A comparative analysis of glucose and carcinoembryonic antigen in diagnosis of pancreatic mucinous cysts: a systematic review and meta-analysis.

BACKGROUND/AIMS: Pancreatic cystic fluid (PCF) analysis is useful to distinguish between different cyst types and guide management. The aim of our study was to compare the diagnostic accuracy of glucose level with carcinoembryonic antigen (CEA) in PCF for mucinous cyst diagnosis. METHODS: We identified studies with PCF obtained by EUS before surgery, with cysts classified as mucinous and nonmucinous according to surgical specimens. A random effects model was used for quantitative meta-analysis. Pooled sensitivities, specificities, and summary receiver operating characteristic (SROC) curve analysis were conducted. RESULTS: For CEA, we included 31 studies with 5268 patients, of which 2083 were referred for surgery and for glucose we included 5 studies with 460 patients, of which 275 were referred for surgery. Glucose performed better than CEA for mucinous cysts diagnosis (premalignant and malignant) with sensitivities of 0.91 (95% CI, 0.86-0.94) and 0.67 (95% CI, 0.65-0.70), specificities of 0.75 (95% CI, 0.68-0.82) and 0.80 (95% CI, 0.76-0.83), and areas under the ROC curve (AUC) of 0.95 and 0.79, respectively. Glucose had a higher sensitivity (91%), with uncommon false negative results, making it an excellent biomarker to exclude a mucinous cyst. Sensitivity analysis demonstrated that the findings of the current meta-analysis are robust. CONCLUSION: Glucose level in PCF is more accurate than CEA for preoperative diagnosis of mucinous cysts. It may become a useful first line test, particularly in small cysts with limited volume of PCF. Larger studies are awaited to confirm glucose as the single test for mucinous cyst diagnosis.

Preoperative biliary drainage in patients performing pancreaticoduodenectomy : guidelines and real-life practice.

BACKGROUND AND AIM: Preoperative biliary drainage (PBD) in patients with pancreatic cancer remains debatable. The aim of this study was to analyse the indications for PBD in patients performing pancreaticoduodenectomy (PD) and to evaluate the impact of this procedure on postoperative outcome. METHODS: Observational retrospective cohort study of patients undergoing PD for pancreatic cancer. Clinical data and postoperative outcome, namely complications and 90-day mortality, were prospectively collected and compared between patients performing PBD or direct surgery (DS). RESULTS: Eighty-two patients were included: 40 underwent PBD and 42 performed DS. Major complications (27.5% vs 33.3%, P=0.156) and 90-day mortality (10% vs 16.7%, P=0.376) were similar between the two groups. There was a trend for higher mean total bilirubin in patients with PBD (P=0.073). The indication for PBD was suspicion of cholangitis/choledocholithiasis or need to perform neoadjuvant chemotherapy in 24 (60%) patients. In the remaining, elevated bilirubin was probably the only reason to perform PBD. Length of hospital stay was longer in PBD group (P=0.003). On multiple logistic regression, 90-day mortality was not related with preoperative bilirubin levels, biliary drainage or its indication, but solely with age (OR 1.15, 95%CI 1.05-1.31, P=0.008). CONCLUSIONS: PBD is often performed in patients undergoing PD without a formal indication, mainly due to high bilirubin levels. No increased morbidity/mortality was observed but length of hospital stay was prolonged in patients performing PBD.

Low Golimumab Trough Levels at Week 6 Are Associated With Poor Clinical, Endoscopic and Histological Outcomes in Ulcerative Colitis Patients: Pharmacokinetic and Pharmacodynamic Sub-analysis of the Evolution Study.

