1   780 181 CELL-FREE DNA PROMOTER HYPERMETHYLATION IN PLASMA AS A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA. BACKGROUND: PANCREATIC CANCER HAS A 5-YEAR SURVIVAL RATE OF ONLY 5-7%. DIFFICULTIES IN DETECTING PANCREATIC CANCER AT EARLY STAGES RESULTS IN THE HIGH MORTALITY AND SUBSTANTIATES THE NEED FOR ADDITIONAL DIAGNOSTIC TOOLS. SURGERY IS THE ONLY CURATIVE TREATMENT AND UNFORTUNATELY ONLY POSSIBLE IN LOCALIZED TUMOURS. A DIAGNOSTIC BIOMARKER FOR PANCREATIC CANCER WILL HAVE A MAJOR IMPACT ON PATIENT SURVIVAL BY FACILITATING EARLY DETECTION AND THE POSSIBILITY FOR CURATIVE TREATMENT. DNA PROMOTER HYPERMETHYLATION IS A MECHANISM OF EARLY CARCINOGENESIS, WHICH CAN CAUSE INACTIVATION OF TUMOUR SUPPRESSOR GENES. THE AIM OF THIS STUDY WAS TO EXAMINE PROMOTER HYPERMETHYLATION IN A PANEL OF SELECTED GENES FROM CELL-FREE DNA, AS A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA. METHODS: PATIENTS WITH SUSPECTED OR BIOPSY-VERIFIED PANCREATIC CANCER WERE INCLUDED PROSPECTIVELY AND CONSECUTIVELY. PATIENTS WITH CHRONIC/ACUTE PANCREATITIS WERE INCLUDED AS ADDITIONAL BENIGN CONTROL GROUPS. BASED ON AN OPTIMIZED ACCELERATED BISULFITE TREATMENT PROTOCOL, METHYLATION-SPECIFIC PCR OF A 28 GENE PANEL WAS PERFORMED ON PLASMA SAMPLES. A DIAGNOSTIC PREDICTION MODEL WAS DEVELOPED BY MULTIVARIABLE LOGISTIC REGRESSION ANALYSIS USING BACKWARD STEPWISE ELIMINATION. RESULTS: PATIENTS WITH PANCREATIC ADENOCARCINOMA (N = 95), CHRONIC PANCREATITIS (N = 97) AND ACUTE PANCREATITIS (N = 59) AND PATIENTS SCREENED, BUT NEGATIVE FOR PANCREATIC ADENOCARCINOMA (N = 27), WERE INCLUDED. THE DIFFERENCE IN MEAN NUMBER OF METHYLATED GENES IN THE CANCER GROUP (8.41 (95% CI 7.62-9.20)) VS THE TOTAL CONTROL GROUP (4.74 (95% CI 4.40-5.08)) WAS HIGHLY SIGNIFICANT (P < 0.001). A DIAGNOSTIC PREDICTION MODEL (AGE >65, BMP3, RASSF1A, BNC1, MESTV2, TFPI2, APC, SFRP1 AND SFRP2) HAD AN AREA UNDER THE CURVE OF 0.86 (SENSITIVITY 76%, SPECIFICITY 83%). THE MODEL PERFORMANCE WAS INDEPENDENT OF CANCER STAGE. CONCLUSIONS: CELL-FREE DNA PROMOTER HYPERMETHYLATION HAS THE POTENTIAL TO BE A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA AND DIFFERENTIATE BETWEEN MALIGNANT AND BENIGN PANCREATIC DISEASE. THIS STUDY BRINGS US CLOSER TO A CLINICAL USEFUL DIAGNOSTIC MARKER FOR PANCREATIC CANCER, WHICH IS URGENTLY NEEDED. EXTERNAL VALIDATION IS, HOWEVER, REQUIRED BEFORE THE TEST CAN BE APPLIED IN THE CLINIC. TRIAL REGISTRATION: CLINICALTRIALS.GOV, NCT02079363.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  6112  46 THE EPIGENETIC CLOCK AS A PREDICTOR OF DISEASE AND MORTALITY RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: AGEING IS ONE OF THE PRINCIPAL RISK FACTORS FOR MANY CHRONIC DISEASES. HOWEVER, THERE IS CONSIDERABLE BETWEEN-PERSON VARIATION IN THE RATE OF AGEING AND INDIVIDUAL DIFFERENCES IN THEIR SUSCEPTIBILITY TO DISEASE AND DEATH. EPIGENETIC MECHANISMS MAY PLAY A ROLE IN HUMAN AGEING, AND DNA METHYLATION AGE BIOMARKERS MAY BE GOOD PREDICTORS OF AGE-RELATED DISEASES AND MORTALITY RISK. THE AIMS OF THIS SYSTEMATIC REVIEW WERE TO IDENTIFY AND SYNTHESISE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERIPHERALLY MEASURED DNA METHYLATION AGE AND LONGEVITY, AGE-RELATED DISEASE, AND MORTALITY RISK. METHODS: A SYSTEMATIC SEARCH WAS CONDUCTED IN LINE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. USING RELEVANT SEARCH TERMS, MEDLINE, EMBASE, COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS, AND PSYCHINFO DATABASES WERE SEARCHED TO IDENTIFY ARTICLES MEETING THE INCLUSION CRITERIA. STUDIES WERE ASSESSED FOR BIAS USING JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLISTS. DATA WAS EXTRACTED FROM STUDIES MEASURING AGE ACCELERATION AS A PREDICTOR OF AGE-RELATED DISEASES, MORTALITY OR LONGEVITY, AND THE