Fatty Acid Synthase Promotes Hepatocellular Carcinoma Growth via S-Phase Kinase-Associated Protein 2/p27KIP1 Regulation.

Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN's tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27KIP1 non-phosphorylatable (p27KIP1-T187A) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27KIP1 activators.

Helicobacter pylori infection and occurrence of celiac disease in subjects HLA-DQ2/DQ8 positive: A prospective study.

BACKGROUND: Celiac disease (CD) occurs in subjects positive for HLA-DQ2 and/or DQ8 gene loci at any age following ingestion of gluten-containing food. An increased permeability of the mucosa allows interactions between gliadin macromolecules and genetic factors. It has been observed that Helicobacter pylori has the ability to modulate the integrity of the duodenal epithelium. We aimed to determine whether H. pylori infection may enhance the occurrence of CD in genetically susceptible subjects. MATERIALS AND METHODS: This was a prospective observational study. Patients undergoing upper endoscopy for any reason and positive for HLA-DQ2 and/or DQ8 haplotypes with or without CD were included. H. pylori infection was defined as a positive gastric histopathology and/or 13C-urea breath test. Prevalence of infection was compared between enrolled subjects with and without CD. Multiple logistic regression analysis, adjusting odds ratios for patient age, gender, smoking habit, residency, body mass index, and assumption of nonsteroidal anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors (PPIs) were performed. RESULTS: A total of 397 genetically susceptible individuals (mean age: 37.7 ± 15.3 years; 86% women) were enrolled between October 2014 and October 2017. There were 265 (68%) patients with a diagnosis of CD. Overall, the prevalence of H. pylori infection was 33% and was similar in patients with and without CD (32% vs 36%). Adjustment for all covariates did not reveal any significant association, although adjusted odds ratio (OR) for CD was higher in female (OR = 1.302), in patients H. pylori positive (OR = 1.277), followed by use of NSAIDs (OR = 1.126), respectively. The use of PPIs appeared to be mildly protective against CD (OR = 0.644). CONCLUSION: Our study did not reveal any significant relationship between H. pylori and CD risk, even taking into account other confounders. More importantly, our findings do not support a "protective" role of H. pylori infection against CD, as previously reported. Therefore, there are no reasons to avoid eradication of H. pylori also in subject genetically susceptible for CD.

Treatment of Helicobacter pylori infection in 2018.

Treatment options for the eradication of Helicobacter pylori continue to evolve. There have been many guidelines for H. pylori treatment published, which may lead to some confusion. However, most are in agreement with the most recent iteration of the Maastricht treatment guidelines. Triple therapy is still the most frequently used treatment, especially in areas of low clarithromycin resistance. Its best results are achieved when taken for a minimum of 10 days and with high-dose acid suppression. Quadruple therapy is gaining in popularity particularly in areas with increasing resistance to standard triple therapy. Whether three antibiotics, or bismuth and two antibiotics are used, excellent eradication rates are achieved, albeit with increased side effects. Levofloxacin second-line therapy is widely used; however bismuth, when available, is an increasingly successful option. Sequential therapy is challenging in terms of compliance and is no longer recommended. This past year witnessed a notable increase in the number of studies based on antimicrobial susceptibility testing and tailored eradication therapy, reflecting the role of culture-guided treatment, which may well represent the future of H. pylori treatment and prevent the inappropriate use of antibiotics.

Role of Helicobacter pylori Infection in Body Height of Adult Dyspeptic Patients.

INTRODUCTION: The prevalence of H. pylori infection is high in underdeveloped countries and is associated with growth retardation. In the first half of the 20th century, Sardinia was an underdeveloped region; however, more recent development resulted in a decline in H. pylori infection. Because body height is correlated with health and nutritional status in childhood, the association among H. pylori infection and height was explored. MATERIALS AND METHODS: A retrospective observational study was conducted involving patients undergoing endoscopy for dyspepsia from 2002 to 2012. H. pylori status was assessed by histology plus the rapid urease test or 13Carbon-urea breath test. RESULTS: Body height and H. pylori status were assessed in 5045 adult patients: 3257 (64.6%) were women. Patients born after 1950 showed a significant increase in height (average 3.22 cm) compared to patients born before 1950 (163.93 vs 160 cm; 95% confidence interval, CI = 2.74-3.70 cm) (p < .0001). H. pylori-infected patients were nearly 1 cm shorter than uninfected patients (95% CI = -1.35 to·-0.09 cm) (p = .012). The multivariate linear regression analysis showed male gender, birth cohort, and occupational categories to be strongly associated with height, while the weak effect of H. pylori infection disappeared. CONCLUSIONS: Our results demonstrate a strong secular trend related to body height in Sardinia with a minimal influence of H. pylori infection.

