Pharmacogenetic Analysis of the MIR146A rs2910164 and MIR155 rs767649 Polymorphisms and Response to Anti-TNF Treatment in Patients with Crohn's Disease and Psoriasis.

The clinical heterogeneity regarding the response profile of the antitumor necrosis factor (anti-TNF) in patients with Crohn's disease (CD) and psoriasis (PsO) is attributed, amongst others, to genetic factors that influence the regulatory mechanisms which orchestrate the inflammatory response. Here, we investigated the possible associations between the MIR146A rs2910164 and MIR155 rs767649 variants and the response to anti-TNF therapy in a Greek cohort of 103 CD and 100 PsO patients. We genotyped 103 CD patients and 100 PsO patients via the PCR-RFLP method, utilizing the de novo formation of a restriction site for the SacI enzyme considering the MIR146A rs2910164, while Tsp45I was employed for the MIR155 rs767649 variant. Additionally, we investigated the potential functional role of the rs767649 variant, exploring in silico the alteration of transcription factor binding sites (TFBSs) mapped on its genomic location. Our single-SNP analysis displayed a significant association between the rare rs767649 A allele and response to therapy (Bonferroni-corrected p value = 0.012) in patients with PsO, a result further enhanced by the alteration in the IRF2 TFBS caused by the above allele. Our results highlight the protective role of the rare rs767649 A allele in the clinical remission of PsO, implying its utilization as a pharmacogenetic biomarker.

Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.

OBJECTIVES: This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients. MATERIALS AND METHODS: A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment. RESULTS: Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073). CONCLUSION: Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

A multicenter, prospective, observational study of the long-term outcomes of Crohn's disease patients under routine care management in Greece.

BACKGROUND: Real-world data on management patterns and long-term outcomes of patients with inadequately controlled Crohn's disease (CD) in Greece are scarce. METHODS: This was a multicenter, prospective observational study of 18-65-year-old CD patients whose physicians judged that their current therapy was inadequate to control their condition and therefore decided to switch treatment. Data were collected at enrollment (time of switch), and 30, 54 and 104 weeks post-enrollment. RESULTS: Sixty-six eligible patients (median age: 35.8 years; 56.1% males; median CD diagnosis duration: 2.3 years) were enrolled by nine hospital sites. At the time of treatment switch, 66.7% had "mild" (CD activity index [CDAI] <220) and 30.3% "moderate-to-severe" (220≤CDAI≤450) disease activity. Ileocolonic involvement, extraintestinal manifestations, prior CD-related surgeries and prior corticosteroid use were reported in 65.2%, 51.5%, 24.2% and 78.8% of patients, respectively. Throughout the study, most patients were managed with anti-tumor necrosis factor (TNF) medications (74.2%/74.1% infliximab; 10.6%/13.8% adalimumab at enrollment/end of study, respectively). At 54 and 104 weeks post-enrollment, the baseline CDAI score (median 174.5) decreased to 145.5 and 146.0 points (P<0.001) and the baseline C-reactive protein level (median: 13.6 mg/L) decreased to 3.5 and 3.0 mg/L (P<0.001), respectively, not differing statistically between patients with "mild" and "moderate-to-severe" disease activity. In this patient population, 56.1% were corticosteroid-free throughout observation, while for the remaining 43.9%, the mean percentage corticosteroid-free period was 80.2%. CD-related surgeries and hospitalizations were reported in 8.1% and 19.4%, respectively. CONCLUSION: Under routine care in Greece, inadequately controlled CD patients were mainly switched to anti-TNFs, which lowered disease activity and reduced corticosteroid use.

The impact of peri-operative anti-TNF treatment on anastomosis-related complications in Crohn's disease patients. A critical review.

INTRODUCTION: Tumor necrosis factor (TNF)α is a cytokine exerting pleiotropic effects on critical cell functions and, most importantly, is the main regulator of pro-inflammatory cytokine production and a key player in the pathophysiology of numerous autoimmune diseases, including Crohn's disease. METHODS: TNFα became a therapeutic target and TNFα blocking agents are currently used in the treatment of inflammatory diseases. Beyond the therapeutic benefits deriving from TNFα neutralization, amendments in the cellular functions of the immune system may as well induce potent immunosuppressive effects. An attenuated immune response may compromise the intestinal healing ability, thus leading to weaker anastomosis and increased risk of anastomotic leak and septic complications. RESULTS: This hypothesis raises great concerns about the safety of perioperative administration of anti-TNF and has been the endpoint of numerous studies. CONCLUSION: The aim of this review is to critically evaluate the evidence regarding the role of TNFα in anastomosis related complications after abdominal surgery in Crohn's disease patients.

The role of variations within microRNA in inflammatory bowel disease.

MicroRNAs (miRNAs) are small noncoding RNAs that are implicated in gene expression regulation at both a transcriptional and at a translational level. Single-nucleotide polymorphisms may occur in miRNA biogenesis pathway genes, primary miRNA, pre-miRNA, or a mature miRNA sequence. Such polymorphisms may be functional with respect to biogenesis and actions of mature miRNA. These single-nucleotide polymorphisms may have a potential to affect the efficiency of miRNA binding to the target sites or can create or disrupt binding sites. The resulting gene dysregulation may involve changes in phenotype and may eventually prove critical for the susceptibility to inflammatory bowel disease and its onset. In this review, we summarize their importance as candidate inflammatory bowel disease biomarkers.

Greek results of the "ENERGIB" European study on non-variceal upper gastrointestinal bleeding.

