1 3170 101 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED. 2023 2 5180 27 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA. 2013 3 5783 31 SPONTANEOUS AND TRANSGENIC RODENT MODELS OF INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A MULTIFACTORIAL DISORDER WITH MANY DIFFERENT PUTATIVE INFLUENCES MEDIATING DISEASE ONSET, SEVERITY, PROGRESSION AND DIMINUTION. SPONTANEOUS NATURAL IBD IS CLASSICALLY EXPRESSED AS CROHN'S DISEASE (CD) AND ULCERATIVE COLITIS (UC) COMMONLY FOUND IN PRIMATES; LYMPHOPLASMOCYTIC ENTERITIS, EOSINOPHILIC GASTRITIS AND COLITIS, AND ULCERATIVE COLITIS WITH NEURONAL HYPERPLASIA IN DOGS; AND COLITIS IN HORSES. SPONTANEOUS INFLAMMATORY BOWEL DISEASE HAS BEEN NOTED IN A NUMBER OF RODENT MODELS WHICH DIFFER IN GENETIC STRAIN BACKGROUND, INDUCED MUTATION, MICROBIOTA INFLUENCES AND IMMUNOPATHOGENIC PATHWAYS. HISTOLOGICAL LESIONS IN CROHN'S DISEASE FEATURE NONCASEATING GRANULOMATOUS INFLAMMATION WHILE UC LESIONS TYPICALLY EXHIBIT ULCERATION, LAMINA PROPRIA INFLAMMATORY INFILTRATES AND LACK OF GRANULOMA DEVELOPMENT. INTESTINAL INFLAMMATION CAUSED BY CD AND UC IS ALSO ASSOCIATED WITH INCREASED INCIDENCE OF INTESTINAL NEOPLASIA. TRANSGENIC MURINE MODELS HAVE DETERMINED UNDERLYING ETIOLOGICAL INFLUENCES AND APPROPRIATE THERAPEUTIC TARGETS IN IBD. THIS LITERATURE REVIEW WILL DISCUSS CURRENT OPINION AND FINDINGS IN SPONTANEOUS IBD, HIGHLIGHT SELECTED TRANSGENIC RODENT MODELS OF IBD AND DISCUSS THEIR RESPECTIVE PATHOGENIC MECHANISMS. IT IS VERY IMPORTANT TO PROVIDE ACCOMMODATION OF INDUCED PUTATIVE DEFICITS IN ACTIVITIES OF DAILY LIVING AND TO ASSESS DISCOMFORT AND PAIN LEVELS IN THE FACE OF SIGNIFICANT MORBIDITY AND/OR MORTALITY IN THESE MODELS. EPIGENETIC, ENVIRONMENTAL (MICROBIOME, METABOLOME) AND NUTRITIONAL FACTORS ARE IMPORTANT IN IBD PATHOGENESIS, AND EVALUATING WAYS IN WHICH THEY INFLUENCE DISEASE EXPRESSION REPRESENT POTENTIAL INVESTIGATIVE APPROACHES WITH THE GREATEST POTENTIAL FOR NEW DISCOVERIES. 2015 4 563 32 BARRETT'S ESOPHAGUS: CAN BIOMARKERS PREDICT PROGRESSION TO MALIGNANCY? BARRETT'S ESOPHAGUS (BE) IS ONE OF THE MOST COMMON PREMALIGNANT LESIONS AND CAN PROGRESS TO ESOPHAGEAL ADENOCARCINOMA. IT IS CHARACTERIZED HISTOLOGICALLY BY A SPECIALIZED INTESTINAL METAPLASIA THAT REPLACES THE SQUAMOUS EPITHELIUM OF THE DISTAL ESOPHAGUS, AND IS ASSOCIATED WITH CHRONIC GASTROESOPHAGEAL REFLUX DISEASE AND OBESITY. SIMILAR TO THE ADENOMA-CARCINOMA SEQUENCE OF COLORECTAL CARCINOMAS, ESOPHAGEAL ADENOCARCINOMA DEVELOPS THROUGH PROGRESSION FROM BE TO LOW- AND HIGH-GRADE DYSPLASIA, THEN TO ADENOCARCINOMA WITH ACCUMULATION OF GENETIC AND EPIGENETIC ABNORMALITIES. THE EXACT MALIGNANCY POTENTIAL OF BE IS UNCERTAIN. DYSPLASIA IS THE MOST PREDICTIVE MARKER FOR RISK OF ESOPHAGEAL ADENOCARCINOMA, WHEREAS ENDOSCOPIC AND HISTOLOGICAL DIAGNOSES ARE STILL THE GOLD STANDARD FOR SURVEILLANCE OF PATIENTS WITH BE. HOWEVER, BOTH ARE LIMITED, EITHER BY SAMPLING ERRORS IN BIOPSIES OR BY DIFFERENCES IN HISTOLOGICAL INTERPRETATION. SEVERAL STUDIES HAVE IDENTIFIED CANDIDATE BIOMARKERS THAT MAY HAVE PREDICTIVE VALUE AND MAY SERVE AS ADDITIONAL FACTORS FOR THE RISK ASSESSMENT OF ESOPHAGEAL ADENOCARCINOMA. THIS REVIEW DISCUSSES THE ROLE OF BIOMARKERS IN THE PROGRESSION FROM BE TO ADENOCARCINOMA, FOCUSING ON CLINICAL AND MOLECULAR MARKERS. 