Diverticular Disease of the Colon: Neuromuscular Function Abnormalities.

Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients.

Gastrointestinal symptoms and Helicobacter pylori infection in school-age children residing in Porto Torres, Sardinia, Italy.

BACKGROUND: Helicobacter pylori infection is typically acquired in childhood, and following the acute event, it is thought that most infections remain asymptomatic. H. pylori has been suggested to protect against diarrhea in childhood. AIM: To examine the role of H. pylori in gastrointestinal symptoms in children. MATERIALS AND METHODS: A cross-sectional sero-epidemiologic study was conducted in Porto Torres, Sardinia, Italy. Demographic information, socioeconomic factors, and the frequency of upper gastrointestinal symptoms during the previous 3 months (e.g., abdominal pain, diarrhea, nausea, heartburn, halitosis, slow digestion, belching, and weight loss) were evaluated by a questionnaire. H. pylori status was determined by ELISA. RESULTS: Approximately 95% (N = 1741) of school children between the age of 6 and 15 years from Porto Torres participated. The sero-prevalence of H. pylori infection was 13.3% (229/1727) and similar in boys (13%) and girls (14%) (p = .57). Nausea/vomiting (odds ratio (OR) = 2.2 (95% CI = 1.2-5.1)) and diarrhea (OR = 2.1 (95% CI = 1.3-2.8)) were each significantly associated with H. pylori infection, and these associations remained significant after controlling for other study variables. There was no significant association between H. pylori and abdominal pain or heartburn (p > .25). CONCLUSIONS: The study does not support either a role of H. pylori infection in abdominal pain in children or a protective role against diarrheal illnesses or nausea/vomiting.

Helicobacter pylori therapy demystified.

We discuss the role of comparators in Helicobacter pylori treatment trials and why anti-H. pylori therapeutic trials (an infectious disease) are fundamentally different from common gastrointestinal diseases (e.g., the absence of a placebo response, the expectation that cure rates in excess of 95%, and the ability to understand why treatment fails). No comparator is absolutely required other than to 100% success and comparison trials should be limited to comparisons between therapies that reliably achieve 90% or greater success (i.e., good therapies). Comparisons with known low success regimens (i.e., bad therapies) are unethical as is withholding information from the subject regarding current effectiveness of a regimen even if that information would reduce the likelihood that the subject would volunteer. We also discuss how it is possible to predict the outcome of a published but locally untried new regimen. The reason for different outcomes of typical gastrointestinal therapies is shrouded in mystery. In contrast, treatment success for H. pylori should be predictable and treatment failures explainable. For too long expectations and analyses of H. pylori therapy has been confused with what is appropriate for gastrointestinal disease such as constipation or irritable bowel syndrome rather than for infectious diseases such as pneumonia.

OLGA gastritis staging in young adults and country-specific gastric cancer risk.

Geographical differences have been shown in the clinical outcomes of Helicobacter pylori-associated gastritis phenotypes and in gastric cancer risk. This study tested whether the Operative Link on Gastritis Assessment (OLGA) staging correlated with gastric cancer risk in populations from 3 continents. Mapped gastric biopsies were obtained from 316 dyspeptic adults aged less than 41 years from 8 geographic areas that differed in gastric cancer risk. Gastric atrophy was assessed according to internationally validated criteria. Gastritis stage was established according to the OLGA staging system. The most prevalent gastritis stages were 0 to II, which included all subjects entered from Chile, Germany, India, Italy, and Thailand. Gastritis Stages III and IV were limited to the Chinese and Korean populations. Indians had a high prevalence of H pylori infection without high-stage gastritis. In populations at different cancer risk, the gastritis OLGA stage mirrored the gastric cancer incidence. Gastritis staging identifies a subgroup of higher-risk patients.

Short article: Small intestinal mucosal injury in patients taking chemotherapeutic agents for solid cancers.