FINDINGS FOR SIMILAR OUTCOMES COMPARED. USING REVIEW MANAGER 5.3 SOFTWARE, TWO META-ANALYSES (ONE PER EPIGENETIC CLOCK) WERE CONDUCTED ON STUDIES MEASURING ALL-CAUSE MORTALITY. RESULTS: TWENTY-THREE RELEVANT ARTICLES WERE IDENTIFIED, INCLUDING A TOTAL OF 41,607 PARTICIPANTS. FOUR STUDIES FOCUSED ON AGEING AND LONGEVITY, 11 ON AGE-RELATED DISEASE (CANCER, CARDIOVASCULAR DISEASE, AND DEMENTIA), AND 11 ON MORTALITY. THERE WAS SOME, ALTHOUGH INCONSISTENT, EVIDENCE FOR AN ASSOCIATION BETWEEN INCREASED DNA METHYLATION AGE AND RISK OF DISEASE. META-ANALYSES INDICATED THAT EACH 5-YEAR INCREASE IN DNA METHYLATION AGE WAS ASSOCIATED AN 8 TO 15% INCREASED RISK OF MORTALITY. CONCLUSION: DUE TO THE SMALL NUMBER OF STUDIES AND HETEROGENEITY IN STUDY DESIGN AND OUTCOMES, THE ASSOCIATION BETWEEN DNA METHYLATION AGE AND AGE-RELATED DISEASE AND LONGEVITY IS INCONCLUSIVE. INCREASED EPIGENETIC AGE WAS ASSOCIATED WITH MORTALITY RISK, BUT POSITIVE PUBLICATION BIAS NEEDS TO BE CONSIDERED. FURTHER RESEARCH IS NEEDED TO DETERMINE THE EXTENT TO WHICH DNA METHYLATION AGE CAN BE USED AS A CLINICAL BIOMARKER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  1785  33 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  6043  41 THE COMBINED PROGNOSTIC SIGNIFICANCE OF ALKALINE PHOSPHATASE AND INTRACRANIAL ARTERIAL CALCIFICATIONS IN HEMODIALYSIS PATIENTS. INTRODUCTION: THE PREVALENCE OF INTRACRANIAL ARTERIAL CALCIFICATION (ICAC) IN MAINTENANCE HEMODIALYSIS (MHD) PATIENTS IS ABOUT 90%, AND ITS SEVERITY IS CORRELATED WITH AGE, HEMODIALYSIS VINTAGE, AND MINERAL BONE DISEASE. ELEVATED CONCENTRATIONS OF CALCIUM AND PHOSPHORUS ARE NOT SUFFICIENT FOR MEDIAL CALCIFICATION BECAUSE OF INHIBITION BY PYROPHOSPHATE. ALKALINE PHOSPHATASE (ALP) PROMOTES CALCIFICATION BY HYDROLYZING EXTRACELLULAR PYROPHOSPHATE. EPIGENETIC MECHANISMS INVOLVING ALP INHIBITION BY APABETALONE WERE INVESTIGATED AS A POTENTIAL TARGET FOR PREVENTING VASCULAR CALCIFICATIONS (VCS). THIS STUDY ASSESSED THE COMBINED IMPACT OF VCS AND ELEVATED SERUM ALP ON MORTALITY AMONG CHRONIC HD PATIENTS. METHODS: VCS REPRESENTED BY ICAC WERE MEASURED SIMULTANEOUSLY WITH MINERAL BONE DISEASE PARAMETERS INCLUDING SERUM ALP OF MHD PATIENTS WHO UNDERWENT NONCONTRAST BRAIN COMPUTED TOMOGRAPHY FROM 2015 TO 2018 IN OUR INSTITUTION. RESULTS: THIS RETROSPECTIVE STUDY INCLUDED 150 MHD PATIENTS (MEAN AGE 71.3 +/- 12.1 YEARS, 60.1% MALE). OF THE TOTAL COHORT, 12 (7.8%) HAD NO BRAIN CALCIFICATIONS AND 69 (45.1%) HAD MULTIPLE INTRACRANIAL CALCIFICATIONS. CONSIDERING THE PATIENTS WITH NORMAL ALP AND NO CALCIFICATION AS THE REFERENCE GROUP YIELDED ADJUSTED ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 4.6 (95% CI: 1.7-12.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND NORMAL ALP (P = 0.003) AND ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 6.1 (95% CI: 2.1-17.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND ELEVATED ALP (P= 0.001). CONCLUSION: WE FOUND AN INDEPENDENT ASSOCIATION BETWEEN ICAC AND THE RISK OF DEATH AMONG MHD PATIENTS. THE COMBINED EFFECT OF ICAC AND ELEVATED ALP WAS ASSOCIATED WITH A HIGHER ODDS RATIO FOR ALL-CAUSE MORTALITY IN MHD PATIENTS AND MAY CONTRIBUTE TO THE RISK STRATIFICATION OF THESE PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  2960  44 GENETIC AND EPIGENETIC MARKERS IN THE EVALUATION OF PANCREATIC MASSES. BACKGROUND: METHYLATION MARKERS HAVE SHOWN PROMISE IN THE EARLY DIAGNOSIS OF PANCREATIC CARCINOMA. THE AIM OF THIS STUDY WAS TO ASSESS THE DIAGNOSTIC UTILITY OF HYPERMETHYLATION STATUS OF CANDIDATE GENES IN COMBINATION WITH KRAS MUTATION DETECTION IN THE EVALUATION OF PANCREATIC MASSES. EXPERIMENTAL DESIGN: SIXTY-ONE FINE NEEDLE ASPIRATES OF PANCREATIC MASSES (43 PANCREATIC ADENOCARCINOMAS AND 18 CHRONIC PANCREATITIS) WERE