Urban–rural environmental exposure during childhood and subsequent risk of inflammatory bowel disease: a meta-analysis

Background: The relationship between living conditions in urban and rural areas during childhood and subsequent inflammatory bowel disease (IBD) remains controversial.

Aim: To explore the association between environmental exposures early in life and the subsequent risk of IBD.

Methods: Literature searches were conducted in the following databases: PubMed, EMBASE, and Conference Proceedings Citation Index. Studies were analyzed separately using rate ratios (RRs) or odds ratios (ORs) with 95% confidence intervals.

Results: The search strategy identified 15 studies. Of these, 9 studies explored the association between urban exposure during childhood and ulcerative colitis (UC), and 12 and 4 studies explored this relationship with Crohn’s disease (CD) and IBD, respectively. A meta-analysis showed that the pooled ORs estimated for the case–control studies of UC, CD, and IBD were 1.16 (0.83, 1.61), 1.45 (1.45, 1.85), and 1.34 (1.11, 1.62), respectively. The pooled RR estimated for the cohort studies of CD and IBD was 1.48 (1.17, 1.87). The stratified analysis and meta-regression showed significant relationships between CD and living conditions in case–control studies published during 2010–2017 and in non-European countries (P < 0.05).

Conclusions: Living conditions during childhood are positively associated with the subsequent development of IBD. Urban living environment is more common among those with CD than UC.     

Indirect comparison of vedolizumab and adalimumab for biologic-naive patients with ulcerative colitis

Aim: Indirect comparison of efficacy and safety of vedolizumab with adalimumab in biologic-naïve patients with moderate to severe ulcerative colitis (UC).

Methods: Vedolizumab is a gut-selective medication for moderate to severe UC. Since no comparative trials are available for direct comparison of vedolizumab vs adalimumab in UC, a systematic review of literature databases was conducted to identify randomized, placebo-controlled trials of the two drugs in patients with moderate to severe UC after failure of conventional treatment. Studies were screened for eligibility by two reviewers based on predefined inclusion criteria. Bucher’s adjusted indirect comparison was used to compare vedolizumab and adalimumab indirectly through placebo as common comparator.

Results: One vedolizumab study (GEMINI 1) and three adalimumab studies (ULTRA 1, ULTRA 2 and M10-447) met the eligibility criteria. Baseline characteristics of the included populations were similar in biologic-naïve UC patients across study arms. Although no statistically significant differences between treatments were found for induction efficacy endpoints, there was a trend toward a benefit of vedolizumab over adalimumab. There were also no significant differences between treatments for any maintenance efficacy endpoints, with no clear trend favoring either agent. Vedolizumab exhibited statistically superior maintenance safety compared with adalimumab, with significant reductions in risks of adverse events (relative risk 0.67 [95% confidence interval 0.57–0.80]; p?<?.0001), serious adverse events (0.20 [0.09–0.42]; p?<?.0001) and adverse events leading to discontinuation (0.14 [0.05–0.43]; p?=?.0006).

Conclusion: This analysis indicates that vedolizumab has comparable efficacy to adalimumab with improved safety in biologic-naïve patients with moderate to severe UC.     

MTHFD1 promoter hypermethylation increases the risk of hypertension

Objectives: Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) plays an essential role in folate-mediated one-carbon metabolism which determines both homocysteine remethylation and de novo thymidylate biosynthesis. Hyperhomocysteinemia is positively associated with essential hypertension. This study aimed to investigate the association of MTHFD1 promoter methylation with essential hypertension.

Methods: Using the quantitative methylation-specific polymerase chain reaction (qMSP), the levels of MTHFD1 promoter methylation in 243 essential hypertension patients, 218 age- and gender-matched healthy controls. The relative changes in serum MTHFD1 promoter methylation were analyzed using the 2^?ΔΔCt method. The percent of methylated reference (PMR) of MTHFD1 was used to evaluate the MTHFD1 promoter methylation levels.