BACKGROUND AND AIMS: Golimumab has an established exposure-response relationship in patients with ulcerative colitis [UC]. However, the association of serum golimumab trough levels [TL] with objective markers of disease activity, such as endoscopic and histological activity scores and concentrations of biomarkers, remains less understood. This report describes the relationship of serum golimumab TL at the end of the induction period [Week 6] with clinical, endoscopic, histological, and biomarker parameters. METHODS: This was an open-label, uncontrolled, prospective and interventional study. Moderate to severely active UC patients naïve to biologic therapy were treated with golimumab. Serum golimumab TL and faecal calprotectin levels were measured at baseline [Week 0 of induction] and Week 6. RESULTS: A total of 34 patients completed the induction phase [Week 6] and were included in this analysis. Overall, 47.1% and 14.7% of patients achieved clinical response and remission with significantly higher serum golimumab TL in patients with early response or remission [3.7 µg/mL vs 1.3 µg/mL, p = 0.0013; and 3.1 µg/mL vs 1.7 µg/mL, p = 0.0164, respectively]. In addition, golimumab TL were significantly higher in patients achieving histological remission [4.2 µg/mL vs 1.7 µg/mL, p = 0.0049]. Week 6 golimumab TL were inversely correlated with the total Mayo score [rs = -0.546; p = 0.0008], the Mayo endoscopic subscore [rs = -0.381; p = 0.0262], the Geboes histological activity score [rs = -0.464; p = 0.0057], and faecal calprotectin levels [rs = -0.497; p = 0.0044]. CONCLUSIONS: A higher early exposure to golimumab is associated with a better objective response in active UC patients and appears to drive the outcome at Week 6.

The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease.

BACKGROUND: Patients with primary sclerosing cholangitis associated with inflammatory bowel disease (PSC-IBD) have a very high risk of developing colorectal neoplasia. Alterations in the gut microbiota and/or gut bile acids could account for the increase in this risk. However, no studies have yet investigated the net result of cholestasis and a potentially altered bile acid pool interacting with a dysbiotic gut flora in the inflamed colon of PSC-IBD. AIM: The aim of this study was to compare the gut microbiota and stool bile acid profiles, as well as and their correlation in patients with PSC-IBD and inflammatory bowel disease alone. METHODS: Thirty patients with extensive colitis (15 with concomitant primary sclerosing cholangitis) were prospectively recruited and fresh stool samples were collected. The microbiota composition in stool was profiled using bacterial 16S rRNA sequencing. Stool bile acids were assessed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: The total stool bile acid pool was significantly reduced in PSC-IBD. Although no major differences were observed in the individual bile acid species in stool, their overall combination allowed a good separation between PSC-IBD and inflammatory bowel disease. Compared with inflammatory bowel disease alone, PSC-IBD patients demonstrated a different gut microbiota composition with enrichment in Ruminococcus and Fusobacterium genus compared with inflammatory bowel disease. At the operational taxonomic unit level major shifts were observed within the Firmicutes (73%) and Bacteroidetes phyla (17%). Specific microbiota-bile acid correlations were observed in PSC-IBD, where 12% of the operational taxonomic units strongly correlated with stool bile acids, compared with only 0.4% in non-PSC-IBD. CONCLUSIONS: Patients with PSC-IBD had distinct microbiota and microbiota-stool bile acid correlations as compared with inflammatory bowel disease. Whether these changes are associated with, or may predispose to, an increased risk of colorectal neoplasia needs to be further clarified.

Interference of single walled carbon nanotubes (SWCNT) in the measurement of lipid peroxidation in aquatic organisms through TBARS assay.

