Nivolumab-Induced Colitis in a Patient With Esophageal Adenocarcinoma: A Case Report.

Nivolumab is an immune checkpoint inhibitor used in the treatment of several types of cancer. Among the adverse effects of this drug, immune-mediated colitis (IMC) has been described. However, in contrast to other checkpoint inhibitors, such as ipilimumab, drug-induced colitis due to nivolumab is not commonly reported. We report the case of a 59-year-old male who had undergone surgical resection for gastroesophageal junction adenocarcinoma, had been on nivolumab during the past five months, and presented with worsening diarrhea. Colonoscopy demonstrated local edema and mild colitis in a region of the colonic mucosa located 30 cm distal to the ileocecal valve. Biopsies revealed acute moderate colitis. The patient responded well to loperamide and dietary modifications. Although nivolumab rarely causes IMC, this occurrence requires proper management in order to avoid further complications.

The Effect of Ceratonia siliqua Supplement on Bone Mineral Density in Ovariectomy-induced Osteoporosis in Rats.

AIM: This study aimed to investigate the effect of Ceratonia siliqua on bone mineral density (BMD) as a non-pharmaceutical alternative treatment for postmenopausal osteoporosis. MATERIALS AND METHODS: Thirty mature female Wistar rats were randomly separated into three groups of 10: Control, ovariectomized (OVX), and ovariectomized-plus-C. siliqua (OVX+CS). Total and proximal BMD were measured by dual-energy X-ray absorptiometry (DEXA) in all groups before ovariectomy, and at 3 and 6 months postoperatively. At the end of the study, the femurs were subjected to a three-point bending test. RESULTS: DEXA revealed no statistically significant difference in absolute values or percentage changes for total tibial BMD between OVX+CS and OVX groups throughout the study. In the proximal tibia, both absolute values and BMD percentage changes from baseline were higher in the OVX+CS group compared to the OVX group after 3 and 6 months of C. siliqua administration. Three-point bending test revealed a significantly higher thickness index in the OVX+CS group compared to the OVX group and a higher cross-sectional area index compared to the control group. CONCLUSION: Long-term administration of C. siliqua may be considered a non-pharmaceutical alternative treatment for postmenopausal osteoporosis. Further research is required to properly investigate the effects, and suitable treatment dose and schedule.

Serum zonulin levels in patients with liver cirrhosis: Prognostic implications.

BACKGROUND: Increased gut permeability and bacterial translocation play an important role in liver cirrhosis. Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier. AIM: To investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications. METHODS: Consecutive cirrhotic patients who attended our liver clinic were included in the study. Serum zonulin levels, clinical, radiological and biochemical data were collected at baseline. Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo. RESULTS: We enrolled 116 cirrhotics [mean Child-Turcotte-Pugh (CTP) score: 6.2 ± 1.6; model for end-stage liver disease score: 11 ± 3.9]. The causes of cirrhosis were viral hepatitis (39%), alcohol (30%), non-alcoholic fatty liver disease (17%), and other (14%). At baseline, 53% had decompensated cirrhosis, 48% had ascites, and 32% had history of hepatic encephalopathy. Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class (4.2 ± 2.4 ng/dL vs 3.5 ± 0.9 ng/dL, P = 0.038), with than without ascites (P = 0.006), and with than without history of encephalopathy (P = 0.011). Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year (P = 0.039), with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation. Higher CTP score (P = 0.021) and portal vein diameter (P = 0.022) were independent predictors of mortality. CONCLUSION: Serum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation.

Esophageal manifestation in patients with scleroderma.

The esophagus is the most commonly affected part of the gastrointestinal system in patients with systemic sclerosis (SSc). Esophageal involvement may lead to a significant reduction in patient quality of life. The exact pathophysiology is complex and not yet fully elucidated. Ultimately, esophageal smooth muscle becomes atrophied and replaced by fibrous tissue leading to severe motility disturbance of the distal esophagus. Symptoms are mainly attributed to gastroesophageal reflux disease and to esophageal dysmotility. Compelling evidence has correlated esophageal involvement to the severity of pulmonary disease. No formed guidelines exist about the diagnostic modalities used to assess esophageal disease in patients with SSc, though upper gastrointestinal endoscopy is the first and most important modality used as it can reveal alterations commonly observed in patients with SSc. Further exploration can be made by high resolution manometry and pH-impedance study. Proton pump inhibitors remain the mainstay of treatment, while prokinetic agents are commonly used as add-on therapy in patients with symptoms attributed to gastroesophageal reflux disease not responding to standard therapy as well as to motility disturbances. Gastroesophageal reflux disease symptoms in patients with SSc are frequently difficult to manage, and new therapeutic modalities are emerging. The role of surgical treatment is restricted and should only be preserved for resistant cases.