Results: In our current study, the MTHFD1 promoter methylation of hypertensive patients were both higher than the healthy control group (median PMR were 8.97% and 5.69%, respectively, all p < 0.001). Multivariable analysis showed MTHFD1 promoter hypermethylation increase the risk of essential hypertension (OR, 1.336; 95%CI, 1.235–1.446; p < 0.001). The area under the curve (AUC) of MTHFD1 promoter methylation was 0.739 in total patients with essential hypertension.

Conclusions: MTHFD1 promoter hypermethylation was a potential biomarker for the diagnosis of essential hypertension.     

Real world data on effectiveness,safety and therapeutic drug monitoring of vedolizumab in patients with inflammatory bowel disease. A single center cohort

Background and aims: The efficacy of vedolizumab (VDZ) has been demonstrated in clinical trials. The aim of this report is to evaluate the long-term effectiveness and safety of VDZ in a real-world cohort and to explore possible associations between concentration measurements of VDZ and treatment effectiveness.

Methods: This is a prospective clinical follow-up including all adult patients with ulcerative colitis (UC) and Crohn’s disease (CD) treated with VDZ from October 2014 until September 2017 at a single center in Norway. The patients were followed for at least 14 weeks or until termination of treatment. Clinical and biochemical activity were obtained at every infusion throughout follow-up. Plasma measurements of VDZ (p-VDZ) were performed before every infusion during maintenance therapy.

Results: In total, 71 patients received VDZ. Improvement of CRP and hemoglobin was observed in CD but not in UC, whereas Partial Mayo Score improved in UC while no change in Harvey Bradshaw Index was revealed in CD. Furthermore, CRP at baseline was negatively correlated with p-VDZ at week 14 in CD but not in UC patients.

Conclusion: Improvement of biochemical markers of inflammation was observed in CD while clinical activity scores improved in UC patients. For CD, baseline CRP was correlated with lower concentrations of p-VDZ at week 14.     

Multidonor FMT capsules improve symptoms and decrease fecal calprotectin in ulcerative colitis patients while treated – an open-label pilot study

Background: Growing evidence indicates that gut dysbiosis is a factor in the pathogenesis of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) appears to be promising in inducing UC remission, but there are no reports regarding administration using capsules.

Methods: Seven patients with active UC, aged 27–50 years, were treated with 25 multidonor FMT capsules daily for 50 days as a supplement to their standard treatment in an open-label pilot study. The primary objective was to follow symptoms through the Simple Clinical Colitis Activity Index (SCCAI). Secondary objectives were to follow changes in fecal calprotectin and microbial diversity through fecal samples and quality of life through the Inflammatory Bowel Disease Questionnaire (IBDQ). Participants were followed through regular visits for six months.

Results: From a median of 6 at baseline, the SCCAI of all participants decreased, with median decreases of 5 (p?=?.001) and 6 (p?=?.001) after 4 and 8 weeks, respectively. Three of the seven patients had flare-up/relapse of symptoms after the active treatment period. The median F-calprotectin of ≥1800?mg/kg at baseline decreased significantly during the treatment period, but increased again in the follow-up period. The median IBDQ improved at all visits compared to baseline. The fecal microbiota α-diversity did not increase in the study period compared to baseline. All participants completed the treatment and no serious adverse events were reported.

Conclusion: Fifty days of daily multidonor FMT capsules temporarily improved symptoms and health-related life quality and decreased F-calprotectin in patients with active UC.     

A single vial is enough in the absence of endoscopic suspected intestinal metaplasia – less is more!

Background: For the correct staging of chronic atrophic gastritis (AG) and gastric intestinal metaplasia (GIM) at least 4 biopsies are recommended: 2 from the antrum/incisura and 2 from the body sent in two different vials. As virtual chromoendoscopy with narrow-band-imaging (NBI) is valid both in the diagnosis and staging of GIM, it is reasonable to question the need to separate biopsy samples in all procedures.

Aims: To evaluate if biopsy samples can be placed in the same vial without implications in the diagnosis and follow-up of the patient, if during gastroscopy no typical endoscopic pattern of GIM with NBI is observed.

