1 960 168 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 2 962 75 CHRONIC MYELOMONOCYTIC LEUKEMIA: FOCUS ON CLINICAL PRACTICE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER WITH FEATURES THAT OVERLAP THOSE OF MYELODYSPLASTIC SYNDROMES (MDSS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CHRONIC MYELOMONOCYTIC LEUKEMIA OFTEN RESULTS IN PERIPHERAL BLOOD MONOCYTOSIS AND HAS AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CLONAL CYTOGENETIC CHANGES ARE SEEN IN APPROXIMATELY 30% OF PATIENTS, AND MOLECULAR ABNORMALITIES ARE SEEN IN MORE THAN 90%. GENE MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT, WITH NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS BEING THE ONLY MUTATIONS IDENTIFIED THUS FAR TO HAVE AN INDEPENDENT NEGATIVE PROGNOSTIC EFFECT ON OVERALL SURVIVAL. CONTEMPORARY MOLECULARLY INTEGRATED PROGNOSTIC MODELS (INCLUSIVE OF ASXL1 MUTATIONS) INCLUDE THE MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. GIVEN THE LACK OF FORMAL TREATMENT AND RESPONSE CRITERIA, MANAGEMENT OF CMML IS OFTEN EXTRAPOLATED FROM MDS AND MPN, WITH ALLOGENEIC STEM CELL TRANSPLANT BEING THE ONLY CURATIVE OPTION. HYDROXYUREA AND OTHER CYTOREDUCTIVE AGENTS HAVE BEEN USED TO CONTROL MPN-LIKE FEATURES, WHILE EPIGENETIC MODIFIERS SUCH AS HYPOMETHYLATING AGENTS HAVE BEEN USED FOR MDS-LIKE FEATURES. GIVEN THE RELATIVELY POOR RESPONSE TO THESE AGENTS AND THE INHERENT RISKS ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT, NEWER DRUGS EXPLOITING MOLECULAR AND EPIGENETIC ABNORMALITIES IN CMML ARE BEING DEVELOPED. THE CREATION OF CMML-SPECIFIC RESPONSE CRITERIA IS A MUCH NEEDED STEP IN ORDER TO IMPROVE CLINICAL OUTCOMES. 2016 3 6633 23 UNHEALTHY SMOKERS: SCOPES FOR PROPHYLACTIC INTERVENTION AND CLINICAL TREATMENT. BACKGROUND: GLOBALLY, TOBACCO USE CAUSES APPROXIMATELY 6 MILLION DEATHS PER YEAR, AND PREDICTIONS REPORT THAT WITH CURRENT TRENDS; MORE THAN 8 MILLION DEATHS ARE EXPECTED ANNUALLY BY 2030. CIGARETTE SMOKINGS IS CURRENTLY ACCOUNTABLE FOR MORE THAN 480,000 DEATHS EACH YEAR IN UNITED STATES (US) AND IS THE LEADING CAUSE OF PREVENTABLE DEATH IN THE US. ON AVERAGE, SMOKERS DIE 10 YEARS EARLIER THAN NONSMOKERS AND IF SMOKING CONTINUES AT ITS CURRENT PROPORTION AMONG ADOLESCENTS, ONE IN EVERY 13 AMERICANS AGED 17 YEARS OR YOUNGER IS EXPECTED TO DIE PREMATURELY FROM A SMOKING-RELATED ILLNESS. EVEN THOUGH THERE HAS BEEN A MARGINAL SMOKING DECLINE OF AROUND 5% IN RECENT YEARS (2005 VS 2015), SMOKERS STILL ACCOUNT FOR 15% OF THE US ADULT POPULATION. WHAT IS ALSO CONCERNING IS THAT 41,000 OUT OF 480,000 DEATHS RESULTS FROM SECONDHAND SMOKE (SHS) EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE FOR THE SCOPE OF CLINICAL TREATMENT. CONCLUSIONS: CONSIDERING THESE PREMISES, IT IS EVIDENT THAT MUCH DETAILED TRANSLATIONAL AND CLINICAL STUDIES ARE NEEDED. FACTORS SUCH AS THE LENGTH OF SMOKING CESSATION FOR EX-SMOKERS, THE LEVEL OF SMOKE EXPOSURE IN CASE OF SHS, PRE-ESTABLISHED HEALTH CONDITIONS, GENETICS (AND EPIGENETICS MODIFICATION CAUSED BY CHRONIC SMOKING) ARE FEW OF THE CRITERIA THAT NEED TO BE EVALUATED TO BEGIN ASSESSING THE PROPHYLACTIC AND/OR THERAPEUTIC IMPACT OF TREATMENTS AIMED AT CHRONIC AND FORMER SMOKERS (ESPECIALLY EARLY STAGE EX-SMOKERS) INCLUDING THOSE FREQUENTLY SUBJECTED TO SECOND HAND TOBACCO SMOKE EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS ABOUT PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE AND SCOPE FOR CLINICAL TREATMENT. 