The 100 most cited manuscripts in esophageal motility disorders: a bibliometric analysis.

BACKGROUND: The use of bibliometrics can help us identify the most impactful articles on a topic or scientific discipline and their influence on clinical practice. We aimed to identify the 100 most cited articles covering esophageal motility disorders and examine their key characteristics. METHODS: The Web of Science database was utilized to perform the search, using predefined search terms. The returned dataset was filtered to include full manuscripts written in the English language. After screening, we identified the 100 most cited articles and analyzed them for title, year of publication, names of authors, institution, country of the first author, number of citations and citation rate. RESULTS: The initial search returned 29,521 results. The top 100 articles received a total of 20,688 citations. The most cited paper was by Inoue et al. (665 citations) who first described peroral endoscopic myotomy (POEM) for treating achalasia. The article with the highest citation rate was the third version of the Chicago Classification system, written by Kahrilas and colleagues. Gastroenterology published most papers on the list (n=32) and accrued the highest number of citations (6,675 citations). Peter Kahrilas was the most cited author (3,650 citations) and, along with Joel Richter, authored the highest number of manuscripts (n=14). Most articles were produced in the USA (n=66) between the years 1991 and 2000 (n=32). CONCLUSIONS: By analyzing the most influential articles, this work is a reference on the articles that shaped our understanding of esophageal motility disorders, thus serving as a guide for future research.

Contribution of ghrelin to functional gastrointestinal disorders' pathogenesis.

Functional gastrointestinal disorders (FGID) are heterogeneous disorders with a variety of clinical manifestations, primarily defined by signs and symptoms rather than a definite underlying cause. Their pathophysiology remains obscure and, although it is expected to differ according to the specific FGID, disruptions in the brain-gut axis are now thought to be a common denominator in their pathogenesis. The hormone ghrelin is an important component of this axis, exerting a wide repertoire of physiological actions, including regulation of gastrointestinal motility and protection of mucosal tissue. Ghrelin's gene shows genetic polymorphism, while its protein product undergoes complex regulation and metabolism in the human body. Numerous studies have studied ghrelin's relation to the emergence of FGIDs, its potential value as an index of disease severity and as a predictive marker for symptom relief during attempted treatment. Despite the mixed results currently available in scientific literature, the plethora of statistically significant findings shows that disruptions in ghrelin genetics and expression are plausibly related to FGID pathogenesis. The aim of this paper is to review current literature studying these associations, in an effort to uncover certain patterns of alterations in both genetics and expression, which could delineate its true contribution to FGID emergence, either as a causative agent or as a pathogenetic intermediate.

Large Paraesophageal Hiatus Hernia: Is Surgery Mandatory?

Purpose/Aim: Paraesophageal hiatus hernias are seldom found, however the incidence is increasing accounting for 5-10% of all hiatal hernias. The aim of this review is to emphasize controversies in clinical presentation, essential workup investigations and highlight non-surgical and surgical management options. Materials and Methods: A PubMed literature search using the keywords "large or giant paraesophageal hernia", "hiatus or hiatal hernia", "laparoscopic surgery", "antireflux surgery", "mesh", "gastric volvulus" and "diaphragmatic hernia" published between 1998 until 2017 was conducted. Results: Presenting symptoms are non-specific and can be erroneously attributed to various more common medical conditions. Significant complications as gastric volvulus and stomach necrosis, may occur and the obscured clinical presentation can be confusing for the clinician. Management options in the elective setting are controversial, and surgical repair cannot be easily justified for a minimally symptomatic condition, especially in an elderly and perhaps frail patient. However, in the era of laparoscopic surgery around the hiatus, reduced operative stress makes surgical repair appealing in the elective setting. Surgical matters as the adjunct of an antireflux procedure or not, the use of prosthetic mesh to reinforce the hiatus, gastropexy and the clinical importance of radiological or endoscopic recurrence are still under debate. Conclusions: The laparoscopic treatment of paraesophageal hiatus hernias is effective with low morbidity rates, offered in symptomatic patients and good operative risk asymptomatic individuals. More studies are needed to assess improvement suggestions, as the use of prosthetic mesh or gastropexy, regarding complications and recurrence risks.