OBJECTIVE: Chemotherapy for cancer is a systemic treatment often associated with side effects than can be debilitating and, in some cases, life-threatening. Few data are available on intestinal enterotoxicity. Wireless video capsule endoscopy (VCE) is a noninvasive method of imaging the small intestine. This study presents the results of VCE in patients with solid tumors undergoing antineoplastic regimens with agents, notably for toxicity for the gastrointestinal mucosa (i.e. carboplatin, cyclophosphamide, 5-fluorouracil, methotrexate, and cisplatin). MATERIALS AND METHODS: The capsule endoscopy procedure was performed 4-13 days after the end of the antineoplastic course. Each patient received a polyethylene-glycol solution (1000 mg×2 in 2 l of water) for bowel preparation and fasted for 10 h before ingestion of the capsule. Videos were evaluated by one operator, supervised by a second operator, and conclusions were drawn by an expert reader. RESULTS: Twenty (age range: 38-77 years) patients were evaluated. The cecum was reached in 70% before exhaustion of the battery. The video capsule showed small widespread intestinal ulcerations in 25% and erosions in only one patient. The villus architecture appeared normal in all. VCE detected metastases in one patient with a melanoma. Few patients had more than one lesion. All capsules were passed in the stool. CONCLUSION: Our results suggest that chemotherapy in patients with solid cancers is associated with minimal visual small bowel injury. Factors other than damage of the intestinal mucosa causing loss of epithelium are likely involved in gastrointestinal toxicity and related symptoms.

Anti-Thyroid Peroxidase Antibodies and Male Gender Are Associated with Diabetes Occurrence in Patients with Beta-Thalassemia Major.

BACKGROUND: Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with ß-thalassemia (ß-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with ß-T major. METHODS: 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed. RESULTS: Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; p = 0.008) and male gender (OR = 1.98; p = 0.025) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665 µg/L versus 2922 ± 2773 µg/L; p < 0.0001). CONCLUSIONS: In patients with ß-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients.

Glucose-6-phosphate dehydrogenase deficiency and risk of colorectal cancer in Northern Sardinia: A retrospective observational study.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with a lower cancer risk, possibly via a reduction of mutagenic oxygen-free radicals and by reducing nicotinamide-adeninedinucleotide-phosphate for replicating cells. In Sardinia, the enzyme defect is frequent as a consequence of selection by malaria in the past. This study investigated the relationship between G6PD deficiency and colorectal cancer (CRC).A retrospective case-control study of 3901 patients from Sardinia, who underwent a colonoscopy between 2006 and 2016, was performed. G6PD phenotype was assessed for each subject. The proportion of pre and malignant colorectal lesions was compared in cases (G6PD-deficient) and controls (G6PD-normal). Data concerning age, sex, family history of CRC, smoking habits, body height, and weight, and also associated diseases were collected.The CRC risk reduction was 43.2% among G6PD-deficient compared with G6PD-normal subjects (odds ratio 0.57, 95% confidence interval 0.37-0.87, P = 0.010). Age, sex, family history of CRC, and also comorbidities such as type 1 diabetes and ischemic heart disease, were significantly associated with CRC risk. The protective effect of G6PD deficiency remained significant after adjusting for all covariates by logistic regression analysis, and was consistently lower across all age groups.Glucose-6-phosphate dehydrogenase enzyme deficiency is associated with a reduced risk of CRC.

Implication of Cytotoxic Helicobacter pylori Infection in Autoimmune Diabetes.

Background. Type 1 diabetes (T1D) and type 2 diabetes (T2D) have been linked to Helicobacter pylori infection, although results are conflicting. No previous study addressed a possible link between H. pylori infection and latent autoimmune diabetes in adults (LADA). In this study, a correlation among H. pylori infection and the risk of autoimmune diabetes in comparison with T2D was investigated. Methods. Sera from 234 LADA patients, 105 patients with late-onset T1D, and 156 patients with T2D were analyzed for anti-H. pylori and the cytotoxin-associated antigen (CagA) IgG antibodies. Results. H. pylori seroprevalence was comparable in LADA (52%), late-onset T1D (45%), and T2D (49%) with no gender differences. The seroprevalence of CagA IgG was significantly higher in autoimmune diabetes (late-onset T1D: 45%, LADA: 40%) compared to T2D (25%; p < 0.028). Conclusions. Although H. pylori seroprevalence was similar in LADA, T1D, and T2D, anti-CagA positivity was significantly increased among patients with autoimmune diabetes, suggesting that more virulent H. pylori strains might be a trigger for immune mechanisms involved in their pathogenesis.

Inclusion of Lactobacillus Reuteri in the Treatment of Helicobacter pylori in Sardinian Patients: A Case Report Series.