STUDIED. METHYLATION STATUS OF HRH2, EN1, SPARC, CDH13 AND APC WERE ANALYSED USING MELTING CURVE ANALYSIS AFTER DNA BISULFITE TREATMENT. KRAS MUTATIONS WERE ALSO ANALYSED. RESULTS: THE METHYLATION PANEL HAD A SENSITIVITY OF 73% (27 OF 37, CI 95% 56 TO 86%) AND A SPECIFICITY OF 100% WHENEVER TWO OR MORE PROMOTERS WERE FOUND HYPERMETHYLATED. KRAS MUTATIONS SHOWED A SENSITIVITY OF 77% (33 OF 43, CI 95% 62 TO 88%) AND A SPECIFICITY OF 100%. BOTH MOLECULAR ANALYSES ADDED USEFUL INFORMATION TO CYTOLOGY BY INCREASING THE NUMBER OF INFORMATIVE CASES. WHEN GENETIC AND EPIGENETIC ANALYSES WERE COMBINED SENSITIVITY WAS 84% (36 OF 43 CI 95% 69 TO 93%) MAINTAINING A 100% SPECIFICITY. CONCLUSIONS: ANALYSIS OF HYPERMETHYLATION STATUS OF A PANEL OF GENES AND KRAS MUTATION DETECTION OFFER A SIMILAR DIAGNOSTIC YIELD IN THE EVALUATION OF PANCREATIC MASSES. THE COMBINED MOLECULAR ANALYSIS INCREASES THE NUMBER OF INFORMATIVE CASES WITHOUT DIMINISHING SPECIFICITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  1431  40 DIFFERENTIAL FREQUENCIES OF P16(INK4A) PROMOTER HYPERMETHYLATION, P53 MUTATION, AND K-RAS MUTATION IN EXFOLIATIVE MATERIAL MARK THE DEVELOPMENT OF LUNG CANCER IN SYMPTOMATIC CHRONIC SMOKERS. PURPOSE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE FREQUENCY OF THREE (EPI)GENETIC ALTERATIONS (P53 AND K-RAS MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION) IN SYMPTOMATIC CHRONIC SMOKERS COMPARED WITH PATIENTS WITH LUNG CANCER AND TO EVALUATE THE USE OF EXFOLIATIVE MATERIAL FOR SUCH ANALYSES. PATIENTS AND METHODS: FIFTY-ONE PATIENTS WITH HISTOLOGICALLY CONFIRMED LUNG CANCER AND 25 CHRONIC SMOKERS (> 20 PACK-YEARS) WERE INVESTIGATED FOR MUTATIONS IN THE K-RAS (CODON 12) AND P53 (CODONS 248, 249, AND 273) GENES AND FOR ALLELIC HYPERMETHYLATION OF THE P16(INK4A) GENE. DNA WAS ISOLATED FROM SPUTUM AND BILATERAL BRONCHIAL LAVAGE, AND BRUSHINGS WERE TAKEN AT BRONCHOSCOPY. RESULTS: FORTY-ONE GENETIC LESIONS WERE DETECTED WITHIN EXFOLIATIVE MATERIAL FROM THE GROUP OF 51 PATIENTS WITH LUNG CANCER AND 10 LESIONS IN THE CHRONIC SMOKER GROUP. K-RAS MUTATIONS OCCURRED EXCLUSIVELY IN THE LUNG CANCER GROUP, WHEREAS P53 MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION WERE ALSO FOUND IN CHRONIC SMOKERS. THREE OF EIGHT CHRONIC SMOKERS WHO HARBORED AN (EPI)GENETIC ALTERATION WERE SUBSEQUENTLY DIAGNOSED WITH LUNG CANCER. ANALYSIS OF SPUTUM YIELDED INFORMATION EQUIVALENT TO THAT OF SAMPLES OBTAINED DURING BRONCHOSCOPY. CONCLUSION: P16(INK4A) PROMOTER HYPERMETHYLATION AND P53 MUTATIONS CAN OCCUR IN CHRONIC SMOKERS BEFORE ANY CLINICAL EVIDENCE OF NEOPLASIA AND MAY BE INDICATIVE OF AN INCREASED RISK OF DEVELOPING LUNG CANCER OR OF EARLY DISEASE. K-RAS MUTATIONS OCCUR EXCLUSIVELY IN THE PRESENCE OF CLINICALLY DETECTABLE NEOPLASTIC TRANSFORMATION. MOLECULAR ANALYSIS OF SPUTUM FOR SUCH MARKERS MAY PROVIDE AN EFFECTIVE MEANS OF SCREENING CHRONIC SMOKERS TO ENABLE EARLIER DETECTION AND THERAPEUTIC INTERVENTION OF LUNG CANCER.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7   779  69 CELL-FREE DNA PROMOTER HYPERMETHYLATION AS A DIAGNOSTIC MARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA - AN EXTERNAL VALIDATION STUDY. BACKGROUND: WE RECENTLY IDENTIFIED A DIAGNOSTIC PREDICTION MODEL BASED ON PROMOTER HYPERMETHYLATION OF EIGHT SELECTED GENES IN PLASMA CELL-FREE (CF) DNA, WHICH SHOWED PROMISING RESULTS AS A DIAGNOSTIC BIOMARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDAC). THE AIM OF THE PRESENT STUDY WAS TO VALIDATE THIS BIOMARKER PROFILE IN AN EXTERNAL PATIENT COHORT AND EXAMINE ANY ADDITIONAL EFFECT OF SERUM CA 19-9. METHODS: PATIENTS WITH PDAC (N = 346, STAGE I-IV) AND CHRONIC PANCREATITIS (N = 25) WERE INCLUDED. METHYLATION-SPECIFIC PCR OF A 28-GENE PANEL WAS PERFORMED