Severe oesophageal disease and its associations with systemic sclerosis.

OBJECTIVES: Severe oesophageal disease in patients with systemic sclerosis (SSc), referred as scleroderma oesophagus, is characterised by ineffective or absent peristalsis along with hypotensive oesophagogastric junction (hEGJ). The associations between scleroderma oesophagus and different clinical and laboratory manifestations of SSc is still controversial. In this study we aimed to assess associations between scleroderma oesophagus, diagnosed by high resolution manometry (HRM), and other manifestations of disease. METHODS: Fifty-four consecutive SSc patients (49 women, mean age 50.6±11.6) with oesophageal symptoms underwent clinical interview, medical records review and HRM. HRMs were analysed according to the Chicago Classification in order to provide oesophageal motility diagnosis; EGJ <9 mmHg was considered hypotensive. Demographic characteristics, patient-reported symptoms, SSc subtypes, pulmonary fibrosis, cutaneous ulcers, and anti-Scl-70 positivity were compared between SSc patients with or without scleroderma oesophagus. Comparison was also performed in computed tomography (CT) findings of oesophageal lumen in 26 patients with available data. Oesophageal dilatation was deemed present when the diameter was >9 mm. RESULTS: Absent contractility was present in 37 (68.5%) patients; among these patients hEGJP was found in 32, thus 32/54 (59.2%) patients had classic scleroderma oesophagus. There were no associations with gender, age, oesophageal symptoms, skin involvement extent, anti-Scl-70, pulmonary fibrosis and cutaneous ulcers. Notably, oesophageal dilation on chest CT was more frequent in patients with scleroderma oesophagus compared to those without (77% vs. 7%, p=0.04, respectively). CONCLUSIONS: Scleroderma oesophagus diagnosed by HRM was present in less than 2/3 of symptomatic patients with SSc and associated only with oesophageal dilation in CT. Although further studies are needed, oesophageal dilation on chest CT may be a non-invasive alternative for evaluation of SSc patients with oesophageal symptoms.

Changes in the esophageal mucosa of patients with non erosive reflux disease: How far have we gone?

The normal esophageal mucosa creates a protective epithelial barrier that constrains the acidic reflux in the esophageal lumen. Microscopic findings and functional studies indicate that this barrier might be impaired in patients with non erosive reflux disease (NERD) but not in patients with functional heartburn (FH). Whereas endoscopy and pH monitoring are the most important diagnostic tools in the diagnosis of NERD, recent studies suggest that esophageal biopsies might have a complementary role. Particularly in the differential diagnosis between NERD and FH, the application of histological severity scores showed very promising results. Further evaluation of the scores could lead to routine application of histology in specific NERD populations.

The evolution of Helicobacter pylori antibiotics resistance over 10 years in Greece.

BACKGROUND: Increasingly, over time, antibiotic resistance is considered a problem for the efficacy of H. pylori eradication treatment. The aim of our study was to evaluate the changes in clarithromycin and levofloxacin resistance of H. pylori strains in Greek patients in two different time periods (in 2000 and in 2010). METHODS: Gastric biopsies of consecutive H. pylori-positive patients were investigated retrospectively. Mutations in H. pylori 23S rRNA and gyrA genes associated with resistance to clarithromycin and quinolones, respectively, were determined by allelic specific polymerase chain reaction. RESULTS: In the first time period (2000), H. pylori resistance patterns were evaluated in 50 and in the second period (2010) in 57 patients. During the first time period 30 and 0% of patients were infected with clarithromycin- or quinolone-resistant strains, respectively. In the second time period (2010), the percentage of patients infected with clarythromycin or quinolone resistance strains increased to 42 and 5.3%, respectively. CONCLUSIONS: Our study showed an increase in the prevalence of both clarithromycin and quinolones resistance of H. pylori. Although the resistance rate to quinolones increased over the years, it is relatively low justifying its use for the eradication of H. pylori infections.

Association of rs1568885, rs1813443 and rs4411591 polymorphisms with anti-TNF medication response in Greek patients with Crohn's disease.

