% being hepatisis C virus positive. Moreover, 35.2% were staged as BCLC-A and 60.2% as BCLC-B. After a median follow-up of 19.2 months, 29.3% were alive, 4.3% needed treatment with sorafenib and 56.1% underwent DEB-TACE retreatment. Median OS was 22.8 [95% confidence interval (CI)=19.6-25.9]. After censoring for ascites and more than one nodule, OS was 23.87 (95% CI =20.72-27.01) and 26.89 (95% CI =21.00-32.78), respectively. The risk of death decreased by 22.3% with the number of DEB-TACE sessions (hazard ratio=0.777) and increased by 25.9% with higher Child-Pugh score (hazard ratio=1.259). Overall, 61.2% of the cohort had an ART score between 0 and 1.5. There were no statistical differences in OS between cohort groups with ART of 0-1.5 and at least 2.5. CONCLUSION: The results validate the efficacy and safety of DEB-TACE in patients with HCC and the importance of some prognostic factors for patient survival.

Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers. / Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros.

BACKGROUND AND OBJECTIVE: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. MATERIAL AND METHODS: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. RESULTS: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). CONCLUSIONS: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC.

Accuracy of GastroPanel for the diagnosis of atrophic gastritis.

BACKGROUND: It has been suggested that GastroPanel might be a useful tool for the diagnosis of chronic atrophic gastritis (CAG) measuring four biomarkers in blood: basal gastrin-17 (G17), pepsinogen I and II (PGI and PGII), and Helicobacter pylori antibodies. AIM: To determine the accuracy of GastroPanel for the diagnosis of CAG. METHODS: This was a prospective, blinded, multicenter study that included dyspeptic patients. G17, PGI, and PGII were determined by enzyme immunoassays. Three antrum and two corpus biopsies were obtained for standard histological analysis and rapid urease test. Biopsies were analyzed by a single blinded expert pathologist. RESULTS: Ninety-one patients were included (77% women, mean age 44 years, 51% H. pylori positive, 17% with CAG). G17 was reduced in patients with antrum CAG (5.4 vs. 13.4 pmol/l; P<0.01) and increased in patients with corpus CAG (11 vs. 24 pmol/l; P<0.05), but its accuracy was only acceptable in the case of corpus localization [area under the receiver operating characteristic curve (AUC), 74%]; PGII difference was almost statistically significant only when testing for corpus atrophy (33 vs. 21 µg/l; P=0.05; AUC=72%). The PGI and PGI/PGII ratio showed no significant differences (AUCs were all unacceptably low). Helicobacter pylori antibody levels were higher in H. pylori-infected patients (251 vs. 109 EIU, P=0.01; AUC=70). The accuracy of GastroPanel for the diagnosis of CAG was as follows: sensitivity 50%; specificity 80%; positive 25% and negative 92% predictive values; and positive 2.4 and negative 0.6 likelihood ratios. CONCLUSION: GastroPanel is not accurate enough for the diagnosis of CAG; thus, its systematic use in clinical practice cannot be recommended.

Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin.

AIM: To assess the aetiological role of Helicobacter pylori (H. pylori) infection in adult patients with iron-refractory or iron-dependent anaemia of previously unknown origin. METHODS: Consecutive patients with chronic iron-deficient anaemia (IDA) with H. pylori infection and a negative standard work-up were prospectively evaluated. All of them had either iron refractoriness or iron dependency. Response to H. pylori eradication was assessed at 6 and 12 mo from follow-up. H. pylori infection was considered to be the cause of the anaemia when a complete anaemia resolution without iron supplements was observed after eradication. RESULTS: H. pylori was eradicated in 88 of the 89 patients. In the non-eradicated patient the four eradicating regimens failed. There were violations of protocol in 4 patients, for whom it was not possible to ascertain the cause of the anaemia. Thus, 84 H. pylori eradicated patients (10 men; 74 women) were available to assess the effect of eradication on IDA. H. pylori infection was considered to be the aetiology of IDA in 32 patients (38.1%; 95%CI: 28.4%-48.8%). This was more frequent in men/postmenopausal women than in premenopausal women (75% vs 23.3%; P < 0.0001) with an OR of 9.8 (95%CI: 3.3-29.6). In these patients, anaemia resolution occurred in the first follow-up visit at 6 mo, and no anaemia or iron deficiency relapse was observed after a mean follow-up of 21 ± 2 mo. CONCLUSION: Gastric H. pylori infection is a frequent cause of iron-refractory or iron-dependent anaemia of previously unknown origin in adult patients.