2008 5 1799 37 EFFECT OF HELICOBACTER PYLORI INFECTION ON THE COMPOSITION OF GASTRIC MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. BACKGROUND: GASTRIC CANCER IS ONE OF THE MOST COMMON CANCER TYPES WORLDWIDE. IN CHINA, GASTRIC CANCER HAS BECOME ONE OF THE MAJOR THREATS FOR PUBLIC HEALTH, RANKING SECOND ON INCIDENCE AND THIRD ON CAUSE OF CANCER DEATH. DESPITE THE COMMON RISK FACTORS THAT PROMOTE THE DEVELOPMENT OF GASTRIC CANCER, THE HUGE QUANTITY OF MICROORGANISM COLONIES WITHIN THE GASTROINTESTINAL TRACT, PARTICULARLY HELICOBACTER PYLORI INFECTION, DEMONSTRATES A CORRELATION WITH CHRONIC INFLAMMATION AND GASTRIC CARCINOGENESIS, AS EPIDEMIOLOGICAL STUDIES HAVE DETERMINED THAT H. PYLORI INFECTION CONFERS APPROXIMATELY 75% OF THE ATTRIBUTABLE RISK FOR GASTRIC CANCER. SUMMARY: THE CURRENT ARTICLE DRAWS AN OVERVIEW ON THE CORRELATION BETWEEN THE MICROBIOTA, INFLAMMATION AND GASTRIC TUMORIGENESIS. H. PYLORI INFECTION HAS BEEN IDENTIFIED AS THE MAIN RISK FACTOR AS IT TRIGGERS EPITHELIAL BARRIER DISRUPTION, SURVIVAL SIGNALING AS WELL AS GENETIC/EPIGENETIC MODULATION. APART FROM H. PYLORI, THE EXISTENCE OF A DIVERSE AND COMPLEX COMPOSITION OF MICROBIOTA IN THE STOMACH HAS BEEN IDENTIFIED, WHICH SUPPORTS A ROLE OF MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. MOREOVER, METAGENOMICS STUDIES FOCUSED ON THE COMPOSITION AND FUNCTION OF THE MICROBIOTA HAVE ASSOCIATED MICROBIOTA WITH GASTRIC METABOLIC DISEASES AND EVEN TUMORIGENESIS. APART FROM THE GASTRIC MICROBIOTA, INFLAMMATION IS ANOTHER IDENTIFIED CONTRIBUTOR TO CANCER DEVELOPMENT AS WELL. KEY MESSAGE: THOUGH H. PYLORI INFECTION AND THE NON-H. PYLORI MICROBIOTA PLAY A ROLE IN GASTRIC CANCER, THE PROPERTIES OF GASTRIC MICROBIOTA AND MECHANISMS BY WHICH THEY PARTICIPATE IN THE GENESIS OF GASTRIC CANCER ARE STILL NOT CLEARLY DEPICTED. MOREOVER, IT REMAINS TO BE UNDERSTOOD HOW THE PRESENCE OF MICROBIOTA ALONG WITH H. PYLORI INFECTION AFFECTS THE PROGRESS FROM GASTRIC DISEASE TO CANCER. PRACTICAL IMPLICATIONS: THIS ARTICLE SUMMARIZED A CLUE OF THE CURRENT STUDIES ON MICROBIOTA, H. PYLORI INFECTION AND THE PROGRESSION FROM GASTRIC DISEASE TO CANCER. 2015 6 196 19 ACID REFLUX AND OESOPHAGEAL CANCER. BARRETT'S METAPLASIA IS ONE OF THE COMMONEST PREMALIGNANT LESIONS IN THE WESTERN WORLD FOLLOWING COLORECTAL ADENOMAS. ONE IN 50 OF THE ADULT POPULATION DEVELOPS BARRETT'S AS A CONSEQUENCE OF CHRONIC GASTRO-OESOPHAGEAL REFLUX. THE MUCOSAL INFLAMMATION SEEN WITHIN PATIENTS WITH GASTRO-OESOPHAGEAL REFLUX SEEMS LIKELY TO DRIVE THE GROWTH OF THE METAPLASTIC MUCOSA AND ALSO HELP DIRECT FURTHER ONCOLOGICAL CHANGE, YET THE MOLECULAR EVENTS THAT CHARACTERIZE THE PATHWAY FROM INFLAMMATION TO METAPLASIA TO