Methods: Multicentre prospective study of a consecutive sample of patients (n?=?183) submitted to gastroscopy using NBI with no superficial neoplastic lesions and no suggestive areas of GIM. Biopsies of both antrum/incisure and body were performed in all patients and samples were placed in the same vial for histologic assessment [according to OLGA (operative link for gastritis assessment) and OLGIM (operative link for gastric intestinal metaplasia)], blinded to endoscopic features.

Results: In all patients, OLGA and OLGIM calculation was possible as the pathologists could distinguish biopsy samples from antrum/incisure from those of gastric body. The negative predictive value was 100% for advanced stages of GIM or AG as 179 (98%) patients presented OLGIM 0 and only 4 (2%) presented OLGIM I. Regarding AG, 150 (82%) presented OLGA 0, 23 (13%) OLGA I and 10 (6%) OLGA II.

Conclusion: In the absence of a typical endoscopic pattern of GIM using NBI, it is effective to place biopsies’ specimens in the same vial (for Helicobacter pylori diagnosis) or even to abstain from biopsies as no single patient with significant changes seems to be missed. This change in clinical practice can have a significant impact on endoscopy costs.     

Relapse rates and predictors for relapse in a real-life cohort of IBD patients after discontinuation of anti-TNF therapy

Objective: We investigated relapse rates after anti-tumor necrosis factor (anti-TNF) withdrawal in inflammatory bowel disease (IBD) patients, response to restart of anti-TNF treatment and predictors for relapse.

Methods: IBD patients in remission receiving infliximab or adalimumab treatment for ≥1 year who discontinued treatment were included. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis.

Results: In total, 101 patients were included (77?CD, 24 UC). A total of 56 patients (55%) experienced a relapse (CD 38, UC 18) with a median time to relapse of 32 and 18 months in CD and UC, respectively. Of patients that were retreated with the same anti-TNF agent, 84% responded. A trough serum concentration ≥2 µg/ml within 1 year prior to anti-TNF discontinuation was associated with a higher relapse rate in CD patients (HR 2.89; p?=?.018), which was more evident in patients requiring retreatment with biologicals, bowel-related surgery or experimental medication (HR: 4.18; p?=?.009). A young age (<17 years) at diagnosis was associated with a higher relapse rate (HR: 2.29; p?=?.040) and fecal calprotectin levels <25?µg/g with a lower relapse rate in CD patients (HR: 0.34; p?=?.041). Relapse rates, requiring treatment with biologicals or experimental medication, was lower in UC patients who continued immunosuppressive treatment (HR: 0.26; p?=?.042).

Conclusions: Approximately 55% of patients relapsed after anti-TNF withdrawal with a median time to relapse of 32 and 18 months in CD and UC, respectively. Retreatment with the same anti-TNF was successful in 84% of patients.     

Unchanged mortality in patients with acute cholangitis despite an increase in malignant etiologies – a 25-year epidemiological study

Background and aims: Acute cholangitis (AC) is a rare but serious condition, with an incidence of 7.0 per 10,000 people and mortality rates up to 10%. The aim of this study was to describe changes in obstruction etiology, comorbidities, clinical factors, and mortality among AC patients during a 25-year period.

Methods: Using a database of 11,563 consecutive ERCP-procedures performed from 1990–2015 at Odense University Hospital, we identified all AC cases during that period. Clinical and epidemiological data were collected from the database and the Danish Patient Registry. Association with 30-day mortality was investigated using multiple logistic regression analysis with adjustment for confounding factors.

Results: In total, 775 consecutive and individual cases of AC were included. Among cases, 42% (n?=?326) were of malignant etiology, with an increasing incidence over time (regression coefficient [95% CI]: 0.03 [0.01–0.04] per year; p?=?.01). Mean Charlson Comorbidity Index was 1.4, with an increase over time (regression coefficient [95% CI]: 0.04 [0.03–0.05] per year; p?<?.01). Malignant obstruction etiology was associated with 30-day mortality (OR [95% CI]: 1.11 [1.04–1.18]; p?<?.01). Overall 30-day mortality was 12% (n?=?91). After adjustment for confounding factors, no significant changes in 30-day mortality were observed over time (OR [95% CI]: 1 [1–1.00]; p?=?.91 per year).