Comparison of lymphocyte isolation methods for endoscopic biopsy specimens from the colonic mucosa.

An ideal method of immune cell isolation should provide maximum cell yield without disturbing functional properties. Intestinal endoscopic biopsies, in contrast to surgical samples, allow the study of all disease stages but have the drawback of a minimum amount of tissue available, making protocol optimization mandatory. We compared for the first time two methods of separation of colonic epithelium and five methods of lamina propria cell isolation for colonic biopsy specimens (mechanical, enzymatic and organ culture protocols). Lymphocyte number, viability and phenotype (CD45+, CD103+, CD3+, CD4+, CD8+, CD19+, CD16-56+) were analyzed by flow cytometry. Neither of the two epithelial detachment protocols achieved proper epithelial separation, though the high intensity ion chelation method was more accurate. Maximum cell yield of lamina propria lymphocytes without phenotypic modification was obtained with overnight smooth enzymatic digestion. High dose collagenase incubation caused a marked decrease in CD4+ lymphocytes of the lamina propria as compared to low enzymatic method (p=0.004). Mechanical and biopsy culture are not advisable methods because of the low cell yield, and phenotypic alterations and high contamination rate, respectively.

Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohn's disease.

BACKGROUND: Apoptosis resistance of T-cells is considered an abnormality of immune pathways in Crohn's disease (CD). It has been previously shown that corticosteroids induce apoptosis of cells involved in inflammation. Thus, our aim was to assess the apoptosis of mononuclear cells and pro/antiinflammatory cytokines in the intestinal mucosa of patients with active CD, related to steroid response, and identify cellular and molecular factors that may predict this response to therapy. METHODS: Patients with CD (n = 26), ulcerative colitis (UC) (n = 32), and controls (n = 10) were prospectively studied with mucosal biopsies before and 7-10 days after corticosteroid treatment. Immunophenotype and apoptosis of T and B lymphocytes, plasma cells, and macrophages were assessed by flow cytometry, immunohistochemistry, and immunofluorescence. The cytokine expression pattern was evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Apoptosis resistance of T and B lymphocytes was observed only in steroid-refractory and -dependent CD patients as compared to responsive patients (P = 0.032; P = 0.004, respectively), being evident after steroid treatment. Interleukin (IL)-10 was markedly increased at baseline in steroid-responsive patients compared to the nonresponders (P = 0.006; sensitivity: 88.8%; specificity: 66.6% to predict steroid response). CONCLUSIONS: Apoptosis resistance of mucosal T and B cells in steroid-refractory and -dependent CD patients appears during the evolution of the acute phase, limiting its clinical application as a predictor marker. In contrast, increased expression of IL-10 at an early stage of active steroid-sensitive CD patients supports its usefulness at predicting a good steroid response. Steroid-dependent and -refractory CD patients share similar molecular and cellular pathophysiological mechanisms.

Evolution of the incidence of collagenous colitis and lymphocytic colitis in Terrassa, Spain: a population-based study.

BACKGROUND: Previous studies suggest an increase in the incidence rate of microscopic colitis in recent decades. The aim was to evaluate changes in the population-based incidence rate of microscopic colitis and its subtypes over time in Terrassa, Spain. METHODS: This was a prospective study during the period 2004-2008, with a comparison of data from the period 1993-1997. The catchment area was a mixed rural-urban type, with nearly 290,000 inhabitants. All patients with nonbloody chronic diarrhea referred for a diagnostic colonoscopy were included. Multiple biopsy specimen samples were obtained when the macroscopic appearance of the colonic mucosa was normal to rule out microscopic colitis. Crude and adjusted incidence rates based on either the year of diagnosis or the date of onset of symptoms were calculated. RESULTS: Forty patients with collagenous colitis (CC) and 32 with lymphocytic colitis (LC) were identified. The mean annual incidence of CC and LC based on the year of onset of symptoms was 2.6/10(5) inhabitants (95% confidence interval [CI], 1.9-3.3), and 2.2/10(5) inhabitants (95% CI, 1.5-3.0), respectively. Incidence rates for CC based on the year of onset of symptoms were significantly higher in the period 2004-2008 than in 1993-1997 (2.6 versus 1.1/10(5) ; P = 0.012). The increase in CC incidence was more marked in women (P = 0.047) than in men (P = 0.19). CONCLUSIONS: The annual incidence of CC in Terrassa increased over time, mainly in women. Nevertheless, the rates were much lower than those observed in northern Europe, suggesting that there is a north-south difference in the incidence of microscopic colitis.