2017 4 6029 32 THE BURDEN OF DIABETES: EMERGING DATA. IN RECENT TIMES, THE GLOBAL PREVALENCE OF DIABETES HAS INCREASED SUBSTANTIALLY, REACHING 8.3% IN 2014, WHICH CORRESPONDS TO 387 MILLION PATIENTS. STUDIES IN EUROPE AND USA HAVE SHOWN INCREASED INCIDENCE OF TYPE 1 DIABETES (T1D) OVER TIME AT A RATE OF 3-5% PER YEAR. ANOTHER MOST WORRYING FEATURE OF THE RAPID INCREASE OF DIABETES IS THE EMERGENCE OF TYPE 2 DIABETES (T2D) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS. THE WELL-KNOWN BEHAVIORAL RISKS FACTORS AND EPIGENETIC MECHANISMS RECENTLY OBSERVED REQUIRE AN INTEGRATED APPROACH TO PREVENT T2D. DIABETES SIGNIFICANTLY INFLUENCES THE PATIENT' SURVIVAL, QUALITY OF LIFE, AND DEVELOPMENT OF ORGAN SYSTEM DEGENERATION. EPIDEMIOLOGICAL STUDIES HAVE SHOWN INCREASED MORTALITY IN DIABETIC PATIENTS, ESPECIALLY WOMEN, WHICH INCREASED APPROXIMATELY FIVEFOLD, WHEREAS CARDIOVASCULAR MORTALITY INCREASED 20- TO 30-FOLD WHEN COMPARED TO THE NORMAL POPULATION. DIABETES IS THE LEADING CAUSE OF END-STAGE RENAL DISEASE AND VISION LOSS IN DEVELOPED COUNTRIES. AROUND 40% OF T1D AND T2D START ON RENAL REPLACEMENT THERAPY. WHILE AFTER 40 YEARS OF DIABETES, THE CUMULATIVE PROPORTION OF PATIENTS WITH ANY RETINOPATHY AND ADVANCED RETINOPATHY WAS 84.1 AND 50.2%, RESPECTIVELY. HOWEVER, THE MOST PREVALENT CHRONIC COMPLICATION OF DIABETES IS NEUROPATHY. DISTAL SYMMETRIC POLYNEUROPATHY OCCURS IN AT LEAST 20% OF PEOPLE WITH T1D AFTER 20 YEARS AND IN 10-15% OF NEWLY DIAGNOSED T2D, INCREASING TO 50% AFTER 10 YEARS. CARDIOVASCULAR AUTONOMIC NEUROPATHY MAY BE PRESENT IN UP TO 60% OF PATIENTS AFTER 15 YEARS AND IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR MORTALITY. 2017 5 255 35 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 6 957 45 CHRONIC MYELOMONOCYTIC LEUKAEMIA: A CONCISE CLINICAL AND PATHOPHYSIOLOGICAL REVIEW. CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) IS A CLONAL HAEMATOPOIETIC STEM CELL DISORDER WITH MYELODYSPLASTIC AND MYELOPROLIFERATIVE OVERLAP FEATURES, AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKAEMIA. APPROXIMATELY 30% OF PATIENTS PRESENT WITH CLONAL CYTOGENETIC ABNORMALITIES, WHILE ALMOST 90% HAVE MOLECULAR ABERRATIONS INVOLVING EPIGENETIC REGULATION, THE SPLICEOSOME COMPONENT MACHINERY, TUMOUR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS/REGULATORS. NUMEROUS PROGNOSTIC MODELS EXIST FOR CMML, WITH MORE RECENT MODELS INCORPORATING PROGNOSTIC MUTATIONS, SUCH AS THOSE INVOLVING ASXL1. OTHER VARIABLES THAT SEEM TO CONSISTENTLY AFFECT OUTCOMES INCLUDE THE DEGREE OF LEUCOCYTOSIS/MONOCYTOSIS, ANAEMIA AND THROMBOCYTOPENIA. ALLOGENEIC STEM CELL TRANSPLANT REMAINS THE ONLY CURATIVE OPTION FOR CMML, WHILE HYPOMETHYLATING AGENTS CAN BE USED FOR TRANSPLANT-INELIGIBLE PATIENTS OR THOSE WITHOUT SUITABLE STEM CELL SOURCES. TARGETING BIOLOGICAL PATHWAYS ACTIVATED IN CMML OFFERS POTENTIAL HOPE FOR MORE EFFECTIVE AND LESS TOXIC THERAPIES. 