Nanomaterials (NM) exhibit unique properties due their size and relative area, but the mechanisms and effects in the living organisms are yet to be unfold in their totality. Potential toxicity mechanisms concerning NM as carbon nanotubes include oxidative stress generation. Several fluorimetric and colorimetric methods have been systematically used to measure NM toxicity, and controversial results have been reported. One of the problems can be related to the interference effects induced by NM, leading to artifacts that can lead to misleading conclusions. In present study, it was performed in vitro assays with two aquatic species: the zebrafish Danio rerio and the polychaete Laeonereis acuta to evaluate the potential interference capacity of single-wall carbon nanotubes (SWCNT) in a fluorometric method (TBARS assay) to measure lipid peroxidation. Obtained results indicated that gills and brain of zebrafish presented a lowered fluorescence only at extremely high concentrations (50 and 500mg/L). Determinations in anterior, middle, and posterior body regions of L. acuta showed a quite different pattern: high fluorescence at low SWCNT concentrations (0.5mg/L) and lowering at the highest (500mg/L). To eliminate matrix effect of biological samples, tests employing the standard for TBARS assay, 1,3,3-tetramethoxipropane, were run and the results showed again higher fluorescence values at low concentrations (0.5-5mg SWCNT/L), a technique artifact that could lead to misleading conclusions since higher fluorescence values implicate higher TBARS concentration, implying oxidative stress. Using the colorimetric FOX assay with cumene hydroperoxide as standard presented remarkable better results since no artifacts were observed in the same SWCNT concentration range that employed with the TBARS technique.

Cutaneous Richter syndrome: a better place to transform?

The development of high-grade lymphoma in patients with chronic lymphocytic leukaemia is known as Richter syndrome (RS) and is associated with a grave prognosis, with a mean survival of 8 months despite treatment. Cutaneous RS has been described in a handful of cases and may be associated with a better outcome than the more common extracutaneous variants. We review the literature with particular emphasis on pathogenesis, treatment and survival of RS. We postulate that the absence of B symptoms and a normal lactate dehydrogenase level, presumably reflecting localized or limited disease, and a lower tumour burden, may explain the apparently better survival in some patients with cutaneous RS than with extracutaneous variants.

Estimating the prevalence of inflammatory bowel disease in Portugal using a pharmaco-epidemiological approach.

PURPOSE: To estimate inflammatory bowel disease (IBD) prevalence in Portugal from 2003 to 2007, and to obtain disease, sex and age specific estimates. METHODS: A pharmaco-epidemiological approach based on intestinal anti-inflammatory (IAI) drugs consumption was used. Proportion of patients taking IAI drugs and mean prescribed daily dose (PDD) were estimated from a sample of 513 IBD patients. Assumptions were made about unknown parameters and sensitivity analysis performed: drug compliance (80% in base case; range 70-85%) and proportion of sulphasalazine used in IBD (52%; range 40-80%). Sex and age specific estimates were based on a proposed methodological extension and results from a nationwide (n = 5893) cross-sectional study. RESULTS: IBD prevalence increased from 86 patients per 100 000 in 2003 to 146 in 2007. Regions more affected were Lisboa and Porto (173 and 163 per 100 000 in 2007, respectively). Prevalence increased from 42 and 43 per 100 000 in 2003 to 71 and 73 in 2007, respectively for ulcerative colitis (UC) and Crohn's disease (CD). In 2007, prevalence was higher in the 40-64 age stratum for UC (99 per 100 000) and in the 17-39 stratum for CD (121). Prevalence was consistently higher in females. CONCLUSIONS: Portugal is half way between countries with the highest and lowest IBD prevalence, but is steeply making the road to the highest-level group. Despite limitations of the proposed methods, assumptions were reasonable and estimates seem to be valid. Feasibility and comparability of this methodology makes it an interesting tool for future studies on IBD epidemiology.

Langerhans cell histiocytosis in an adult: good response of cutaneous lesions to acitretin.

A 57-year-old man presented with a 2-year history of bilateral erosive lesions on the inguinal region, and erythematous, brown and crusted papules over the trunk. Histological examination of one lesion in conjunction with immunohistochemical study and electron microscopy led to the diagnosis of Langerhans' cell histiocytosis. After a thorough examination, the only associated findings were retroperitoneal fibrosis and hypergonadotrophic hypogonadism with a granulomatous testicular infiltrate. The patient was treated with oral acitretin for 1 year (with a topical corticosteroid for the inguinal lesions), resulting in clearing of the cutaneous lesions. He underwent placement of bilateral double-J ureteral catheters and was started on hormone replacement therapy. At follow-up 1 year after treatment with acitretin ceased, the patient remained free of cutaneous lesions and his overall condition, including the retroperitoneal fibrosis, had improved. This case had an uncommon combination of features, with a good response to acitretin.

APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas.

Patients presenting familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP) or multiple colorectal adenomas (MCRAs) phenotype are clinically difficult to distinguish. We aimed to genetically characterize 107 clinically well-characterized patients with FAP-like phenotype, and stratified according to the recent guidelines for the clinical management of FAP: FAP, AFAP, MCRA (10-99 colorectal adenomas) without family history of colorectal cancer or few adenomas (FH), MCRA (10-99) with FH, MCRA (3-9) with FH. Overall, APC or MUTYH mutations were detected in 42/48 (88%), 14/20 (70%) and 10/38 (26%) of FAP, AFAP and MCRA patients, respectively. APC and MUTYH mutations accounted for 81% and 7% of FAP patients and for 30% and 40% of AFAP patients, respectively. Notably, MCRA patients did not present APC mutations. In 26% of these patients, an MUTYH mutation was identified and the detection rate increased with the number of adenomas, irrespectively of family history, being significantly higher in MCRA patients presenting more than 30 adenomas [7/12 (58%) vs 2/14 (14%), p = 0.023]. We validate the recently proposed guidelines in our patient's cohort and show that APC or MUTYH germline defects are responsible for the majority of clinically well-characterized patients with FAP and AFAP phenotype, and patients with more than 30 colorectal adenomas. The different mutation frequencies according to family history and to the number of adenomas underscore the importance of an adequate familial characterization, both clinically and by colonoscopy, in the management of FAP-like phenotypes. The phenotypes of the mutation-negative patients suggest distinct etiologies in these cases.

Cutaneous sarcoidosis: a histopathological study.

BACKGROUND: Sarcoidosis is a granulomatous disease of uncertain aetiology in which the skin is frequently involved. Naked sarcoidal granulomas are the characteristic histological feature in specific lesions of sarcoidosis. OBJECTIVE: This study aims to describe the histological findings in a population of patients with cutaneous sarcoidosis. MATERIALS AND METHODS: This study is a retrospective analysis of 31 biopsies of specific lesions of cutaneous sarcoidosis, corresponding to 30 patients. RESULTS: Typical naked granuloma was found in the majority of cases (71%). In 9 cases (29%), granulomas had a significant number of lymphocytes. Necrosis was found in two cases (6%). Periadnexal distribution (mostly perisudoral) was found in 32% of cases. Interstitial distribution of granulomas was observed in five cases (16%). Foreign material was detected in 13% of cases (without the use of polarized light microscopy). Epidermal changes were found in 55% of cases, with atrophy and parakeratosis being the most frequent alterations. CONCLUSIONS: Although typical naked sarcoid granulomas are the most common features of cutaneous sarcoidosis, the dermatopathologist must be aware of possible atypical findings, which are more common than previously expected, because of the differential diagnosis with other causes of cutaneous granulomas, namely infectious diseases.

Inflammatory bowel disease: a patient's and caregiver's perspective.

The purpose of this study was to conduct a survey examining the impact of inflammatory bowel disease (IBD) on patients' and their caregivers' daily activities. Questionnaires were distributed to patients registered in the APDI (Portuguese Association for IBD) database and their respective caregivers in 2007. Of 422 patient respondents, 251 had Crohn's disease (CD) and 171 had ulcerative colitis (UC), with the majority of patients being women (58.1%) and aged over 40 years (37.4%). The number of disease flares experienced by IBD patients was slightly higher for patients with CD than for patients with UC (2.64 vs. 2.34), and surgery was more often required in CD patients as compared to UC patients (42.4 vs. 7%). Sixty percent (60%) of patients reported having no problems with mobility, daily activities, or personal hygiene; however, over half of all patients experienced some pain and anxiety. Adult patients and children and adolescents respectively experienced time off work or school due to their disease but caregivers were not affected in this regard. The caregivers life (N=324) was affected by anxiety, with the major concern reported as the risk of the patient developing cancer. Both IBD patients and caregivers thought that the provision of information on new drugs and contact time with a doctor would have the biggest impact on improving care. The symptoms and complications of IBD have a considerable impact on the lives of patients and their caregivers, and several actions could be taken to improve their care.