Conclusion: Significant increases in the incidence of malignant obstruction etiology and severity of comorbidities among AC patients were observed during the study period. Despite those findings, 30-day mortality remained unchanged, potentially reflecting a general improvement in the management of AC.     

CpG island methylator phenotype and its relationship with prognosis in adult acute leukemia patients

Objective

To investigated the relationship between CpG island methylator phenotype (CIMP) and prognosis in adults with acute leukemia.

Methods

Bone marrow samples from 53 acute myeloid leukemia and 50 acute lymphoblastic leukemia patients were collected. The methylation status of 18 tumor suppressor genes was determined using methylation-specific polymerase chain reaction.

Results

Greater than 30% of acute leukemia patients had methylated p15, p16, CDH1, CDH13, RUNX3, sFRP1, ID4, and DLC-1 genes; methylation of ≥4 were defined as CIMP positive. Age, type of leukemia, white blood cell count, and CIMP status were significantly associated with recurrence-free survival (RFS) and overall survival (OS) (P < 0.05). CIMP status was an independent prognostic factor for OS (hazard ratio: 2.07, 95% confidence interval: 1.03–4.15, P = 0.040). CIMP-negative patients had significantly improved RFS and OS (P < 0.05). p16 and DLC1 methylation was significantly associated with RFS and OS (P < 0.05).

Conclusions

CIMP may serve as an independent risk factor for evaluating the prognosis of patients with acute leukemia.     

Effects of gestational diabetes mellitus on time to delivery and pregnancy outcomes in full-term pregnancies with dinoprostone labor induction

Objective: To investigate the effects of gestational diabetes mellitus (GDM) on time to delivery and perinatal outcomes in full-term pregnancies underwent dinoprostone-induced labor.

Methods: GDM patients that underwent labor induction with dinoprostone vaginal inserts were retrospectively recruited. Full-term pregnancies with normal glucose tolerance (NGT) that underwent labor induction at the same period were recruited as control. Time to delivery and perinatal outcomes were compared between the two groups.

Results: A total of 1555 pregnancies with 226 GDM and 1329 NGT were recruited. GDM pregnancies had older ages, lower gestational age, higher body mass index (BMI) and abortion history, and more multigravida than NGT pregnancies (P< 0.05). Univariate analysis showed no significant difference in time to delivery and delivery rates between the two groups. However, after adjusted in a multivariate analysis model, the delivery rates of GDM women delivered within 12, 24, 36 or 48 h and those vaginally delivered within 12 or 36 h were significantly lower than those in the NGT group (P< 0.05). Perinatal outcomes were clinically similar between the two groups.

Conclusion: GDM did not affect the time to delivery, cesarean delivery and other perinatal outcomes in Chinese women underwent dinoprostone-induced labor. However, it may be associated with the lower rates of delivery within different time intervals.     

Age and cystic size are associated with clinical impact of endoscopic ultrasonography-guided fine-needle aspiration on the management of pancreatic cystic neoplasms

Objectives: The clinical impact of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) in managing pancreatic cystic neoplasms (PCNs) remains controversial. The aim of this study was to identify which patients with PCNs would benefit from EUS-FNA.

Methods: A retrospective study was performed on patients with PCNs who underwent EUS-FNA between January 2009 and June 2018. A discordant or a consistent diagnosis after EUS-FNA was analyzed and was correlated with the clinical demographic data and cystic features. Predictors of the change in the diagnosis after EUS-FNA were analyzed.