DYSPLASIA AND ADENOCARCINOMA ARE POORLY UNDERSTOOD. THERE IS HOPE THAT UNDERSTANDING THE ROLE OF OESOPHAGEAL INFLAMMATION WILL PROVIDE IMPORTANT INSIGHT INTO THE DEVELOPMENT OF BARRETT'S METAPLASIA AND OESOPHAGEAL CANCER. THIS CHAPTER WILL DISCUSS THE INFLAMMATION SEEN WITHIN CONTEXT OF BARRETT'S OESOPHAGUS AND ALSO CLINICAL TRIALS WHICH HOPE TO ADDRESS THIS COMMON PREMALIGNANT DISEASE. THERE ARE SEVERAL ONGOING CLINICAL TRIALS WHICH ARE AIMING TO PROVIDE DATA USING ANTI-INFLAMMATORY THERAPIES TO TACKLE THIS IMPORTANT PREMALIGNANT CONDITION. THERE IS NEW DATA PRESENTED WHICH SUGGESTS THAT DATA FROM THE ASPIRIN ESOMEPRAZOLE CHEMOPREVENTION TRIAL (ASPECT) MAY HOLD THE CLUE TO DISEASE TREATMENT AND THAT THE CYTOKINE TNF-ALPHA SEEMS TO BE A KEY SIGNALLING MOLECULE IN THE METAPLASIA-DYSPLASIA-CARCINOMA SEQUENCE. SPECIFICALLY IT APPEARS THAT BOTH EPIGENETIC AND INHERITED GENETICS COOPERATE TO MODULATE THE PROGNOSIS. 2011 7 105 21 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS. 2018 8 4274 30 MICROBIOTA IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS AND THERAPY: IS IT ALL ABOUT DIET? INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING ULCERATIVE COLITIS, CROHN'S DISEASE, AND UNCLASSIFIED IBD, CONTINUES TO CAUSE SIGNIFICANT MORBIDITY. WHILE ITS INCIDENCE IS INCREASING, NO CLEAR ETIOLOGY AND NO CURE HAVE YET BEEN DISCOVERED. RECENT FINDINGS SUGGEST THAT IBD MAY HAVE A MULTIFACTORIAL ETIOLOGY, WHERE COMPLEX INTERACTIONS BETWEEN GENETICS, EPIGENETICS, ENVIRONMENTAL FACTORS (INCLUDING DIET BUT ALSO INFECTIONS, ANTIBIOTICS, AND SANITATION), AND HOST IMMUNE SYSTEM LEAD TO ABNORMAL IMMUNE RESPONSES AND CHRONIC INFLAMMATION. OVER THE PAST YEARS, THE ROLE OF ALTERED GUT MICROBIOTA (IN BOTH COMPOSITION AND FUNCTION) IN IBD PATHOGENESIS HAS EMERGED AS AN OUTSTANDING AREA OF INTEREST. ACCORDING TO NEW FINDINGS, GUT DYSBIOSIS MAY APPEAR AS A KEY ELEMENT IN INITIATION OF INFLAMMATION IN IBD AND ITS COMPLICATIONS. MOREOVER, COMPLEX METAGENOMIC STUDIES PROVIDE POSSIBILITIES TO DISTINGUISH BETWEEN IBD TYPES AND APPRECIATE SEVERITY AND PROGNOSIS OF THE DISEASE, AS WELL AS RESPONSE TO THERAPY. THIS REVIEW PROVIDES AN UPDATED KNOWLEDGE OF RECENT FINDINGS LINKING ALTERED BACTERIAL COMPOSITION AND FUNCTIONS, VIRUSES, AND FUNGI TO IBD PATHOGENESIS. IT ALSO HIGHLIGHTS THE COMPLEX GENETIC, EPIGENETIC, IMMUNE, AND MICROBIAL INTERACTIONS IN RELATION TO ENVIRONMENTAL FACTORS (INCLUDING DIET). WE OVERVIEW THE ACTUAL OPTIONS TO MANIPULATE THE ALTERED MICROBIOTA, SUCH AS MODIFIED DIET, PROBIOTICS, PREBIOTICS, SYNBIOTICS, ANTIBIOTICS, AND FECAL TRANSPLANTATION. FUTURE POSSIBLE THERAPIES ARE ALSO INCLUDED. TARGETING ALTERED MICROBIOTA COULD BE THE NEXT THERAPEUTIC PERSONALIZED APPROACH, BUT MORE RESEARCH AND WELL-DESIGNED COMPARATIVE PROSPECTIVE STUDIES ARE REQUIRED TO FORMULATE ADEQUATE DIRECTIONS FOR PREVENTION AND THERAPY. 