Intoxicação aguda por mercúrio inorgânicoaplicado na pele / Percutaneous inorganic mercury poisoning

Descreve-se o caso de uma doente de 77 anos que, após aplicação inadvertida de pó de brometo de mercúrio nos sulcos submamários, desenvolveuum quadro de dermo-hipodermite e necrose cutânea na zona de contacto, intoxicação sistémica com aumento dos valores séricos de mercúrio e insuficiênciarenal aguda, tendo falecido ao 9º dia de internamento. Deste caso pode inferir-se que, apesar de infrequente, a absorção percutânea de mercúrioinorgânico pode ser suficiente para provocar uma intoxicação sistémica aguda fatal (AU)

A 77 year-old female patient developed an inorganic mercury systemic poisoning after skin contact in the submammary folds with mercury bromide,in an unintentional way, developing dermohypodermitis in the contact area, followed by cutaneous necrosis, acute renal failure and high serum mercurylevels, causing death on the 9th day of admittance. From this case we can infer that despite its infrequency, percutaneous absorption of mercurycan cause serum levels of this metal high enough to induce death (AU)

Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study.

BACKGROUND: Hyperplastic polyposis (HP) is a rare condition characterized by the presence of multiple hyperplastic polyps in the colon, which has been associated to an increased risk of colorectal cancer (CRC). Guidelines for management of this disease remain, so far, undefined. AIMS: To evaluate, in symptomatic patients with HP, phenotypic characteristics as well as results of a screening program in their at-risk first-degree relatives. PATIENTS: Pedigree information and clinical and endoscopic data of 14 patients with HP was studied. SEVENTEEN AND METHODS: at-risk first-degree relatives from six families were also invited to perform screening colonoscopy. RESULTS: Twelve of fourteen (86%) patients had fewer than 100 colorectal polyps. Polyps' sizes ranged from 2 to 25 mm and were uniformly distributed through the whole colon in 43% of the patients. Hyperplastic polyps predominated, but 11/14 (79%) patients also harbored serrated as well as classic adenomatous polyps. CRC was present in 6/14 (43%) of the patients at the time of diagnosis. Familial history of CRC/polyps was positive in 6/12 (50%) of cases. Colonoscopy in at-risk relatives disclosed polyps in 10/17 (59%) of cases with at least one additional patient having criteria for HP. CONCLUSIONS: Although small, this series demonstrates that a high level of suspicion is needed to diagnose the HP syndrome, in which serrated adenomas seem to be the hallmark. Although an elevated percentage of CRC was observed in this series of symptomatic patients with HP, prospective studies in asymptomatic individuals are needed to clearly quantify the risk of CRC in patients with HP. Because familial aggregation of HP was present in 3/12 (25%) of kindreds, screening colonoscopy should be offered to first-degree relatives.

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing.

BACKGROUND: In hereditary non-polyposis colorectal cancer, over 90% of the identified mutations are in two genes, hMSH2 and hMLH1. A large proportion of the mutations detected in these genes are of the missense type which may be either deleterious mutations or harmless polymorphisms. AIM: To investigate whether nine missense and one splice site mutation of hMLH1 and hMSH2, in 10 kindreds with a familial history of colorectal cancer or young age of onset, could be interpreted as pathogenic. METHODS: Clinical and genetic characteristics were collected: (i) evolutionary conservation of the codon involved; (ii) type of amino acid change; (iii) occurrence of mutation in healthy controls; (iv) cosegregation of mutation with disease phenotype; (v) functional consequences of gene variant; and (vi) microssatellite instability and immunoexpression of hMSH2 and hMLH1 analysis. RESULTS: Seven different missense and one splice site mutation were identified. Only 1/8 was found in the control group, 2/7 occurred in conserved residues, and 5/7 resulted in non-conservative changes. Functional studies were available for only 2/8 mutations. Segregation of the missense variant with disease phenotype was observed in three kindreds. CONCLUSION: In the majority of families included, there was no definitive evidence that the missense or splice site alterations were causally associated with an increased risk of developing colorectal cancer. Until further evidence is available, these mutational events should be regarded and interpreted carefully and genetic diagnosis should not be offered to these kindreds.

Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype.

There are two well-defined pathways for colorectal carcinogenesis, the suppressor and the mutator pathways. The latter is characteristic of hereditary non-polyposis colorectal cancer (HNPCC), but can also be found in a subset of sporadic colorectal cancer (SCC) possessing distinctive clinical and pathological features, namely early age of onset, location in the right colon, poor differentiation, and a predominant mucinous component. This mutator pathway results from inactivation of mismatch repair (MMR) genes, namely MSH2 and MLH1. The aim of this study was to ascertain if abnormal MMR protein gene expression is a good indicator for identifying tumours from the mutator pathway. Seventy-six cases of SCC were studied by immunohistochemistry using two monoclonal mouse antibodies that react against MSH2 and MLH1 protein gene products. Immunoexpression was assessed both in tumour and in non-neoplastic, adjacent and distant mucosa. Microsatellite instability (MSI) was detected by evaluating the length of poly(CA) repeated sequences at seven loci, or by the detection of small unstable alleles in a poly(A) repeat - BAT-26. Except for BAT-26, in which only tumour DNA was used, MSI analysis was performed in both tumour and normal mucosal DNA. MSI was classified as high (MSI-H), low (MSI-L) or stable (MSS). Abnormal protein expression was found in 9/76 (12%) tumours. Immunohistochemistry for hmlh1 and hmsh2 detected 75% of MSI-H. There was also a highly significant correlation between the observed immunoexpression and several clinical and pathological characteristics described as the phenotypic profile of the mutator pathway, such as right-sided location (p=0.003), mucin production (p=0.008), and a peritumoural lymphoid infiltrate (p=0.009). Non-neoplastic adjacent mucosa showed normal hMSH2 expression in all cases, but in ten cases there was no hMLH1 expression in this transitional mucosa, which is known to display an alterated mucin pattern and a high proliferative rate. These results demonstrated a good correlation between hMLH1 and hMSH2 gene immunoexpression and the clinico-pathological features characteristic of the mutator phenotype and support the use of this method as a rapid and efficient way to detect tumours arising from this pathway.

Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status.

The objective of this review is to present and discuss the current perspectives of homocysteine and one carbon metabolism in chronic alcoholism. Chronic alcoholics frequently suffer from specific micronutrient deficiencies, including vitamins involved in one carbon metabolism, i.e., folate, vitamin B(6) and vitamin B(12). The possible link between homocysteine and alcoholism stems from the fact that homocysteine metabolism is closely linked to the metabolism of these three vitamins. In fact, homocysteine stands at the intersection of two pathways: methylation and transsulfuration. In methylation, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate in a vitamin B(12) dependent reaction, whereas in the transsulfuration pathway, homocysteine condenses with serine to form cystathionine in an irreversible reaction catalyzed by the pyridoxal-5'-phosphate-containing enzyme, cystathionine-beta-synthase. Due to these relationships, nutritional deficiency of one of these vitamins, as a consequence of chronic alcohol intake, could lead to metabolic disruption and potentially to hyperhomocysteinemia. Consistent with an interference of alcohol in these metabolic pathways, a previous study performed in chronic alcoholics in whom hyperhomocysteinemia was observed along with disturbed vitamin status, DNA hypomethylation in peripheral lymphocytes was demonstrated as well. Because all these alterations were observed in the absence of clinically overt disease, one might speculate whether these metabolic abnormalities could be involved in the pathogenesis of organic diseases associated to chronic alcoholism.