ON SERUM CFDNA SAMPLES. THE PREVIOUSLY DEVELOPED DIAGNOSTIC PREDICTION MODEL (AGE>65 YEARS, BMP3, RASSF1A, BNC1, MESTV2, TFPI2, APC, SFRP1 AND SFRP2) WAS VALIDATED ALONE AND IN COMBINATION WITH SERUM CA 19-9 IN THIS EXTERNAL PATIENT COHORT. RESULTS: PATIENTS WITH PDAC HAD A HIGHER NUMBER OF HYPERMETHYLATED GENES (MEAN 8.11, 95% CI 7.70-8.52) THAN PATIENTS WITH CHRONIC PANCREATITIS (MEAN 5.60, 95% CI 4.42-6.78, P = 0.011). VALIDATION OF THE DIAGNOSTIC PREDICTION MODEL YIELDED AN AUC OF 0.77 (95% CI 0.69-0.84). THE COMBINATION OF SERUM CA 19-9 AND OUR TEST HAD AN AUC OF 0.93 (95% CI 0.89-0.96) IN THE PRIMARY STUDY AND 0.85 (95% CI 0.79-0.91) IN THE VALIDATION STUDY. CONCLUSION: IN THIS VALIDATION STUDY, PDAC WAS ASSOCIATED WITH A HIGHER NUMBER OF HYPERMETHYLATED GENES IN SERUM CFDNA THAN CHRONIC PANCREATITIS. OUR DIAGNOSTIC TEST WAS SUPERIOR TO THE PREDICTIVE VALUE OF SERUM CA 19-9 ALONE IN BOTH THE PRIMARY AND THE VALIDATION STUDY. THE COMBINATION OF OUR TEST WITH CA 19-9 MAY SERVE AS A CLINICALLY USEFUL DIAGNOSTIC BIOMARKER FOR PDAC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  5218  32 PREVENTION OF HEPATOCELLULAR CARCINOMA. PREVENTION IS THE ONLY REALISTIC APPROACH FOR REDUCING MORTALITY RATES ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. VACCINATION AGAINST HEPATITIS B AND SCREENING OF BLOOD DONATIONS ARE EFFECTIVE MEASURES OF PRIMARY PREVENTION. SCREENING OF BLOOD DONATIONS HAS LED TO A SUBSTANTIAL REDUCTION IN VIRAL HEPATITIS TRANSMISSION AMONG THE GENERAL POPULATION, AND IN TAIWAN VACCINATION AGAINST HEPATITIS B CAUSED A SIGNIFICANT REDUCTION IN HCC INCIDENCE AMONG INFANTS. PRIMARY PREVENTION ALSO INCLUDES APPROACHES THAT ALTER EPIGENETIC AND GENETIC CHANGES IN HEPATOCYTES, KNOWN TO INCREASE SUSCEPTIBILITY TO HCC, AS WELL AS TREATMENTS SLOWING PROGRESSION TO CIRRHOSIS. THE ONLY EVIDENCE THAT CHEMOPREVENTION REDUCES HCC RISK IS A MULTICENTER RANDOMIZED PROSPECTIVE STUDY IN ASIAN PATIENTS WITH ADVANCED HEPATITIS B WHO RECEIVED THE ORAL NUCLEOSIDE ANALOGUE LAMIVUDINE. CIRCUMSTANTIAL EVIDENCE SUGGESTS THAT HCC RISK IS ALSO REDUCED IN PATIENTS WITH CHRONIC HEPATITIS C WHO HAVE HAD A SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON THERAPY. HCC IS NOT SUBSTANTIALLY REDUCED IN PATIENTS WITH HEPATITIS B TREATED WITH INTERFERON AND PATIENTS WITH HEPATITIS C WHO DID NOT RESPOND TO INTERFERON. SECONDARY PREVENTION, THAT IS, PREVENTION OF TUMOR RECURRENCE AFTER HEPATIC RESECTION OR LOCAL ABLATIVE THERAPIES, HAS BEEN PURSUED WITH DIFFERENT APPROACHES. RETINOIDS, HEPATIC EMBOLIZATION WITH (131)I LIPIODOL, AND ADOPTIVE ADJUVANT IMMUNOTHERAPY HAVE YIELDED ENCOURAGING RESULTS. OTHER APPROACHES, INCLUDING THOSE BASED ON INTERFERON ALFA OR BETA, PROVIDED INCONCLUSIVE EVIDENCE FOR SECONDARY PROPHYLAXIS OF HCC, MAINLY BECAUSE OF THE POOR METHODOLOGIES AND SCIENTIFIC BACKGROUND OF THE STUDIES. DIETARY INTERVENTIONS AND ANTIAFLATOXIN AGENTS MIGHT HELP TO PREVENT HCC IN SUSCEPTIBLE INDIVIDUALS, BUT THE REAL EFFICACY OF THESE APPROACHES IS FAR FROM BEING DEMONSTRATED.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  1955  41 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  1151  30 CONNECTIONS AMONG BIOLOGIC EMBEDDING OF CHILDHOOD ADVERSITY, ADULT CHRONIC ILLNESS, AND WOUND CARE: A REVIEW OF THE LITERATURE. ADVERSE CHILDHOOD EXPERIENCES (ACES) BIOLOGICALLY EMBED BY ALTERING BRAIN DEVELOPMENT AND INFLUENCING EPIGENETIC MECHANISMS. THESE EXPERIENCES MAY GENERATE HEALTH RISK FACTORS. PURPOSE: A LITERATURE REVIEW WAS CONDUCTED TO COMPARE ACE-GENERATED HEALTH RISK FACTORS WITH RISK FACTORS FOR WOUND DEVELOPMENT AND ABERRANT HEALING, AS WELL AS TO IDENTIFY A GAP IN LITERATURE REGARDING CRITICAL CONNECTIONS BETWEEN ACES, CHRONIC ILLNESS, AND WOUND DEVELOPMENT/HEALING, WITH ASSOCIATED