A short review of malabsorption and anemia.

Anemia is a frequent finding in most diseases which cause malabsorption. The most frequent etiology is the combination of iron and vitamin B12 deficiency. Celiac disease is frequently diagnosed in patients referred for evaluation of iron deficiency anemia (IDA), being reported in 1.8%-14.6% of patients. Therefore, duodenal biopsies should be taken during endoscopy if no obvious cause of iron deficiency (ID) can be found. Cobalamin deficiency occurs frequently among elderly patients, but it is often unrecognized because the clinical manifestations are subtle; it is caused primarily by food-cobalamin malabsorption and pernicious anemia. The classic treatment of cobalamin deficiency has been parenteral administration of the vitamin. Recent data suggest that alternative routes of cobalamin administration (oral and nasal) may be useful in some cases. Anemia is a frequent complication of gastrectomy, and has been often described after bariatric surgery. It has been shown that banding procedures which maintain digestive continuity with the antrum and duodenum are associated with low rates of ID. Helicobacter pylori (H. pylori) infection may be considered as a risk factor for IDA, mainly in groups with high demands for iron, such as some children and adolescents. Further controlled trials are needed before making solid recommendations about H. pylori eradication in these cases.

Paucicellular lymphocytic colitis: is it a minor form of lymphocytic colitis? A clinical pathological and immunological study.

OBJECTIVES: It has been suggested that paucicellular lymphocytic colitis (PLC) should be considered to be part of the morphological spectrum of microscopic colitis. The aim of the study was to evaluate whether PLC may be considered to be a true microscopic colitis, and in this case, whether it is a minor form of lymphocytic colitis (LC) or a different entity. METHODS: All incident cases of PLC, LC, and collagenous colitis (CC) during the period 2004-2006 were included. The incidence rate and the clinical, histopathological, and immunological features of PLC were assessed and compared with those of both LC and CC. Immunoreactivities to CD25, c-Kit, and FOXP3 in lamina propria were assessed. RESULTS: In all, 19 patients with CC, 19 with LC, and 26 with PLC were identified. CD25+FOXP3+ expression was seen only in classical forms of microscopic colitis: 12 of 19 LC, 14 of 20 CC, and none of 20 PLC cases (P < 0.0001). Diarrhea ceased in 21 of the 26 patients, with a decrease in the daily stool number from 5.08 +/- 0.44 to 1.7 +/- 0.2 (P < 0.005). The five patients with no response to therapy fulfilled the Rome II criteria of irritable bowel syndrome (IBS). CONCLUSIONS: The incidence rate of PLC, identified using objective histological criteria, was higher than those of CC and LC. The lack of expression of CD25+FOXP3+ cells in PLC, in contrast to those seen in both LC and CC, would suggest the existence of different pathophysiological mechanisms and does not support that PLC is a minor form of LC.

Lack of clinical usefulness of Das-1 monoclonal antibody and mucin expression as risk markers of gastric carcinoma in patients with gastric intestinal metaplasia.

Our aim was to evaluate the usefulness of the monoclonal antibody Das-1 as a premalignant marker of gastric intestinal metaplasia (GIM) associated with gastric cancer and its association with mucin expression. We evaluated Das-1 and mucin expression in 4 groups: 1 (n = 50), gastric carcinoma, paired samples of the cancer area and GIM away from the tumor; 2 (n = 25), gastric or duodenal ulcer with Helicobacter pylori infection with GIM and chronic gastritis; 3 (n = 25),H pylori- autoimmune chronic atrophic gastritis with GIM; and 4 (n = 25),H pylori- chronic gastritis without GIM. Das-1 immunostaining was observed in 20 (40%) of 50 cases in cancer areas. The expression of Das-1 in GIM from group 1 cases away from the cancer area was different from that in GIM from nontumor cases (groups 2 and 3): 13 (26%) of 50 vs 2 (8%) and 0 (0%) of 25 (P = .004). There was no association between Das-1 and mucin expression. Das-1 expression was associated with GIM from patients with gastric cancer. However, this relation was weaker than previously reported, precluding clinical usefulness as a premalignant marker of GIM.