2015 9 3229 34 HELICOBACTER PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. HELICOBACTER PYLORI (H. PYLORI) INFECT OVER HALF OF THE WORLD'S POPULATION. THE PREVALENCE OF H. PYLORI INFECTION AND THE PREDOMINANT GENOTYPE OF H. PYLORI VIRULENCE FACTORS VARY CONSIDERABLY ACROSS DIFFERENT GEOGRAPHICAL REGIONS. H. PYLORI COULD UNIQUELY PERSIST FOR DECADES IN THE HARSH STOMACH ENVIRONMENT, WHERE IT DAMAGES THE GASTRIC MUCOSA AND CHANGES THE PATTERN OF GASTRIC HORMONE RELEASE, THEREBY AFFECTS GASTRIC PHYSIOLOGY. BY UTILIZING VARIOUS VIRULENCE FACTORS, H. PYLORI TARGETS DIFFERENT CELLULAR PROTEINS TO MODULATE THE HOST INFLAMMATORY RESPONSE AND INITIATE MULTIPLE "HITS" ON THE GASTRIC MUCOSA, RESULTING IN CHRONIC GASTRITIS AND PEPTIC ULCERATION. AMONG THE LONG-TERM CONSEQUENCES OF H. PYLORI INFECTION IS GASTRIC MALIGNANCIES, PARTICULARLY GASTRIC CANCER (GC) AND GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA. AS SUCH, H. PYLORI HAS BEEN RECOGNIZED AS A CLASS I CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. DESPITE A CLOSE CAUSAL LINK BETWEEN H. PYLORI INFECTION AND THE DEVELOPMENT OF GASTRIC MALIGNANCIES, THE PRECISE MECHANISMS INVOLVED IN THIS PROCESS ARE STILL OBSCURE. STUDIES OVER THE PAST TWO DECADES HAVE REVEALED THAT H. PYLORI EXERT ONCOGENIC EFFECTS ON GASTRIC MUCOSA THROUGH A COMPLEX INTERACTION BETWEEN BACTERIAL FACTORS, HOST FACTORS, AND ENVIRONMENTAL FACTORS. NUMEROUS SIGNALING PATHWAYS CAN BE ACTIVATED BY H. PYLORI. IN THIS REVIEW, WE AIM TO ELABORATE ON THE RECENT DEVELOPMENTS IN THE PATHOPHYSIOLOGICAL MECHANISMS OF H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. 2014 10 4673 30 NEW INSIGHTS INTO THE PATHOGENESIS AND TREATMENT OF IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS ONE OF THE MOST COMMON FUNCTIONAL GASTROINTESTINAL DISORDERS (FGID), CHARACTERIZED BY ABDOMINAL PAIN AND A CHANGE IN STOOL FORM THAT CANNOT BE EXPLAINED BY STRUCTURAL ABNORMALITIES. ITS PREVALENCE RANGES FROM 9 TO 23% OF THE WORLDWIDE POPULATION. THE PATHOPHYSIOLOGY OF IBS IS DIVERSE AND NOT WELL UNDERSTOOD. BIOPSYCHOSOCIAL CONCEPT ASSUMES THAT THE DISEASE IS A PRODUCT OF PSYCHOSOCIAL FACTORS AND ALTERED AT MULTIPLE LEVELS OF GUT PHYSIOLOGY INTERACTIONS. SOME AETIOLOGICAL FACTORS HAVE BEEN IDENTIFIED, YET. ONE OF THE MOST IMPORTANT IS THE DISRUPTION OF BRAIN-GUT MUTUAL COMMUNICATION THAT LEADS TO VISCERAL HYPERSENSITIVITY. ALSO GENETIC AND EPIGENETIC FACTORS ARE INVOLVED. CHRONIC STRESS MAY PREDISPOSE TO IBS AS WELL AS EXACERBATE ITS SYMPTOMS. BOTH QUANTITATIVE AND QUALITATIVE DISORDERS OF THE GUT MICROBIOTA ARE OBSERVED. THERE IS ALSO A RELATIONSHIP BETWEEN THE IBS SYMPTOMS AND THE INTAKE OF A SPECIFIC TYPE OF FOOD PRODUCTS. IN THE DIARRHOEA TYPE OF IBS THE ROLE OF PREVIOUS GASTROINTESTINAL INFECTION IS DEMONSTRATED. RECENT STUDIES HAVE SUGGESTED THAT VISCERAL HYPERSENSITIVITY IN PATIENTS WITH IBS MAY BE SECONDARY TO THE ACTIVATION OF THE IMMUNE CELLS AND LOW-GRADE INFLAMMATION. CLINICAL SYMPTOMS OF IBS INCLUDE ABDOMINAL PAIN AND CHANGE IN BOWEL HABITS AS WELL AS SOMATIC AND PSYCHIATRIC COMORBIDITIES. IBS IS DIAGNOSED ON THE BASIS OF ROME DIAGNOSTIC CRITERIA. RECENTLY, THEIR NEWEST VERSION (ROME IV) HAS BEEN PRESENTED. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE PAST DECADE PROGRESS IN IBS DIAGNOSIS, MAIN PATHOPHYSIOLOGICAL ASPECTS AND THERAPEUTIC MANAGEMENT STRATEGY. 2017 11 3804 23 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 12 2938 22 GENETIC AND EPIGENETIC ALTERATIONS IN BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA. ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPS FROM BARRETT'S ESOPHAGUS (BE), WHEREIN NORMAL SQUAMOUS EPITHELIA IS REPLACED BY SPECIALIZED INTESTINAL METAPLASIA IN RESPONSE TO CHRONIC GASTROESOPHAGEAL ACID REFLUX. BE CAN PROGRESS TO LOW- AND HIGH-GRADE DYSPLASIA, INTRAMUCOSAL, AND INVASIVE CARCINOMA. BOTH BE AND EAC ARE CHARACTERIZED BY LOSS OF HETEROZYGOSITY, ANEUPLOIDY, SPECIFIC GENETIC MUTATIONS, AND CLONAL DIVERSITY. GIVEN THE LIMITATIONS OF HISTOPATHOLOGY, GENOMIC AND EPIGENOMIC ANALYSES MAY IMPROVE THE PRECISION OF RISK STRATIFICATION. ASSAYS TO DETECT MOLECULAR ALTERATIONS ASSOCIATED WITH NEOPLASTIC PROGRESSION COULD BE USED TO IMPROVE THE PATHOLOGIC ASSESSMENT OF BE/EAC AND TO SELECT HIGH-RISK PATIENTS FOR MORE INTENSIVE SURVEILLANCE. 2015 13 566 28 BASES FOR THE ADEQUATE DEVELOPMENT OF NUTRITIONAL RECOMMENDATIONS FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC AND RELAPSING INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT; IT IS A HETEROGENEOUS AND MULTIFACTORIAL DISORDER RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENETIC VARIATION, INTESTINAL MICROBIOTA, THE HOST IMMUNE SYSTEM AND ENVIRONMENTAL FACTORS SUCH AS DIET, DRUGS, BREASTFEEDING AND SMOKING. THE INTERACTIONS BETWEEN DIETARY NUTRIENTS AND INTESTINAL IMMUNITY ARE COMPLEX. THERE IS A COMPELLING ARGUMENT FOR ENVIRONMENTAL FACTORS SUCH AS DIET PLAYING A ROLE IN THE CAUSE AND COURSE OF IBD, GIVEN THAT THREE IMPORTANT FACTORS IN THE PATHOGENESIS OF IBD CAN BE MODULATED AND CONTROLLED BY DIET: INTESTINAL MICROBIOTA, THE IMMUNE SYSTEM AND EPITHELIAL BARRIER FUNCTION. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE EPIDEMIOLOGICAL FINDINGS REGARDING DIET AND TO FOCUS ON THE EFFECTS THAT NUTRIENTS EXERT ON THE INTESTINAL MUCOSA-MICROBIOTA-PERMEABILITY INTERACTION. THE NATURE OF THESE INTERACTIONS IN IBD IS INFLUENCED BY ALTERATIONS IN THE NUTRITIONAL METABOLISM OF THE GUT MICROBIOTA AND HOST CELLS THAT CAN INFLUENCE THE OUTCOME OF NUTRITIONAL INTERVENTION. A BETTER UNDERSTANDING OF DIET-HOST-MICROBIOTA INTERACTIONS IS ESSENTIAL FOR UNRAVELLING THE COMPLEX MOLECULAR BASIS OF EPIGENETIC, GENETIC AND ENVIRONMENTAL INTERACTIONS UNDERLYING IBD PATHOGENESIS AS WELL AS FOR OFFERING NEW THERAPEUTIC APPROACHES FOR THE TREATMENT OF IBD. 2019 14 5181 27 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER. 2010 15 3232 28 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 16 5317 32 PSYCHOLOGICAL STRESS, INTESTINAL BARRIER DYSFUNCTIONS, AND AUTOIMMUNE DISORDERS: AN OVERVIEW. AUTOIMMUNE DISORDERS (ADS) ARE MULTIFACTORIAL DISEASES