Results: One hundred eighty-eight cases of PCNs were analyzed. EUS-FNA changed the diagnosis in 45.7% of all patients with PCNs and 54.5% patients with presumed branch ductal type intraductal papillary mucinous neoplasm (BD-IPMN) and impacted the recommendation in 35.6% of patients with PCNs and 50.5% patients with BD-IPMN. Patients with a discordant diagnosis after EUS-FNA were younger in age (54.8?±?12.6 vs. 61.2?±?14.2; p=.037) and had a cyst size larger than 3?cm than patients with a consistent diagnosis after EUS-FNA. The only worrisome feature (WF) that differed between patients with a discordant and a consistent diagnosis after EUS-FNA was the main pancreatic duct (MPD) between 5 and 9?mm (p=.013). In multivariate analysis, a cyst size >3?cm and age were independent predictors of diagnostic changes after EUS-FNA (OR: 5.33, 95% CI: 1.79–15.88, p?=?.003; OR: 0.96, 95% CI: 0.93–0.99, p = .031).

Conclusions: EUS-FNA made a significant change in the management of nearly half of the patients with PCNs, especially in younger patients and in patients with a cyst size larger than 3?cm.     

Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy

Background: Renin-angiotensin system (RAS) is a complex network of enzymes and peptides with the essential role in blood pressure control. The relationships between RAS components, RAS-related genetic polymorphisms and therapy response in essential hypertension (EH) were widely explored but the results were inconclusive.

Aim: The aim of this study was to explore the functional role of ACE insertion/deletion (I/D) polymorphism on the systemic quantity of angiotensin-converting enzyme (ACE), its homolog - ACE2, chymase and angiotensin II in EH patients with respect to achieved therapeutic blood pressure control.

Results: Genotyping of ACE I/D polymorphism was performed among 140 patients with EH from Bulgaria. The serological analyses reveal the significant elevation of the serum quantity of all investigated enzymes in EH than normotensive controls. In addition, serum ACE2 (183.57 pg/ml; vs. 151.78 pg/ml; p = 0.02) and chymase (68.5 pg/ml; vs. 23.66 pg/ml; p = 0.034) were significantly higher in patients with uncontrolled EH than controlled EH in response to ACE-inhibitory therapy. Also, ACE I/D polymorphism showed a significant impact on the serum ACE and chymase levels. ACE quantity was the highest among carriers of DD-genotype, followed by ID and II-genotype. Contrary, chymase was in the highest quantity in II-genotype compared to ID-genotype (p = 0.025) and DD-genotype (p = 0.044).

Conclusions: Our results suggest that insufficient blood pressure control by ACE-inhibitory therapy could be associated with elevation of serum ACE2 and chymase levels. Also, it appears that ACE I/D polymorphism may influence the circulating quantity of chymase in addition to ACE.     

Long-term evolution of direct healthcare costs for inflammatory bowel diseases: a population-based study (2006–2015)

Introduction: We explored the long-term evolution of direct healthcare costs for inflammatory bowel diseases (IBD) using a population-level database in a country with an escalating burden of IBD.

Methods: We searched the database of the Korean National Health Insurance Claims, which covers more than 97% of the South Korean population. An IBD diagnosis was defined as the combination of a billing code for Crohn’s disease (CD: K50.xx) or ulcerative colitis (UC: K51.xx) and at least one claim for IBD-specific drugs. Between 2006 and 2015, a total of 59,447 patients (CD: 17,677; UC: 41,770) were included.

Results: The total and mean cost per capita increased significantly over time. In the last year of the study (2015), the cost for anti-tumor necrosis factor (TNF) therapy accounted for 68.8% (CD) and 48.8% (UC) of the total cost. Age at diagnosis (<20 years vs. ≥30 years) and anti-TNF use were independent predictors of increased total IBD cost. Anti-TNF therapy was the strongest predictor of high-cost outliers (designated as the top 20 percentile of the total costs) for IBD (OR: 160.4; 95% CI: 89.0–289.2). The mean cost among patients with newly diagnosed CD increased significantly over the 8-year follow-up period (p?=?.03), while costs associated with UC remained stable. Only medication costs increased significantly during the follow-up period for CD.

Conclusions: Over the past 10 years, the increased usage of anti-TNF agents has been the key driver of IBD-related healthcare costs. Long-term cost-cutting strategies for patients with CD are warranted.     