Clinical studies have shown that bismuth-containing quadruple therapy given twice a day for 10 to 14 days is effective and safe in the treatment of Helicobacter pylori infection in Sardinia. However, bismuth is no longer available in Italy. To report the effectiveness and tolerability of pantoprazole 20 mg, tetracycline 500 mg, and metronidazole 500 mg given b.i.d. (with the midday and evening meals) for 10 days supplemented with Lactobacillus reuteri (DSM 17938) 10(8)  cfu/tablet once a day for 20 days in patients treated in a routine daily practice setting. H pylori infection was defined as a positive gastric histopathology and/or 13C-Urea Breath Test (UBT) and/or stool antigen testing. Successful eradication was documented by 13C-UBT, and/or stool antigen assay at least 4 weeks post-therapy. Compliance and side effects were recorded after completing treatment. A total of 45 patients (10 men, 35 women; mean age 52.6 years) have completed the treatment regimen with the success rate of 93% (95% confidence interval = 85-99%). Compliance was excellent. Side effects were absent or generally mild.Proton pump inhibitor-tetracycline-metronidazole-L reuteri therapy provided high eradication rates with few side effects and therefore can safely replace bismuth in H pylori treatment. Further studies are needed that include susceptibility testing.

Is There a Role for Probiotics in Helicobacter pylori Therapy?

The role of probiotics in Helicobacter pylori therapy remains unclear. Lactobacilli can be shown to inhibit H pylori in vitro. Some strains of Lactobacilli may exert specific antimicrobial effects. There is no strong evidence of a benefit on eradication rate when probiotics are added to a regimen. Despite promising results obtained using compounds of L reuteri and S boulardii, high-quality trials are needed to define the role of probiotics as adjuvant therapy. Variables that remain to be studied with L reuteri, currently the most promising strain, include dosage, frequency of administration, administration in relation to meals, and duration of therapy.

Tissue resonance interaction accurately detects colon lesions: A double-blind pilot study.

AIM: To investigated the performance of the tissue resonance interaction method (TRIM) for the non-invasive detection of colon lesions. METHODS: We performed a prospective single-center blinded pilot study of consecutive adults undergoing colonoscopy at the University Hospital in Sassari, Italy. Before patients underwent colonoscopy, they were examined by the TRIMprobe which detects differences in electromagnetic properties between pathological and normal tissues. All patients had completed the polyethylene glycol-containing bowel prep for the colonoscopy procedure before being screened. During the procedure the subjects remained fully dressed. A hand-held probe was moved over the abdomen and variations in electromagnetic signals were recorded for 3 spectral lines (462-465 MHz, 930 MHz, and 1395 MHz). A single investigator, blind to any clinical information, performed the test using the TRIMprob system. Abnormal signals were identified and recorded as malignant or benign (adenoma or hyperplastic polyps). Findings were compared with those from colonoscopy with histologic confirmation. Statistical analysis was performed by χ(2) test. RESULTS: A total of 305 consecutive patients fulfilling the inclusion criteria were enrolled over a period of 12 months. The most frequent indication for colonoscopy was abdominal pain (33%). The TRIMprob was well accepted by all patients; none spontaneously complained about the procedure, and no adverse effects were observed. TRIM proved inaccurate for polyp detection in patients with inflammatory bowel disease (IBD) and they were excluded leaving 281 subjects (mean age 59 ± 13 years; 107 males). The TRIM detected and accurately characterized all 12 adenocarcinomas and 135/137 polyps (98.5%) including 64 adenomatous (100%) found. The method identified cancers and polyps with 98.7% sensitivity, 96.2% specificity, and 97.5% diagnostic accuracy, compared to colonoscopy and histology analyses. The positive predictive value was 96.7% and the negative predictive value 98.4%. Among the 281 non-IBD subjects, there were 7 cases with discordant results (2.5%) between TRIMprob and the reference standard including 5 false positive results (1.8%) and 2 false negative (0.7%) results. The main limitation of the TRIMprob system is the need for trained operators. CONCLUSION: The study confirmed that TRIM provides rapid, accurate, convenient and noninvasive means to identify individuals most likely to benefit from colonoscopy.

Myenteric plexitis: A frequent feature in patients undergoing surgery for colonic diverticular disease.