PRACTICE IMPLICATIONS. METHODOLOGY: A LITERATURE SEARCH OF ENGLISH-LANGUAGE ARTICLES WAS CONDUCTED USING THE CUMULATIVE INDEX OF NURSING AND ALLIED HEALTH LITERATURE, MEDLINE, AND PUBMED USING THE SEARCH TERMS ADVERSE CHILDHOOD EXPERIENCES, ADULTS, WOUNDS, CHRONIC DISEASE OR ILLNESS, AND EPIGENETICS. THE SEARCHES YIELDED 561 PUBLICATIONS REGARDING ACES, CHRONIC ILLNESS OR DISEASE, AND ADULT; 182 FOR ACES; AND 547 FOR EPIGENETICS AND WOUNDS. ABSTRACTS WERE REVIEWED TO REMOVE DUPLICATES AND STUDIES WITH PARTICIPANTS WHO WERE <18 YEARS OLD. PUBLICATIONS WERE REVIEWED FOR SALIENCE; THOSE DISCUSSING THE BIOLOGIC PLAUSIBILITY OF ACES CONTRIBUTING TO ADULT ILLNESSES AND ASSOCIATED WOUND DEVELOPMENT AND HEALING WERE REVIEWED FOR INCLUSION. RESULTS: SIXTY-EIGHT (68) PUBLICATIONS WERE FOUND APPROPRIATE FOR REVIEW AND INCLUDED POPULATION-BASED STUDIES; LITERATURE REVIEWS; EPIDEMIOLOGIC DATA; META-ANALYSES; AND SYSTEMATIC, CROSS-SECTIONAL, OBSERVATIONAL, AND PROSPECTIVE STUDIES AS SINGULAR OR MIXED METHODS DESIGNS. A SUBSTANTIAL OVERLAP WAS FOUND IN TERMS OF RISK FACTORS GENERATED BY ACE EXPOSURE AND RISK FACTORS FOR WOUND DEVELOPMENT/HEALING, AS WAS A GAP IN THE LITERATURE REGARDING THIS RELATIONSHIP. EPIGENETIC MECHANISMS AND ALTERED BRAIN DEVELOPMENT ARE IMPLICATED IN PROCESSES THROUGH WHICH CHILDHOOD ADVERSITY ERODES HUMAN HEALTH. CONCLUSION: ADULT HEALTH RISKS AS A RESULT OF EXPOSURE TO ACES AND CRITICAL CONNECTIONS WITH RISKS FOR WOUND DEVELOPMENT AND DISRUPTED WOUND HEALING VIA EPIGENETIC INFLUENCES ARE RECOGNIZED IN THE LITERATURE. PRACTICE IMPLICATIONS INCLUDE CONSIDERING SCREENING FOR THE RISK FACTOR OF ACES EXPOSURE IN ADULT PATIENTS TO IDENTIFY THIS ADDITIONAL RISK FACTOR AND PRACTICING PATIENT-CENTERED, TRAUMA-INFORMED CARE. FURTHER RESEARCH INTO THE INTEGRATIVE ROLES OF THESE FACTORS IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  5522  31 RISK OF OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON AND ARSENIC ON PULMONARY DISORDERS: UNDERSTANDING THE GENETIC-EPIGENETIC INTERPLAY AND FUTURE PROSPECTS. BACKGROUND: EPIDEMIOLOGICAL STUDIES SUGGEST STRONG ASSOCIATION OF LUNG DISORDERS WITH OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON AND ARSENIC. THE CHRONIC OCCUPATIONAL EXPOSURE PRIMARILY THROUGH INHALATION RESULTS IN ADVERSE OUTCOME ON THE RESPIRATORY TRACT WHICH MAY ALSO BE FATAL. ALTHOUGH SEVERAL MECHANISMS HAVE ATTRIBUTED TOWARDS THESE DISEASES; THE MOLECULAR PATHOGENESIS IS STILL UNKNOWN. OBJECTIVE: IN THIS REVIEW, WE INVESTIGATED THE PLAUSIBLE MOLECULAR MECHANISM BASED ON CURRENT RESEARCH THAT MAY IDENTIFY THE GENETIC AND EPIGENETIC SUSCEPTIBILITY OF RESPIRATORY DISORDERS UPON SUCH OCCUPATIONAL EXPOSURES IN HUMANS. METHODS: WE CONSIDERED GENETIC VARIANTS AND EPIGENETIC ALTERATIONS ASSOCIATED WITH PULMONARY EXPOSURE HAZARDS LEADING TO ASBESTOSIS, SILICOSIS AND ARSENICOSIS. OUR REVIEW IS STRINGENTLY BASED ON THE LITERATURES AVAILABLE THROUGH PEER-REVIEWED ARTICLES MOSTLY PUBLISHED IN THE LAST 10 YEARS. RELEVANT SEARCH WERE CONDUCTED USING KEYWORDS LIKE "OCCUPATIONAL LUNG DISORDERS" ALONG WITH "ASBESTOS", "SILICON" AND "ARSENIC". RESULTS: TILL SEPTEMBER 2015, PUBMED SEARCH YIELDED APPROXIMATELY 780 ARTICLES RELATING TO ASBESTOS EXPOSURE; 240 ARTICLES FOR SILICON EXPOSURE AND 60 ARTICLES FOR ARSENIC EXPOSURE. EXTENSIVE SCREENING FOR GENETIC AND EPIGENETIC FACTORS IDENTIFIED CERTAIN GENES AND RELATED PATHWAYS THAT ARE IMPORTANT TO DETERMINE THE SUSCEPTIBILITY OF AN INDIVIDUAL TOWARDS SUCH OCCUPATIONAL EXPOSURE. CONCLUSION: THE LINK BETWEEN GENOTYPE AND PHENOTYPE AND ITS ASSOCIATION WITH DISEASE SUSCEPTIBILITY IS VERY COMPLEX IN NATURE DUE TO SEVERAL FACTORS LIKE PERSON'S ENVIRONMENT, LIFESTYLE AND NUTRITIONAL STATUS. THE EPIGENOME IS DYNAMIC AS WELL AS REVERSIBLE