INVOLVING, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CHARACTERIZED BY AN INAPPROPRIATE IMMUNE RESPONSE TOWARD SELF-ANTIGENS. IN THE PAST DECADES, THERE HAS BEEN A CONTINUOUS RISE IN THE INCIDENCE OF ADS, WHICH CANNOT BE EXPLAINED BY GENETIC FACTORS ALONE. INFLUENCE OF PSYCHOLOGICAL STRESS ON THE DEVELOPMENT OR THE COURSE OF AUTOIMMUNE DISORDERS HAS BEEN DISCUSSED FOR A LONG TIME. INDEED, BASED ON EPIDEMIOLOGICAL STUDIES, STRESS HAS BEEN SUGGESTED TO PRECEDE AD OCCURRENCE AND TO EXACERBATE SYMPTOMS. FURTHERMORE, COMPILING DATA SHOWED THAT MOST OF ADS ARE ASSOCIATED WITH GASTROINTESTINAL SYMPTOMS, THAT IS, MICROBIOTA DYSBIOSIS, INTESTINAL HYPERPERMEABILITY, AND INTESTINAL INFLAMMATION. INTERESTINGLY, SOCIAL STRESS (ACUTE OR CHRONIC, IN ADULT OR IN NEONATE) IS A WELL-DESCRIBED INTESTINAL DISRUPTING FACTOR. TAKEN TOGETHER, THOSE OBSERVATIONS QUESTION A POTENTIAL ROLE OF STRESS-INDUCED DEFECT OF THE INTESTINAL BARRIER IN THE ONSET AND/OR THE COURSE OF ADS. IN THIS REVIEW, WE AIM TO PRESENT EVIDENCES SUPPORTING THE HYPOTHESIS FOR A ROLE OF STRESS-INDUCED INTESTINAL BARRIER DISRUPTION IN THE ONSET AND/OR THE COURSE OF ADS. WE WILL MAINLY FOCUS ON AUTOIMMUNE TYPE 1 DIABETES, MULTIPLE SCLEROSIS AND SYSTEMIC LUPUS ERYTHEMATOSUS, ADS FOR WHICH WE COULD FIND SUFFICIENT CIRCUMSTANTIAL DATA TO SUPPORT THIS HYPOTHESIS. WE EXCLUDED GASTROINTESTINAL (GI) ADS LIKE COELIAC DISEASE TO PRIVILEGE ADS NOT FOCUSED ON INTESTINAL DISORDERS TO AVOID CONFOUNDING FACTORS. INDEED, GIADS ARE CHARACTERIZED BY ANTIBODIES DIRECTED AGAINST INTESTINAL BARRIER ACTORS. 2020 17 1180 30 CONVERGENCE OF GENETIC, NUTRITIONAL AND INFLAMMATORY FACTORS IN GASTROINTESTINAL CANCERS. GASTROINTESTINAL CANCERS ACCOUNT FOR 20% OF ALL CANCER INCIDENCES WORLDWIDE. COLORECTAL CANCER IS THE SECOND MOST COMMON CAUSE OF ALL CANCER-RELATED MORTALITY AND IS INCREASING IN WESTERN SOCIETIES. INFECTION AND INFLAMMATION CONTRIBUTE TO 15-20% OF ALL MALIGNANCIES, AND ARE PREDISPOSING RISK FACTORS FOR GASTROINTESTINAL CANCERS. HELICOBACTER PYLORI INFECTION IS COMMONLY ASSOCIATED WITH GASTRIC CANCERS, AND CHRONIC INFLAMMATION INCREASES THE RISK OF COLORECTAL CANCER BY 1% PER YEAR. MICRONUTRIENT STATUS AND COMMON GENETIC VARIATIONS IN HUMAN POPULATIONS MODIFY RISK FOR GASTROINTESTINAL CANCER. CHRONIC INFLAMMATION PROMOTES CARCINOGENESIS BY INDUCING GENE MUTATIONS, INHIBITING APOPTOSIS, AND STIMULATING ANGIOGENESIS AND CELL PROLIFERATION. INFLAMMATION ALSO INDUCES EPIGENETIC ALTERATIONS THAT ARE ASSOCIATED WITH CANCER DEVELOPMENT. TWO KEY GENES IN THE INFLAMMATORY PROCESS, CYCLOOXYGENASE-2 (COX-2) AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB), PROVIDE A MECHANISTIC LINK BETWEEN INFLAMMATION AND CANCER AND ARE TARGETS FOR CHEMOPREVENTION. DIETARY COMPONENTS, AND HUMAN GENETIC VARIATION THAT AFFECTS NUTRIENT UTILIZATION, CAN DIRECTLY MODIFY INFLAMMATORY PROCESSES AND/OR SUPPRESS GENOMIC ALTERATIONS THAT ARE THE MOLECULAR ANTECEDENTS OF CANCERS. THE PRESENT REPORT FOCUSES ON THE CONVERGENCE OF GENETIC, NUTRITIONAL, AND INFLAMMATORY FACTORS IN THE INITIATION AND PROGRESSION OF GASTROINTESTINAL CANCERS, AND THE EMERGING DIETARY STRATEGIES FOR CANCER PREVENTION. 