2014 7 961 76 CHRONIC MYELOMONOCYTIC LEUKEMIA: A GENETIC AND CLINICAL UPDATE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER, CHARACTERIZED BY PERIPHERAL BLOOD MONOCYTOSIS AND OVERLAPPING FEATURES BETWEEN MYELODYSPLASTIC SYNDROMES (MDS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CLONAL CYTOGENETIC CHANGES ARE SEEN IN UP TO 30 % PATIENTS, WHILE APPROXIMATELY 90 % HAVE DETECTABLE MOLECULAR ABNORMALITIES. MOST PATIENTS ARE DIAGNOSED IN THE SEVENTH DECADE OF LIFE. GENE MUTATIONS IN TEN-ELEVEN TRANSLOCATION (TET) ONCOGENE FAMILY MEMBER 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), AND RAS (20-30 %) ARE FREQUENT, WITH ONLY FRAME SHIFT AND NONSENSE ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. WITH THE LACK OF FORMAL GUIDELINES, MANAGEMENT AND RESPONSE CRITERIA ARE OFTEN EXTRAPOLATED FROM MDS AND MPN. CONTEMPORARY MOLECULARLY INTEGRATED CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) MODEL AND THE MOLECULAR MAYO MODEL, BOTH INCORPORATING ASXL1 MUTATIONAL STATUS. HYPOMETHYLATING AGENTS AND ALLOGENEIC STEM CELL TRANSPLANT REMAIN THE TWO MOST COMMONLY USED TREATMENT STRATEGIES, WITH SUBOPTIMAL RESULTS. CLINICAL TRIALS EXPLOITING EPIGENETIC AND SIGNAL PATHWAY ABNORMALITIES, FREQUENT IN CMML, OFFER HOPE AND PROMISE. 2015 8 5787 31 SPUTUM ANALYSIS: NON-INVASIVE EARLY LUNG CANCER DETECTION. LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED DEATHS OVER THE WORLD, CHARACTERIZED BY A VERY HIGH MORTALITY RATE. MOLECULAR TECHNIQUE DEVELOPMENT TRIES TO FOCUS ON EARLY DETECTION OF CANCERS BY STUDYING MOLECULAR ALTERATIONS THAT CHARACTERIZE CANCER CELLS. WORLDWIDE LUNG CANCER RESEARCH HAS FOCUSED ON AN EVER-INCREASING NUMBER OF MOLECULAR ELEMENTS OF CARCINOGENESIS AT GENETIC, EPIGENETIC AND PROTEIN LEVELS. THE NON-INVASIVENESS IS THE CHARACTERISTIC THAT ALL CLINICAL TRIALS ON CANCER DETECTION SHOULD HAVE. ABNORMAL CHEST IMAGING AND/OR NON-SPECIFIC SYMPTOMS ARE INITIAL SIGNALS OF LUNG CANCER THAT APPEAR IN AN ADVANCED STAGE OF DISEASE. THIS FACT REPRESENTS THE CAUSE OF THE LOW 5-YEAR SURVIVAL RATE: OVER 90% OF PATIENTS DYING WITHIN 5 YEARS OF DIAGNOSIS. SINCE SMOKERS HAVE HIGHER QUANTITY OF SPUTUM CONTAINING EXFOLIATED CELLS FROM THE BRONCHIAL TREE, AND THE SPUTUM REPRESENTS THE MOST EASILY ACCESSIBLE BIOLOGICAL FLUID AND ITS COLLECTION IS NON-INVASIVE, ANALYSIS OF THIS SAMPLE REPRESENTS A GOOD AREA OF RESEARCH IN EARLY LUNG CANCER DIAGNOSIS. CONTINUED CIGARETTE SMOKING IS THE CAUSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), WITH AN ESTIMATED ATTRIBUTABLE RISK FACTOR EXCEEDING 80% IN SMOKING AFFECTED INDIVIDUALS. LUNG CANCER IS FOUND IN 40-70% OF PATIENTS WITH COPD, PARTICULARLY IN SEVERE DISEASE, AND IT IS A COMMON CAUSE OF DEATH IN THESE PATIENTS. A LARGE PROSPECTIVE TRIAL OF ALMOST HALF A MILLION NON-SMOKERS SHOWED AS LUNG CANCER IS ALSO COMMON IN PATIENTS WITH COPD WHO HAVE NEVER SMOKED. THIS REVIEW DESCRIBES ISSUES RELATED TO EARLY LUNG CANCER SCREENING USING NON-INVASIVE METHODS. 