AND CAN BE RESHAPED FURTHER BY CERTAIN DIETARY COMPONENTS THROUGHOUT ITS LIFE. IN THE PRESENT REVIEW, WE HAVE ADDRESSED THE ROLE OF MOLECULAR PATHOGENESIS OF OCCUPATIONAL LUNG DISEASES BASED ON THE GENETIC VARIABILITY AND EPIGENETIC ALTERATIONS AND ALSO ATTEMPTED TO HIGHLIGHT THE PROMISING ASPECT OF DIETARY INTERVENTIONS TO COUNTER TOXIC OUTCOMES UPON OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON OR ARSENIC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  3925  38 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  3560  39 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14   455  36 APPLICATIONS OF YOGA IN ORAL ONCOLOGY: A SYSTEMATIC SCOPING REVIEW. BACKGROUND AND AIMS: YOGA IS WELL-THOUGHT-OUT AS AN ALL-INCLUSIVE APPROACH GLOBALLY AND CAN BE ADMINISTERED IN CLINICAL CARE AS AN INTEGRATIVE OR ALTERNATE APPROACH TO REGULAR TREATMENT. YOGA EXERCISE HAS BEEN DISCLOSED TO INFLUENCE REMISSION FROM CANCER CELLS OVER A LONG PERIOD OF TIME AND ALSO REVERSES EPIGENETIC ALTERATIONS. APPLICATIONS OF YOGA IN THE MANAGEMENT OF ORAL ONCOLOGY PATIENTS ARE SCARCE, HENCE THE NEED FOR A SCOPING REVIEW OF THE LITERATURE. HENCE, THIS STUDY AIMED TO CONDUCT A SCOPING REVIEW OF THE EXISTING EMPIRICAL EVIDENCE ON THE APPLICATIONS OF YOGA IN ORAL ONCOLOGY. METHODS: THE REVIEW METHODOLOGY WAS INFORMED BY JOANNA BRIGG'S INSTITUTE GUIDELINES FOR SYSTEMATIC SCOPING REVIEWS, AND THE REVIEW WAS REPORTED IN ACCORDANCE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES EXTENSION FOR SCOPING REVIEWS. TEN DATABASES WERE SEARCHED. THE RECORDS OF ALL THE LITERATURE RETRIEVED FROM THE SEARCH WERE IMPORTED INTO THE RAYYAN SOFTWARE FOR DEDUPLICATION. AFTER THE FULL-TEXT SCREENING, ONLY TWO WERE FOUND ELIGIBLE FOR INCLUSION IN THE SCOPING REVIEW. DATA OBTAINED IN THE INCLUDED LITERATURE WERE EXTRACTED AND SYNTHESIZED. RESULTS: THIS REVIEW FOUND THAT YOGA WAS NOT SIGNIFICANTLY EFFECTIVE IN THE MANAGEMENT OF STRESS AMONG ORAL CANCER PATIENTS (P-VALUES > 0.04). HOWEVER, IT WAS FOUND THAT YOGA SIGNIFICANTLY REDUCED ANXIETY, SALIVA STICKINESS, AND EPISODES OF FALLING ILL (P-VALUES < 0.05) WHILE IT IMPROVED MENTAL WELL-BEING, COGNITIVE FUNCTIONING, EMOTIONAL FUNCTIONING, AND HEAD AND NECK PAIN OF THOSE ORAL CANCER PATIENTS THAT RECEIVED IT (P-VALUES < 0.05). CONCLUSION: AN INTEGRATIVE CARE APPROACH THAT CONSIDERS NONPHARMACEUTICAL TECHNIQUES SUCH AS YOGA COULD HELP TO REDUCE CARE COST WHILE IMPROVING CARE OUTCOMES AND QUALITY OF LIFE OF ORAL CANCER PATIENTS. HENCE, IT IS IMPERATIVE TO CONSIDER YOGA ALONG WITH ITS POTENTIAL BENEFITS, AND WE RECOMMEND GRADUAL INCORPORATION OF YOGA INTO ORAL CANCER CARE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15  2150  39 EPIGENETIC MEASURES OF AGEING PREDICT THE PREVALENCE AND INCIDENCE OF LEADING CAUSES OF DEATH AND DISEASE BURDEN. BACKGROUND: INDIVIDUALS OF THE SAME CHRONOLOGICAL AGE DISPLAY DIFFERENT RATES OF BIOLOGICAL AGEING. A NUMBER OF MEASURES OF BIOLOGICAL AGE HAVE BEEN PROPOSED WHICH HARNESS AGE-RELATED CHANGES IN DNA METHYLATION PROFILES. THESE MEASURES INCLUDE FIVE 'EPIGENETIC CLOCKS' WHICH PROVIDE AN INDEX OF HOW MUCH AN INDIVIDUAL'S BIOLOGICAL AGE DIFFERS FROM THEIR CHRONOLOGICAL AGE AT THE TIME OF MEASUREMENT. THE FIVE CLOCKS ENCOMPASS METHYLATION-BASED PREDICTORS OF CHRONOLOGICAL AGE (HORVATHAGE, HANNUMAGE), ALL-CAUSE MORTALITY (DNAM PHENOAGE, DNAM GRIMAGE) AND TELOMERE LENGTH (DNAM TELOMERE LENGTH). A SIXTH EPIGENETIC MEASURE OF AGEING DIFFERS FROM THESE CLOCKS IN THAT IT ACTS AS A SPEEDOMETER PROVIDING A SINGLE TIME-POINT MEASUREMENT OF THE PACE OF AN INDIVIDUAL'S BIOLOGICAL AGEING. THIS MEASURE OF AGEING IS TERMED DUNEDINPOAM. IN THIS STUDY, WE TEST THE ASSOCIATION BETWEEN THESE SIX EPIGENETIC MEASURES OF AGEING AND THE PREVALENCE AND INCIDENCE