Drug consumption and the risk of microscopic colitis.

BACKGROUND: Microscopic colitis is a rare disease of unknown etiology. It has been described that some drugs could cause or worsen the disease; however, the scientific evidence is limited. AIM: To investigate the possible association of chronic drug consumption with microscopic colitis. METHODS: This was a case-control study in which groups of cases were: Group 1-39 patients with collagenous colitis; Group 2-39 patients with lymphocytic colitis; and Group 3-52 patients with chronic watery diarrhea of functional characteristics. 103 subjects formed the control group. At diagnosis, a drug consumption history of at least 2-wk duration was registered. An age- and sex-adjusted logistic regression analysis was used, and the odds ratio (OR, 95% CI) was calculated. RESULTS: Drug consumption was more frequent in lymphocytic colitis than in the control group (92.3%vs 76.3%, P < 0.05). The mean daily number of drugs by person was also higher in lymphocytic colitis (3.79 +/- 0.44 vs 2.13 +/- 0.22, P= 0.04). The following associations as compared with the control group were observed: Group 1-Consumption of NSAIDs (46.2%vs 23%, OR 2.9, 1.3-6.4), selective serotonin reuptake inhibitors (SSRIs) (18%vs 1%, OR 21, 2.5-177), specifically, sertraline (15.4%vs 0%, P < 0.0005); Group 2-SSRIs (28%vs 1%, OR 37.7, 4.7-304), beta-blockers (13 vs 3%, OR 4.79, 1.04-20), statins (13%vs 3%, OR 4.6, 1.04-20), biphosphonates (8%vs 0%, P= 0.022); Group 3-SSRIs (15%vs 1%, OR 16.2, 2-135), statins (11.5%vs 3%, OR 5.4, 1.2-24). As compared with the chronic diarrhea group, a significant association with the usage of sertraline in LC (P= 0.005) and a trend for NSAIDs in CC (P= 0.057) were found. CONCLUSIONS: Drug consumption increases the risk of microscopic colitis. Some drugs might be trigger factors of colonic inflammation in predisposed hosts, and others might only worsen self-evolving microscopic colitis.

Intestinal spirochetosis and chronic watery diarrhea: clinical and histological response to treatment and long-term follow up.

BACKGROUND: The clinical significance of intestinal spirochetosis is uncertain, therefore the aim of the present paper was to assess the prevalence of histological intestinal spirochetosis in patients with and without chronic watery diarrhea and to evaluate its clinical relevance. METHODS: A prospective diagnostic work-up of intestinal spirochetosis was made on biopsy samples taken from patients with chronic watery diarrhea submitted between 1994 and 2004 (1174 colonoscopies with multiple biopsies). Three other positive cases identified from routine endoscopic biopsies also were reviewed. In addition, samples from 100 asymptomatic control patients and a random sample of another 104 colonic specimens were reviewed for intestinal spirochetosis. The diagnosis was established by light and electron microscopy. Polymerase chain reaction (PCR) amplification of the 16S ribosomal RNA and reduced nicotinamide adenine dinucleotide (NADH) oxidase genes of the intestinal spirochetes Brachyspira aalborgi and Brachyspira pilosicoli was performed on tissue biopsies of the 11 positive patients. After diagnosis, treatment with penicillin benzatine (PB) or metronidazole was offered to all symptomatic patients and they were followed for a mean of 45.4 months (range: 37-113 months). RESULTS: Eight patients with chronic watery diarrhea were positive for intestinal spirochetosis. Intestinal spirochetosis was not diagnosed in the controls. Histological resolution of the infection paralleled clinical recovery in six patients (following metronidazole treatment in three). Most patients showed mild, non-specific colonic inflammation. Invasion by the spirochetes was not demonstrated by electron microscopy. Brachyspira aalborgi and B. pilosicoli each were identified by PCR in two cases. CONCLUSIONS: Histological intestinal spirochetosis appears to be relatively uncommon in Catalonia (Spain) compared to previous reports from other countries, but was identified in patients (0.7%) with chronic watery diarrhea. Sustained clinical recovery after spontaneous or drug-induced spirochetal disappearance in these individuals suggests that intestinal spirochetosis may play a pathogenic role in chronic watery diarrhea. Treatment with metronidazole is advisable in patients with persistent symptoms.

Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis.

OBJECTIVE: To assess the presence of both genetic and serological markers of coeliac disease in patients with microscopic colitis, and whether there was associated enteropathy. METHODS: HLA-DQ2, HLA-DQ8, serum immunoglobulin A-antiendomysial and immunoglobulin A-anti-tissue transglutaminase antibodies were investigated in 59 patients with microscopic colitis. Seventy healthy subjects acted as the control group. Endoscopic biopsies from the distal duodenum were obtained in DQ2-positive or DQ8-positive patients. Patients with histological changes compatible with gluten-sensitive enteropathy were started on a gluten-free diet. RESULTS: Seventeen of 70 (24.3%) healthy controls were DQ2-positive. Twelve of 25 (48%) patients with lymphocytic colitis (P = 0.027 versus controls), and 11 of 34 (32.3%) with collagenous colitis (P = 0.38 versus controls) were DQ2-positive. There were no differences in the frequency of DQ8-positivity. The coeliac serology was positive in one patient. Duodenal biopsies were performed in 23 DQ2-positive and/or DQ8-positive patients. None had villous atrophy (Marsh III lesion) (0%; 95% confidence interval, 0-6.1). A Marsh type I lesion was found in four patients. Three of these patients were put on a gluten-free diet with disappearance of diarrhoea. CONCLUSIONS: The results suggest that there is an association of lymphocytic colitis with HLA-DQ2 genes, which might be relevant in the pathogenesis of this disease. The association of microscopic colitis with Marsh type III coeliac disease seems to be rare, making it unnecessary to routinely screen for coeliac disease in microscopic colitis patients.

Collagenous and lymphocytic colitis. evaluation of clinical and histological features, response to treatment, and long-term follow-up.

OBJECTIVE: Data on collagenous colitis (CC) and lymphocytic colitis (LC) have been based on retrospective studies of registries of patients from multiple hospitals. Such studies may induce a selection of patients with severe forms of the disease, and conclusions about the clinical spectrum of the disease and treatment efficacy are difficult to be drawn. The aim of this study was to compare the clinical features, response to treatment, and long-term follow-up of CC and LC in a large group of patients prospectively diagnosed in a single center. METHODS: A specific program was undertaken to prospectively diagnose all patients with microscopic colitis from those referred for a full colonoscopy because of recurrent or chronic diarrhea. Detailed clinical and histological features, response to treatment, and long-term follow-up were compared in patients with confirmed CC and LC. RESULTS: Thirty-seven patients with CC and 44 with LC were included. Patients with CC were significantly younger and had a significantly longer duration of diarrhea before diagnosis than those with LC. Otherwise, clinical presentation was similar. Drug-induced disease was suspected for ticlopidine, flutamide, gold salts, and bentazepam in LC. Complete resolution of diarrhea was achieved in all patients, spontaneously occurring in nearly 20% of them. Response to salicylates (mainly, mesalazine) was significantly better in LC than in CC (86% vs 42%, p = 0.005). Cholestyramine was highly effective in patients of both groups with concomitant bile acid malabsorption. Patients with CC required prednisone more often than those with LC (30% vs 4.5%, p = 0.005). Both prednisone and budesonide controlled ileal release were highly effective in patients with CC (82% and 89% efficacy). After cessation of diarrhea, 25% of patients with LC and 30% of those with CC relapsed after a mean follow-up of around 3 yr. CONCLUSIONS: CC and LC share a similar clinical picture and have a benign course with long-term cessation of diarrhea in more than 70% of patients. Mesalazine and budesonide seem to be good options as first-line treatment in LC and CC, respectively. Cholestyramine may be a good alternative in patients with concomitant bile acid malabsorption.