Emu Oil reduces disease severity in a mouse model of chronic ulcerative colitis

Objective: Ulcerative colitis (UC) is characterized by mucosal inflammation and ulceration of the large intestine. Emu Oil (EO) has been reported to protect the intestine against mucositis, NSAID-enteropathy, UC-associated colorectal cancer and acute UC. We aimed to determine whether EO could reduce the severity chronic UC in mice.

Methods: Female C57BL/6 mice (n?=?10/group) were orally administered (gavage) water (Groups 1–2) or EO (Groups 3: low dose-80?µl and 4: high dose-160?µl), thrice weekly. Group 1 mice consumed plain drinking water throughout the trial. Groups 2–4 mice underwent two cycles [each consisting of seven days dextran sulfate sodium (DSS; 2% w/v) and 14 days water], followed by a third DSS week. All mice were euthanized two days later (day 51). Bodyweight, disease activity index (DAI), burrowing activity, myeloperoxidase activity, crypt depth and histologically assessed damage severity were assessed. p?<?.05 was considered significant.

Results: DSS decreased bodyweight and increased DAI compared to normal controls (p?<?.05), which was partially attenuated by both EO doses (p?<?.05). Burrowing activity was impaired in DSS-controls compared to normal controls (days 27 and 40); an effect prevented by both EO doses (p?<?.05). DSS increased colonic myeloperoxidase activity and crypt depth compared to controls (p?<?.05), with no significant EO effect. Moreover, DSS increased colonic damage severity compared to normal controls (p?<?.001). Importantly, both EO doses decreased distal colonic damage severity compared to DSS-controls (p?<?.001).

Conclusions: Emu Oil attenuated clinically- and histologically-assessed disease severity in a mouse model of chronic UC. Emu Oil demonstrates promise as an adjunct to conventional treatment options for UC management.     

A current overview of corticosteroid use in active ulcerative colitis

Introduction: Ulcerative colitis (UC) is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon. New biological drugs have been developed in order to avoid colectomy, but corticosteroids still play a crucial role in management of active UC.

Areas covered: We reviewed the current literature about the importance of corticosteroid use in the treatment of ulcerative colitis. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. This review is a summary of expert opinion in the field without a formal systematic review of evidence.

Expert opinion: Corticosteroids represent the mainstay of treatment in patients with severe UC and are very effective in inducing remission in mild to moderate flares not responding to combined oral and topical mesalazine. A valid alternative to systemic corticosteroids is represented by poorly absorbed steroids, such as Beclomethasone dipropionate and Budesonide MMX. In mild-moderate distal disease topical administration of corticosteroids (both systemic and BDP) is an effective alternative to topical mesalazine. However, corticosteroids do not represent a therapeutic option as a maintenance treatment since they are associated with multiple adverse effects.     

Analysis of risk factors of gastrointestinal stromal tumors in different age groups based on SEER database

Objective: To investigate the risk factors affecting the survival of patients with gastrointestinal stromal tumors (GISTs) in different age groups.

Methods: Information on 6089 GIST patients was screened from the Surveillance, Epidemiology, and End Results (SEER) database. Risk factor analysis was performed using a chi-square test (univariate analysis). Survival analysis was performed using the Kaplan–Meier method (log-rank test) and the COX proportional hazard model. p Value?<?.05 was considered statistically significant.

Results: Analyzed statistically to reveal that in addition to tumor size, mitotic index, and primary location, age, gender, race, and surgical treatment also were independent risk factors for GISTs. Gender, race, and location of disease influenced the survival rate of patients, which was higher in the young group (≤60 years old) than the elderly group (>60 years). Risk factors such as primary location, tumor diameter, and mitotic index varied significantly between the different age groups.

Conclusions: Age, gender, race, and surgical treatment are independent risk factors that influence the prognosis in patients with GISTs. Some risk factors affecting prognosis are age dependent.     