2007 18 2852 29 FROM GASTRIC INFLAMMATION TO GASTRIC CANCER. THE MAJORITY OF GASTRIC ADENOCARCINOMAS ARE RELATED TO CHRONIC INFLAMMATION INDUCED BY HELICOBACTER PYLORI INFECTION. FOR INTESTINAL-TYPE GASTRIC CANCER, A MULTISTEP PROCESS OF MUCOSAL ALTERATIONS LEADING FROM GASTRITIS VIA GLANDULAR ATROPHY, INTESTINAL METAPLASIA AND DYSPLASIA TO INVASIVE CARCINOMA IS WELL RECOGNIZED. ONGOING CLINICAL STUDIES FOCUS ON A 'POINT OF NO RETURN'. IT IS DEFINED AS A SITUATION WHEN CERTAIN ALTERATIONS ARE NO LONGER REVERSIBLE BY H. PYLORI ERADICATION AND PROGRESSION TO GASTRIC CANCER MAY CONTINUE. H. PYLORI AFFECTS THE MUCOSAL AS WELL AS THE SYSTEMIC IMMUNE RESPONSE BY SECRETION OF CYTOKINES AND THE RECRUITMENT OF DISTINCT INFLAMMATORY CELLS. THE IMMUNE RESPONSE IS CHARACTERIZED BY A BALANCE BETWEEN A TH1-DOMINATED RESPONSE AND THE RECRUITMENT OF ANTIGEN-SPECIFIC REGULATORY T CELLS THAT ALLOW THE BACTERIA TO PERSIST IN HUMAN GASTRIC MUCOSA. BESIDES IMMUNE-MEDIATED EFFECTS, H. PYLORI INDUCES CELLULAR ALTERATIONS AS WELL AS GENETIC ALTERATIONS IN GENES THAT ARE ESSENTIAL FOR THE EPIGENETIC INTEGRITY AND MUCOSAL HOMEOSTASIS. THESE GENETIC ALTERATIONS DURING GASTRIC CANCER DEVELOPMENT ARE IN FOCUS OF INTENSIVE RESEARCH AND SHOULD ULTIMATELY ALLOW THE IDENTIFICATION OF RISK FACTORS INVOLVED IN GASTRIC CARCINOGENESIS. THE DETECTION OF INDIVIDUALS AT HIGH RISK FOR GASTRIC CANCER WOULD HELP TO DESIGN APPROPRIATE STRATEGIES FOR PREVENTION AND SURVEILLANCE. 2010 19 1395 32 DIET AND MICROBIOME IN THE BEGINNING OF THE SEQUENCE OF GUT INFLAMMATION. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY CONDITION OF THE GASTROINTESTINAL TRACT DUE, AT LEAST PARTIALLY, TO AN ABERRANT AND EXCESSIVE MUCOSAL IMMUNE RESPONSE TO GUT BACTERIA IN GENETICALLY-PREDISPOSED INDIVIDUALS UNDER CERTAIN ENVIRONMENTAL FACTORS. THE INCIDENCE OF IBD IS RISING IN WESTERN AND NEWLY INDUSTRIALIZED COUNTRIES, PARALLELING THE INCREASE OF WESTERNIZED DIETARY PATTERNS, THROUGH NEW ANTIGENS, EPITHELIAL FUNCTION AND PERMEABILITY, EPIGENETIC MECHANISMS (E.G., DNA METHYLATION), AND ALTERATION OF THE GUT MICROBIOME. ALTERATION IN THE COMPOSITION AND FUNCTIONALITY OF THE GUT MICROBIOME (INCLUDING BACTERIA, VIRUSES AND FUNGI) SEEMS TO BE A NUCLEAR PATHOGENIC FACTOR. THE MICROBIOME ITSELF IS DYNAMIC, AND THE CHANGES IN FOOD QUALITY, DIETARY HABITS, LIVING CONDITIONS AND HYGIENE OF THESE WESTERN SOCIETIES, COULD INTERACT IN A COMPLEX MANNER AS MODULATORS OF DYSBIOSIS, THEREBY INFLUENCING THE ACTIVATION OF IMMUNE CELLS' PROMOTING INFLAMMATION. THE MICROBIOME PRODUCES DIVERSE SMALL MOLECULES VIA SEVERAL METABOLIC WAYS, WITH THE FIBER-DERIVED SHORT-CHAIN FATTY ACIDS (I.E., BUTYRATE) AS MAIN ELEMENTS AND HAVING ANTI-INFLAMMATORY EFFECTS. THESE METABOLITES AND SOME MICRONUTRIENTS OF THE DIET (I.E., VITAMINS, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS) ARE REGULATORS OF