OF THE LEADING CAUSES OF DISEASE BURDEN AND MORTALITY IN HIGH-INCOME COUNTRIES (N </= 9537, GENERATION SCOTLAND: SCOTTISH FAMILY HEALTH STUDY). RESULTS: DNAM GRIMAGE PREDICTED INCIDENCE OF CLINICALLY DIAGNOSED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), TYPE 2 DIABETES AND ISCHEMIC HEART DISEASE AFTER 13 YEARS OF FOLLOW-UP (HAZARD RATIOS = 2.22, 1.52 AND 1.41, RESPECTIVELY). DUNEDINPOAM PREDICTED THE INCIDENCE OF COPD AND LUNG CANCER (HAZARD RATIOS = 2.02 AND 1.45, RESPECTIVELY). DNAM PHENOAGE PREDICTED INCIDENCE OF TYPE 2 DIABETES (HAZARD RATIO = 1.54). DNAM TELOMERE LENGTH ASSOCIATED WITH THE INCIDENCE OF ISCHEMIC HEART DISEASE (HAZARD RATIO = 0.80). DNAM GRIMAGE ASSOCIATED WITH ALL-CAUSE MORTALITY, THE PREVALENCE OF COPD AND SPIROMETRY MEASURES AT THE STUDY BASELINE. THESE ASSOCIATIONS WERE PRESENT AFTER ADJUSTING FOR POSSIBLE CONFOUNDING RISK FACTORS INCLUDING ALCOHOL CONSUMPTION, BODY MASS INDEX, DEPRIVATION, EDUCATION AND TOBACCO SMOKING AND SURPASSED STRINGENT BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLDS. CONCLUSIONS: OUR DATA SUGGEST THAT EPIGENETIC MEASURES OF AGEING MAY HAVE UTILITY IN CLINICAL SETTINGS TO COMPLEMENT GOLD-STANDARD METHODS FOR DISEASE ASSESSMENT AND MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   667  46 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	

17  1797  42 EFFECT OF HELICOBACTER PYLORI ERADICATION ON GASTRIC PRECANCEROUS LESIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: THE QUESTION OF WHETHER ERADICATION OF HELICOBACTER PYLORI (HP) CAN REVERSE GASTRIC PRECANCEROUS LESIONS, INCLUDING INTESTINAL METAPLASIA, REMAINS UNCERTAIN, LEADING TO ONGOING DEBATE. THEREFORE, A META-ANALYSIS WAS PERFORMED TO EVALUATE THE EFFECT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. MATERIALS AND METHODS: PUBMED, EMBASE, COCHRANE LIBRARY, WEB OF SCIENCE, SCOPUS DATABASE, AND CLINICALTRIALS.GOV WERE SYSTEMATICALLY SEARCHED FROM INCEPTION TO APRIL 2023 FOR STUDIES THAT EXPLORED THE IMPACT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. RISK RATIOS (RRS) AND THEIR 95% CONFIDENCE INTERVALS (95% CIS) WERE SELECTED AS THE EFFECT SIZE. WE USED THE RANDOM-EFFECTS MODEL TO ASSESS POOLED DATA. WE ALSO PERFORMED QUALITY ASSESSMENTS, SUBGROUP ANALYSES, AND SENSITIVITY ANALYSES. RESULTS: FIFTEEN STUDIES WERE INCLUDED. COMPARED WITH PLACEBO, HP ERADICATION COULD SIGNIFICANTLY PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS (RR = 0.87, 95% CI: 0.81-0.94, P < 0.01) AND REVERSE THEM (RR = 1.32, 95% CI: 1.17-1.50, P < 0.01). THEN, SPECIFIC PRECANCEROUS LESIONS WERE FURTHER EXPLORED. THE PROGRESSION OF INTESTINAL METAPLASIA WAS SIGNIFICANTLY PREVENTED BY HP ERADICATION COMPARED TO PLACEBO OR NO TREATMENT (RR = 0.80, 95% CI: 0.69-0.94, P < 0.01). MOREOVER, COMPARED WITH PLACEBO OR NO TREATMENT, HP ERADICATION ALSO IMPROVED CHRONIC ATROPHIC GASTRITIS (RR = 1.84, 95% CI: 1.30-2.61, P < 0.01) AND INTESTINAL METAPLASIA (RR = 1.41, 95% CI: 1.15-1.73, P < 0.01). HOWEVER, IN TERMS OF PREVENTING DYSPLASIA PROGRESSION (RR = 0.86, 95% CI: 0.37-2.00) AND IMPROVING DYSPLASIA (RR = 0.89, 95% CI: 0.47-1.70), HP ERADICATION HAD NO ADVANTAGE COMPARED TO PLACEBO OR NO TREATMENT. CONCLUSIONS: HP ERADICATION THERAPY COULD PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS AND REVERSE THEM. NOTABLY, INTESTINAL METAPLASIA CAN BE REVERSED, BUT THIS MAY ONLY BE APPROPRIATE FOR PATIENTS WITH EPIGENETIC ALTERATIONS AND MILDER LESIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  2044  35 EPIGENETIC CLOCK ANALYSIS OF BLOOD SAMPLES IN DRUG-NAIVE FIRST-EPISODE SCHIZOPHRENIA PATIENTS. BACKGROUND: SCHIZOPHRENIA (SCZ) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH PREMATURE AGE-RELATED PHYSIOLOGICAL CHANGES. HOWEVER, NUMEROUS PREVIOUS STUDIES