BACKGROUND: Non-variceal upper gastro-intestinal bleeding (NVUGIB) is a common and challenging emergency situation. We aimed to describe the characteristics and clinical outcomes of patients with NVUGIB in Greece. METHODS: ENERGIB (NCT00797641) was an epidemiological survey conducted in 7 European countries including Greece. It included adult patients with overt NVUGIB from 10 tertiary hospitals across Greece. Data for each patient were collected on admission and up to 30 days thereafter. RESULTS: 201 patients were enrolled. A previous history of NVUGIB was reported by 14% of patients, while 61% had ≥ 1 co-morbidities. At presentation, 59% were on therapy that could harm the gastrointestinal mucosa, 14% on anticoagulant(s) and 42% had sign(s) of hemodynamic instability. 54% of patients showed stigmata of recent hemorrhage. Therapeutic endoscopy was performed in 25% and blood product(s) transfusions were required in 86% of cases. Proton pump inhibitors were administered before and after endoscopy in 70% and 95% of patients, respectively. Uncontrolled bleeding or rebleeding was observed in 11% being more common in elderly, hospitalized patients and patients with ≥1 co-morbidities. Second-look endoscopy was performed in 20%, angiographic intervention in 1.5% and surgical intervention in 4% of patients. Only 5/201 (2.5%) patients died during hospitalization and none died during the 30-day post-hospitalization period. CONCLUSIONS: The majority of patients with NVUGIB in tertiary Greek hospitals are elderly, with co-morbidities, hemodynamic instability and required transfusion(s), while one fourth undergoes therapeutic endoscopic interventions. However, NVUGIB is associated with moderate degrees of continued bleeding/re-bleeding, low surgical rates and, most importantly, low mortality.

Effect of Helicobacter pylori eradication and antisecretory maintenance therapy on peptic ulcer recurrence in cirrhotic patients: a prospective, cohort 2-year follow-up study.

BACKGROUND: The role of Helicobacter pylori eradication to cure peptic ulcer disease in patients with cirrhosis is not clear. AIM: To investigate the course of peptic ulcer disease in cirrhotics, first after healing with either H. pylori eradication or omeprazole therapy and second while on omeprazole maintenance therapy after recurrence. METHODS: Prospective cohort study in a tertiary-care hospital in Greece. Out of 365 consecutive cirrhotic patients who underwent endoscopy, 67 had peptic ulcer and 30 were enrolled. H. pylori positive patients received eradication therapy and H. pylori negative patients received omeprazole treatment. Follow-up endoscopies were performed at 12 and 24 months or when symptoms recurred. Patients with ulcer recurrence were treated with omeprazole maintenance therapy. The main outcome measurement of the study was peptic ulcer relapse rate during follow-up. RESULTS: Twenty-eight patients with healed ulcers were followed for up to 2 years. During follow-up, ulcer relapsed in 17 patients (8/18 H. pylori positive and 9/10 H. pylori negative at study entry, P=0.041), including 2 patients who died from ulcer bleeding. No further ulcer relapse was observed in the remaining 15 patients who received omeprazole maintenance therapy for the rest of follow-up. H. pylori negative status (P=0.002) and severity of cirrhosis (P=0.015) at study entry were independently related to shorter peptic ulcer relapse-free time. CONCLUSIONS: H. pylori eradication does not protect all cirrhotics from ulcer recurrence and the majority of ulcers recur in H. pylori negative patients. Therefore, omeprazole maintenance treatment is mandatory, irrespectively of H. pylori status.

Hospitalization rates for cholelithiasis and acute cholecystitis doubled for the aged population in Greece over the past 30 years.

OBJECTIVE: Gallbladder disease is becoming increasingly prevalent in Western countries and is a common cause of hospitalization. The objective of this study was to determine time trends in cholelithiasis and acute cholecystitis for hospitalization and disease case fatality in Greece between 1970 and 1998. MATERIAL AND METHODS: Data were obtained from the Annual Bulletin for the Social Welfare and Health Statistics of the National Statistics Service of Greece. Percentage changes in time trends were estimated by comparing the median values of the initial (1970-78) to the last (1989-98) 10-year study period for cholelithiasis and acute cholecystitis at discharge and for all deaths attributed to the disease. RESULTS: Over the study period, age-standardized hospitalization rates for cholelithiasis increased. The median hospitalization rate between the initial and last (178 and 258 per 100,000 of the population, respectively) 10-year study period increased by 44.7%, but peaked to 70.1% and 208.3% for the 70-79 and >80 years age groups, respectively. Case fatality rate declined by 56.8% and the median value was 0.24 per 100 patients hospitalized during the last 10-year period. CONCLUSIONS: Hospitalization rates for cholelithiasis and/or acute cholecystitis increased by 45%, and doubled for elderly patients, while the case fatality rate of the disease halved in Greece over the past 30 years.

Primary liposarcoma of esophagus: a case report.

Liposarcoma is the most common soft tissue sarcoma in adult life while esophageal liposarcoma is an extremely rare tumor. In the world literature, only 14 cases of esophageal liposarcomas have been described. We report a 72-year old male patient who was urgently admitted to our hospital for acute epigastric pain with a burning retrosternal sensation, persistent nausea, vomiting and dysphagia. Barium swallow, upper gastrointestinal (GI) endoscopy, esophageal manometry and CT scan, failed to accurately diagnose the lesion. After surgical resection of an esophageal polypoid tumor, the histological examination revealed a well-differentiated grade I liposarcoma. Diagnostic and therapeutic tools were discussed and the results of literature were reviewed.