Comparing the effectiveness of biological disease-modifying antirheumatic drugs using real-world data

Objectives: The objective of this study is to compare the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) by analyzing claims data of 13 Japanese national university hospitals.

Methods: We evaluated 4970 cases of rheumatoid arthritis treated with bDMARDs from the Clinical Information Statistical Analysis database, which has collected and integrated 13 Japanese national university hospitals’ claims data for 10 years. We surveyed the medications and calculated the retention rates of bDMARDs using the Kaplan–Meier method and differentiated the effectiveness between the two bDMARDs by comparing the retention rates after switching from one drug to another.

Results: Of the 4970 cases, 1364 switched bDMARDs at least once. Tocilizumab (TCZ) reported the highest retention rate, whereas abatacept (ABT) revealed a similar rate compared with only naïve cases. The retention rate curves were higher in cases on TCZ that switched from the other bDMARDs than those in the reversed cases. Following TCZ, ABT and etanercept indicated better results than the other bDMARDs.

Conclusion: We could compare the effectiveness among bDMARDs by differentiating the retention rates from big claims data. TCZ reported higher retention rates in both naïve and switched cases than other bDMARDs.     

Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer

Background: The tumor microenvironment in pancreatic cancer has a multifaceted role in disease development and progression. Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) and proteinase 3 (PRTN3) are involved in the synthesis and degradation of collagen in the tumor microenvironment and have been identified as prognostic biomarker candidates for pancreatic cancer in our previous mass spectrometric study. This study aimed at validating prognostic performance of P4HA2 and PRTN3 in a larger cohort of patients.

Methods: The expression of P4HA2 and PRTN3 was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic cancer who underwent surgical resection. Kaplan–Meier and Cox proportional hazards regression modeling were used to explore the association of P4HA2 and PRTN3, either separately or combined, with clinicopathological factors and survival.

Results: Most tumors were positive for P4HA2 (133/140, 95%), whereas 77 tumors (55%) were positive for PRTN3. Expression levels of P4HA2 and PRTN3 did not separately correlate with disease-free or overall survival, in either uni- or multivariable analysis. However, a low P4HA2 and high PRTN3 expression correlated with shorter disease-free survival (median 7.0 vs. 13.4 months, adjusted HR 3.24, 95% CI: 1.13–9.25, p?=?.028) and overall survival (median 8.5 vs. 25.8 months, adjusted HR 8.14, 95% CI: 3.41–19.44, p?<?.001).

Conclusion: Our data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. The tumoral expression of PRTN3 reinforces the therapeutic potential of PR1-targeting immunotherapy in pancreatic cancer.     

Genetic and flow cytometry analysis of seronegative celiac disease: a cohort study

Background: Seronegative celiac disease (CD) poses a diagnostic challenge.

Aims: Characterize and identify differences between seronegative and seropositive CD.

Patients and methods: Retrospective cohort study examining adult patients diagnosed with CD (1980–2017). Clinical, analytical, histological, genetic and immunophenotypic data were compiled. Seronegative CD was defined as a anti-tissue transglutaminase type 2 IgA and endomysial antibodies (EMA) negative and HLA-DQ2 and/or DQ8 positive, showing clinical signs of CD plus an abnormal duodenal biopsy, and responding to a gluten-free diet (GFD). Factors associated with seronegative CD were identified through binomial logistic regression.

Results: Of 315?CD patients, 289 were seropositive (91.7%) and 26 seronegative (8.3%). Among the seronegative patients, higher prevalence was observed for autoimmune thyroiditis (26.9% vs. 9.7%, p?=?.016), HLA-DQ8 heterozygosity (23.1% vs. 2.5%, p???.001) and Marsh I lesion (34.6% vs. 3.7%, p???.001). The two groups showed similar flow cytometry-determined duodenal immunophenotypes and rates of refractory CD.

Conclusions: Seronegative CD differs mostly in genetic (more HLA-DQ8) and histologic (milder atrophy) features as compared with seropositive. Intestinal intraepithelial immunophenotype by flow cytometry, similar in both modalities, is a useful tool to diagnose seronegative CD.