AIM: To investigate the correlation between rs1568885, rs1813443 and rs4411591 polymorphisms and response to infliximab in a cohort of Greek patients with Crohn's disease (CD). METHODS: One hundred and twenty-six patients diagnosed with CD based on standard clinical, endoscopic, radiological, and pathological criteria were enrolled in this study at the Gastroenterology Unit of the 2(nd) Department of Surgery and at the Colorectal Unit of the 1st Department of Propaedeutic Surgery. Infliximab at a dose of 5 mg/kg was administered intravenously at weeks 0, 2, 6 and then every 8 wk. Clinical and serological responses were assessed using the Harvey-Bradshaw Index and serum C-reactive protein (CRP) levels, respectively, and the endoscopic response was evaluated by ileocolonoscopy performed at baseline and after 12-20 wk of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Genomic DNA from whole peripheral blood was extracted and genotyping was performed by allele-specific polymerase chain reactions. χ (2) test with Yate's correction based on the S-Plus was used to compare the genotype frequencies. RESULTS: Eighty patients (63.49%) were classified as complete and 32 (25.39%) as partial responders to infliximab, while 14 (11.11%) were primary non-responders. No correlation was found between response to infliximab and patients' characteristics such as age, gender and disease duration. There was consistency between Harvey-Bradshaw index scores and serum CRP levels. The TT genotype of the rs1568885 polymorphism was significantly related to partial response (P = 0.024) and resistance to infliximab (P = 0.007) while the AT genotype was more frequent in partial responders (P = 0.035) and in primary non-responders (P = 0.032). Regarding rs1813443, the CC genotype was found to be associated with partial response (P = 0.005) and primary resistance (P = 0.002) to infliximab while no association was found between the rs4411591 polymorphism and the clinical response to infliximab. CONCLUSION: Based on our results, the rs1568885 and rs1813443 polymorphisms are associated with clinical and biochemical response to infliximab in Greek patients with Crohn's disease.

Molecular basis of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain, discomfort and bloating. The pathophysiology of IBS is poorly understood, but the presence of psychosocial basis is now known. There is an increasing number of publications supporting the role of genetics in IBS. Most of the variations are found in genes associated with the brain-gut axis, revealing the strong correlation of brain-gut axis and IBS. miRNAs, which play critical roles in physiological processes, are not well studied in IBS. However, so far there is found an involvement of alterations in miRNA expression or sequence, in IBS symptoms. IBS phenotype is affected by epigenetic alteration and environment. Changes in DNA and histone methylation are observed in patients who suffered childhood trauma or abuse, resulting in altered gene expression, such as the glucocorticoid receptor gene. Finally, diet is another factor associated with IBS, which may contribute to symptom onset. Certain foods may affect on bacterial metabolism and epigenetic modifications, predisposing to IBS.

MicroRNA gene polymorphisms in pancreatic cancer.

MicroRNAs (miRNAs) act as regulators of gene expression via translational repression. Single nucleotide polymorphisms (SNPs) in miRNAs have been shown to affect the regulatory capacity of miRNAs by influencing miRNA processing and/or miRNA-mRNA interactions. The purpose of this study was to investigate the association between 2 SNPs commonly found in precursor miRNA and the susceptibility and clinicopathological characteristics of pancreatic cancer. The rs11614913/miR-196a2, rs2910164/miR-146a SNPs were genotyped in 93 patients with pancreatic cancer and in 122 healthy controls. No significant differences in genotype distributions between controls and PC patients were observed. However, rs2910164 GG and rs11614913 CC genotypes and the rs2910164C/rs11614913C and rs2910164G/rs11614913C haplotypes were significantly overrepresented in PC patients with T1 and T2 tumor status than in those with T3 and T4. Our findings suggested that the rs2910164 and rs11614913 SNPs might play a role in pancreatic tumorigenesis, but the molecular mechanism underlying the particular sequence variations in miRNA that can cause aberrant expression remains to be determined.

Patients with refractory gastroesophageal reflux disease: diagnostic tools.

Patients with refractory to proton pump inhibitors (PPIs) gastroesophageal reflux disease (GERD) symptoms are approximately 40% and represent a very common problem in clinical practice. Many of these patients do not have GERD, but suffer from functional heartburn or hypersensitive esophagus. After thorough clinical evaluation and failure of escalation of PPI dose, diagnostic investigations include endoscopy, esophageal manometry, pH testing, esophageal Bilitec and esophageal impedance with pH monitoring.

Role of non-acid reflux in patients with non-erosive reflux disease.