BACKGROUND: Diverticular disease of the colon is frequent in clinical practice, and a large number of patients each year undergo surgical procedures worldwide for their symptoms. Thus, there is a need for better knowledge of the basic pathophysiologic mechanisms of this disease entity. OBJECTIVES: Because patients with colonic diverticular disease have been shown to display abnormalities of the enteric nervous system, we assessed the frequency of myenteric plexitis (i.e. the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for this condition. METHODS: We analyzed archival resection samples from the proximal resection margins of 165 patients undergoing left hemicolectomy (60 emergency and 105 elective surgeries) for colonic diverticulitis, by histology and immunochemistry. RESULTS: Overall, plexitis was present in almost 40% of patients. It was subdivided into an eosinophilic (48%) and a lymphocytic (52%) subtype. Plexitis was more frequent in younger patients; and it was more frequent in those undergoing emergency surgery (50%), compared to elective (28%) surgery (p = 0.007). All the severe cases of plexitis displayed the lymphocytic subtype. CONCLUSIONS: In conclusion, myenteric plexitis is frequent in patients with colonic diverticular disease needing surgery, and it might be implicated in the pathogenesis of the disease.

Risk Factors Associated with Helicobacter pylori Infection among Children in a Defined Geographic Area.

Factors influencing the pattern of Helicobacter pylori infection among children living in adjacent urban and rural areas of northern Sardinia, Italy, were compared. The seroprevalence of H. pylori infection was 22% (625 of 2810 children) in the study population and was significantly higher among children in rural areas (37%) than in urban areas (13%) (odds ratio [OR], 3.8; 95% confidence interval [CI], 3.2-4.7; P<.005). This difference was consistent within each age group. In rural areas, children who had dogs were at greatest risk for H. pylori infection (OR, 1.8; 95% CI, 1.3-2.6; P<.05). No association was seen between H. pylori seropositivity and a history of breast-feeding. Urban children attending day care centers had a higher prevalence of infection (17%) than did those who never attended (12%) (OR, 1.5; 95% CI, 1.1-2.0; P<.05). The epidemiology of H. pylori infection is complex; even within the same geographic area, different factors influence acquisition of H. pylori infection.

Helicobacter pylori may play a contributory role in the pathogenesis of primary sclerosing cholangitis.

Helicobacter pylori (H. pylori) DNA has been identified in human livers and has been implicated in chronic liver disease and liver cancer. To better understand the role of H pylori in primary sclerosing cholangitis (PSC), 25 patients with end-stage PSC and 31 controls were studied. Genomic DNA was extracted from microdissected hilar hepatic ducts of liver explants and was amplified for H pylori DNA. Serum was tested for H pylori antibodies. Helicobacter DNA was detected in 9 of the 56 (16%) patients by 16SrRNA PCR (an additional case [for a total of 18%] was antibody positive). Seven of the 9 cases identified by polymerase chain reaction were positive for the CagA gene, confirming they were H pylori. Seven of the 25 (28%) patients with PSC and 3 of the 31 (9.7%) controls were positive for Helicobacter (P=.087). H pylori DNA was detected in microdissected hilar biliary epithelium in more PSC patients than controls, supporting the hypothesis that bile reflux from the duodenum into the biliary tract might carry H pylori organisms into the proximal biliary system, possibly contributing to PSC development and/or progression in some patients.

Reflux symptoms in professional opera choristers.

BACKGROUND AND AIMS: A specific, occupation-related susceptibility of professional singers to experience gastroesophageal reflux was hypothesized. We investigated the prevalence of gastroesophageal reflux symptoms in a series of professional opera choristers in comparison with a general population sample. METHODS: A total of 351 professional opera choristers from well-known chorus in different Italian regions were identified and a sample of 578 subjects residing in the same areas with a similar distribution in age and sex was selected. Reflux symptoms in the year preceding the survey together with selected individual characteristics and lifestyle habits were investigated in both study groups through a structured questionnaire. Prevalence rate ratios, adjusted for sex, age, body mass index, smoking status, alcohol consumption, and other confounding factors, were computed. RESULTS: Opera choristers reported a statistically significant higher prevalence of heartburn, regurgitation, cough, and hoarse voice than the population sample, with adjusted prevalent rate ratios of 1.60 (95% confidence interval [CI], 1.32-1.94), 1.81 (95% CI, 1.42-2.30), 1.40 (95% CI, 1.18-1.67), and 2.45 (95% CI, 1.97-3.04), respectively. Regurgitation appeared to be associated consistently with the cumulative lifetime duration of singing activity (P = .04) and with the weekly duration of singing activity (P = .005) when different multivariate models were applied. CONCLUSIONS: Opera choristers reported a higher prevalence of reflux symptoms than the population sample. Future studies will be needed to clarify whether gastroesophageal reflux in professional opera choristers is stress-induced and therefore may be considered as a work-related disease.