INNATE AND ADAPTIVE INTESTINAL IMMUNE HOMEOSTASIS. AN EXCESSIVE AND UNHEALTHY CONSUMPTION OF SUGAR, ANIMAL FAT AND A LOW-VEGETABLE AND -FIBER DIET ARE RISK FACTORS FOR IBD APPEARANCE. FURTHERMORE, METABOLISM OF NUTRIENTS IN INTESTINAL EPITHELIUM AND IN GUT MICROBIOTA IS ALTERED BY INFLAMMATION, CHANGING THE DEMAND FOR NUTRIENTS NEEDED FOR HOMEOSTASIS. THIS ROLE OF FOOD AND A REDUCED GUT MICROBIAL DIVERSITY IN CAUSING IBD MIGHT ALSO HAVE A PROPHYLACTIC OR THERAPEUTIC ROLE FOR IBD. THE RELATIONSHIP BETWEEN DIETARY INTAKE, SYMPTOMS, AND BOWEL INFLAMMATION COULD LEAD TO DIETARY AND LIFESTYLE RECOMMENDATIONS, INCLUDING DIETS WITH ABUNDANT FRUITS, VEGETABLES, OLIVE OIL AND OILY FISH, WHICH HAVE ANTI-INFLAMMATORY EFFECTS AND COULD PREVENT DYSBIOSIS AND IBD. DIETARY MODULATION AND APPROPRIATE EXCLUSION DIETS MIGHT BE A NEW COMPLEMENTARY MANAGEMENT FOR TREATMENT AT DISEASE FLARES AND IN REFRACTORY PATIENTS, EVEN REDUCING COMPLICATIONS, HOSPITALIZATIONS AND SURGERY, THROUGH MODIFYING THE LUMINAL INTESTINAL ENVIRONMENT. 2021 20 4594 28 NATURAL HISTORY AND LONG-TERM CLINICAL COURSE OF CROHN'S DISEASE. CROHN'S DISEASE IS A CHRONIC INFLAMMATORY DISEASE PROCESS INVOLVING DIFFERENT SITES IN THE GASTROINTESTINAL TRACT. OCCASIONALLY, SO-CALLED METASTATIC DISEASE OCCURS IN EXTRA-INTESTINAL SITES. GRANULOMATOUS INFLAMMATION MAY BE DETECTED IN ENDOSCOPIC BIOPSIES OR RESECTED TISSUES. GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS APPEAR TO PLAY A ROLE. MULTIPLE SUSCEPTIBILITY GENES HAVE BEEN DESCRIBED IN BOTH FAMILIAL AND NON-FAMILIAL FORMS WHILE THE DISEASE IS PHENOTYPICALLY HETEROGENEOUS WITH A FEMALE PREDOMINANCE. THE DISORDER OCCURS OVER A BROAD AGE SPECTRUM, FROM EARLY CHILDHOOD TO LATE ADULTHOOD. MORE THAN 80% ARE DIAGNOSED BEFORE AGE 40 YEARS USUALLY WITH TERMINAL ILEAL AND COLONIC INVOLVEMENT. PEDIATRIC-ONSET DISEASE IS MORE SEVERE AND MORE EXTENSIVE, USUALLY WITH A HIGHER CHANCE OF UPPER GASTROINTESTINAL TRACT DISEASE, COMPARED TO ADULT-ONSET DISEASE. LONG-TERM STUDIES HAVE SHOWN THAT THE DISORDER MAY EVOLVE WITH TIME INTO MORE COMPLEX DISEASE WITH STRICTURE FORMATION AND PENETRATING DISEASE COMPLICATIONS (I.E., FISTULA, ABSCESS). ALTHOUGH PROLONGED REMISSION MAY OCCUR, DISCRETE PERIODS OF SYMPTOMATIC DISEASE MAY RE-APPEAR OVER MANY DECADES SUGGESTING RECURRENCE OR RE-ACTIVATION OF THIS INFLAMMATORY PROCESS. EVENTUAL DEVELOPMENT OF A CURE WILL LIKELY DEPEND ON IDENTIFICATION OF AN ETIOLOGIC CAUSE AND A FUNDAMENTAL UNDERSTANDING OF ITS PATHOGENESIS. UNTIL NOW, TREATMENT HAS FOCUSED ON REMOVING RISK FACTORS, PARTICULARLY CIGARETTE SMOKING, AND IMPROVING SYMPTOMS. IN CLINICAL TRIALS, CLINICAL REMISSION IS LARGELY DEFINED AS IMPROVED NUMERICAL AND ENDOSCOPIC INDICES FOR "MUCOSAL HEALING". "DEEP REMISSION" IS A CONCEPTUAL, MORE "EXTENDED" GOAL THAT MAY OR MAY NOT ALTER THE LONG-TERM NATURAL HISTORY OF THE DISEASE IN SELECTED PATIENTS, ALBEIT AT A SIGNIFICANT RISK FOR TREATMENT COMPLICATIONS, INCLUDING SERIOUS AND UNUSUAL OPPORTUNISTIC INFECTIONS. 2014