Non-erosive reflux disease (NERD) is the most common presentation of gastroesophageal reflux disease. Although acid reflux is the most important cause of symptom generation in NERD patients, non-acid reflux is also associated with reflux symptoms. The temporal relation between symptoms and reflux episodes is of importance in evaluating the results of combined pH-impedance monitoring in NERD patients. Mucosal hypersensitivity and mechanical stimulation due to great volume of non-acid reflux are among the putative mechanisms of symptom generation.

Hiatal hernia predisposes to nocturnal gastro-oesophageal reflux.

BACKGROUND: Nocturnal reflux has been associated with severe complications of gastro-oesophageal reflux disease and a poorer quality of life. Hiatal hernia predisposes to increased oesophageal acid exposure, but the effect on night reflux symptoms has never been investigated. The aim of the study was to investigate if hiatal hernia is associated with more frequent and severe night reflux symptoms. METHODS: A total of 215 consecutive patients (110 male, mean age 52.6 ± 14.7 years) answered a detailed questionnaire on frequency and severity of specific day and night reflux symptoms. Subsequently, all patients underwent upper endoscopy and were categorized in two groups based on the endoscopic presence of hiatal hernia. RESULTS: Patients with hiatal hernia were more likely to have nocturnal symptoms compared to those without hiatal hernia (78.6 vs. 51.8%, p = 0.0001); 59.2% of patients with hiatal hernia reported heartburn and 60.2% regurgitation compared to 43.8 and 39.3% of those without hiatal hernia, respectively (p = 0.033 and p = 0.003). The proportions of patients with day heartburn or regurgitation were not significantly different between the two groups. Night heartburn and regurgitation were graded as significantly more severe by patients with hiatal hernia (4.9 ± 4.2 vs. 3.2 ± 3.7, p = 0.002, and 3.8 ± 4.2 vs. 2.2 ± 3.5, p = 0.001, respectively). Patients with hiatal hernia had more frequent weekly night heartburn and regurgitation compared to those without hiatal hernia (p = 0.004 and p = 0.008, respectively). CONCLUSIONS: More patients with hiatal hernia reported nocturnal reflux symptoms compared to those without hiatal hernia. Furthermore, nocturnal reflux symptoms were significantly more frequent and graded as significantly more severe in patients with presence of hiatal hernia rather than in those without hiatal hernia.

Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors.

BACKGROUND/AIMS: In patients with non-cardiac chest pain (NCCP), gastroesophageal reflux disease (GERD) is the commonest cause and ambulatory pH is of great value in identifying these patients. However, parameters in the context of predicting therapeutic response are still unknown. By extending the monitoring period, we could better evaluate the best evidence for GERD association. Our aims were (1) to compare the outcomes of 48-hour pH monitoring to 24-hour and (2) to determine whether objective parameters could predict the treatment success in patients with NCCP using Bravo pH system. METHODS: Pathological esophageal acid reflux (PEAR) and positive symptom index (SI) were calculated after 24-hour and compared to the 48-hour study. Evidence suggestive of GERD diagnosis was considered if PEAR and/or SI (+) were present on each different day. After pH study, all patients received proton pump inhibitor twice a day for 4 weeks. Treatment success was determined at the end of therapy. RESULTS: Thirty-two patients with NCCP participated. GERD was identified in 20 (62.5%) patients; 17 (53.1%) had PEAR, 3 (9.4%) SI (+) and 7 (22%) both. Twelve (41%) patients exhibited PEAR values on day 1, while 17 after 2 days; a 12.1% gain. SI (+) was found in 6 patients (18.8%) on day 1 and in 4 more on day 2, a gain of 12.5%. Significantly higher proportion of patients with GERD indicators showed improvement compared to those without (90% vs 16.7%, P < 0.005). CONCLUSIONS: In patients with NCCP, 48-hour pH measurement identified GERD as the cause of NCCP with an increased yield by almost 12% compared to 12 hours. Objective GERD parameters could predict response to antireflux therapy.

Current management of functional dyspepsia: impact of Rome III subdivision.

Functional dyspepsia (FD) is a highly prevalent disease characterized by symptoms originating from the gastroduodenal region in the absence of underlying organic disease. The Rome III consensus made a distinction between meal-induced and meal-unrelated symptoms and proposed subdivision of FD into postprandial distress syndrome and epigastric pain syndrome. The applicability of this subdivision and the impact on management are areas of active research. So far, empirical approaches are still employed for the treatment of FD, although various therapeutic modalities for FD have been explored; acid-suppressive, prokinetic, and fundic relaxant drugs, antidepressants and psychological therapies. FD remains a challenge and presents unmet clinical needs.