EXAMINED THE EPIGENETIC AGE ACCELERATION IN SCZ PATIENTS AND YIELDED INCONCLUSIVE RESULTS. IN THIS STUDY, WE PROPOSE TO EXPLORE THE EPIGENETIC AGE ACCELERATION IN DRUG-NAIVE FIRST-EPISODE SCZ (FSCZ) PATIENTS AND INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT, PSYCHOTIC SYMPTOMS, COGNITION, AND SUBCORTICAL VOLUMES. METHODS: WE ASSESSED THE EPIGENETIC AGE IN 38 DRUG-NAIVE FSCZ PATIENTS AND 38 HEALTHY CONTROLS BY USING THREE INDEPENDENT CLOCKS, INCLUDING HORVATH, HANNUM AND LEVINE ALGORITHMS. THE EPIGENETIC AGE MEASUREMENTS IN SCZ PATIENTS WERE REPEATED AFTER RECEIVING 8 WEEKS RISPERIDONE MONOTHERAPY. RESULTS: OUR FINDINGS SHOWED SIGNIFICANTLY POSITIVE CORRELATIONS BETWEEN EPIGENETIC AGES ASSESSED BY THREE CLOCKS AND CHRONOLOGICAL AGE IN BOTH FSCZ PATIENTS AND HEALTHY CONTROLS. COMPARED WITH HEALTHY CONTROLS, DRUG-NAIVE FSCZ PATIENTS HAVE A SIGNIFICANT EPIGENETIC AGE DECELERATION IN HORVATH CLOCK (P = 0.01), BUT NOT IN HANNUM CLOCK (P = 0.07) AND LEVINE CLOCK (P = 0.43). THE EPIGENETIC AGES OF HANNUM CLOCK (P = 0.002) AND LEVINE CLOCK (P = 0.01) WERE SIGNIFICANTLY ACCELERATED IN SCZ PATIENTS AFTER 8-WEEK RISPERIDONE TREATMENT. HOWEVER, NO SIGNIFICANT ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION AND PSYCHOTIC SYMPTOMS, COGNITIVE FUNCTION, AS WELL AS SUBCORTICAL VOLUMES WERE OBSERVED IN FSCZ PATIENTS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  1956  48 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  3873  37 K-RAS AND P16(INK4A)ALTERATIONS IN SPUTUM OF NSCLC PATIENTS AND IN HEAVY ASYMPTOMATIC CHRONIC SMOKERS. NSCLC RATES AMONG THE MOST FREQUENT AND LETHAL NEOPLASM WORLD-WIDE AND A SIGNIFICANT DECREASE IN MORBIDITY AND MORTALITY RELIES ONLY UPON EFFECTIVE EARLY DIAGNOSTIC STRATEGIES. WE INVESTIGATED K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION IN TUMOR TISSUE AND SPUTUM OF 50 PATIENTS WITH NSCLC AND CORRELATED THEM WITH SPUTUM CYTOLOGY AND WITH TUMOR STAGING, GRADING AND LOCATION, TO ASCERTAIN, IN SPUTUM, THEIR POTENTIAL DIAGNOSTIC IMPACT. THE SAME GENETIC/EPIGENETIC ABNORMALITIES AND CYTOLOGICAL FEATURES WERE ALSO EVALUATED IN SPUTUM FROM 100 CHRONIC HEAVY SMOKERS. GENETIC ANALYSIS IDENTIFIED MOLECULAR ABNORMALITIES IN 64% TUMORS (14/50 K-RAS MUTATIONS AND 24/50 P16(INK4A) HYPERMETHYLATION) AND IN 48% SPUTUM (11/50 K-RAS MUTATIONS AND 16/50 P16(INK4A) HYPERMETHYLATION). IN TUMORS K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION WERE MOSTLY MUTUALLY EXCLUSIVE, BEING FOUND IN THE SAME PATIENTS IN 3 CASES ONLY. GENETIC ABNORMALITIES IN SPUTUM WERE DETECTED ONLY IN MOLECULAR ABNORMAL TUMORS. MOLECULAR CHANGES IN SPUTUM HAD RATES OF DETECTION SIMILAR TO CYTOLOGY (42%) BUT THE CYTO-MOLECULAR COMBINATION INCREASED THE DIAGNOSTIC YIELD UP TO 60%. INTERESTINGLY, THE RATE OF DETECTION OF GENETIC CHANGES IN SPUTUM OF TUMORS AT EARLY STAGE (T1) WAS NOT SIGNIFICANTLY DIFFERENT FROM THAT OF TUMORS AT MORE ADVANCED STAGE (T2-T4). IN FACT K-RAS POINT MUTATIONS WERE FREQUENTLY RECOGNISED IN TUMORS AT EARLY STAGE WHILE P16(INK4A) INACTIVATION PREVAILED IN TUMORS AT ADVANCED STAGE ( P=0.0063). AS EXPECTED, DIAGNOSTIC CYTOLOGICAL FINDINGS WERE MORE FREQUENTLY FOUND IN TUMORS AT ADVANCED STAGE (P=0.004). NO CORRELATION WAS FOUND BETWEEN TUMOR GRADING AND LOCATION (CENTRAL VERSUS PERIPHERAL) AND MOLECULAR CHANGES. P16(INK4A) HYPERMETHYLATION, BUT NOT K-RAS MUTATIONS, WAS DOCUMENTED IN SPORADIC CASES OF ASYMPTOMATIC HEAVY SMOKERS (4%) WHERE IT WAS UNCOUPLED FROM CYTOLOGICAL ABNORMALITIES. IN CONCLUSION THE CYTO-MOLECULAR DIAGNOSTIC STRATEGY ADOPTED IN THIS STUDY WAS ABLE TO DETECT THE MAJORITY OF TUMORS BUT IN ORDER TO BE PROPOSED AS EFFECTIVE AND EARLY DIAGNOSTIC TOOL, THIS MOLECULAR PANEL NEEDS TO BE TESTED IN PROSPECTIVE STUDIES WITH ADEQUATE FOLLOW-UP.	2004