2013 9 4431 30 MOLECULAR CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA AND INTRAHEPATIC CHOLANGIOCARCINOMA: ONE STEP CLOSER TO PERSONALIZED MEDICINE? HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICC) ARE THE TWO MAJOR FORMS OF PRIMARY LIVER CANCERS (PLC), ACCOUNTING FOR APPROXIMATELY 90% AND 5% RESPECTIVELY. THE INCIDENCE OF EACH IS INCREASING RAPIDLY IN THE WESTERN WORLD, HOWEVER OUR KNOWLEDGE OF THE UNDERLYING MECHANISMS REMAINS LIMITED AND THE OUTCOME, DISMAL. THE ETIOLOGIES OF EACH VARY GEOGRAPHICALLY; NEVERTHELESS, CHRONIC INFLAMMATION HAS BEEN IDENTIFIED IN MORE THAN 80% OF THE CASES AND APPEARS TO BE A KEY MEDIATOR IN ALTERING THE LIVER MICROENVIRONMENT, INCREASING THE RISK OF CARCINOGENESIS. HOWEVER, SINCE NOT ALL HCC AND ESPECIALLY ICC CASES HAVE A RECOGNIZED RISK FACTOR, THERE ARE CURRENTLY TWO PROPOSED MODELS FOR LIVER CARCINOGENESIS. THE CLONAL EVOLUTION MODEL DEMONSTRATES A MULTI-STEP PROCESS OF TUMOR DEVELOPMENT FROM PRECANCEROUS LESIONS TO METASTATIC CARCINOMA, ARISING FROM THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES IN A CELL IN THE SETTING OF CHRONIC INFLAMMATION. WHILE THE MAJORITY OF CASES DO OCCUR AS A CONSEQUENCE OF CHRONIC INFLAMMATION, MOST INDIVIDUALS WITH CHRONIC INFECTION DO NOT DEVELOP PLC, SUGGESTING THE INVOLVEMENT OF INDIVIDUAL GENETIC AND ENVIRONMENTAL FACTORS. FURTHER, SINCE HEPATOCYTES AND CHOLANGIOCYTES BOTH HAVE REGENERATIVE POTENTIAL AND ARISE FROM THE SAME BI-POTENTIAL PROGENITOR CELL, THE MORE RECENTLY PROPOSED CANCER STEM CELL MODEL IS GAINING ITS DUE ATTENTION. THE INTEGRATION OF THESE MODELS AND THE CONSTANT IMPROVEMENT IN MOLECULAR PROFILING PLATFORMS IS ENABLING A BROADER UNDERSTANDING OF THE MECHANISMS UNDERLYING THESE TWO DEVASTATING MALIGNANCIES, PERHAPS MOVING US CLOSER TO A NEW WORLD OF MOLECULARLY-INFORMED PERSONALIZED MEDICINE. 2011 10 32 47 A CASE OF TYROSINE KINASE INHIBITOR-RESISTANT CHRONIC MYELOID LEUKEMIA, CHRONIC PHASE WITH ASXL1 MUTATION. HEMATOLOGICAL MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), EXHIBIT ASXL1 MUTATIONS; HOWEVER, THE FUNCTION AND MOLECULAR MECHANISM OF THESE MUTATIONS REMAIN UNCLEAR. ASXL1 WAS ORIGINALLY IDENTIFIED AS TUMOR SUPPRESSOR GENE, IN WHICH LOSS OF FUNCTION CAUSES MYELODYSPLASTIC SYNDROME (MDS). ASXL1 MUTATIONS ARE COMMON AND ASSOCIATED WITH DISEASE PROGRESSION IN MYELOID MALIGNANCIES INCLUDING MDS, ACUTE MYELOID LEUKEMIA, AND SIMILARLY IN CML. IN MDS, ASXL1 MUTATIONS HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS; HOWEVER, THE IMPACT OF ASXL1 MUTATIONS IN CML HAS NOT BEEN WELL DESCRIBED. A 31-YEAR-OLD MALE WAS DIAGNOSED AS CML-CHRONIC PHASE (CP). LABORATORY FINDINGS SHOWED A WHITE BLOOD CELL COUNT OF 187,200/MICROL, WITH ASYMPTOMATIC SPLENOMEGALY. BLAST COUNT WAS 5.0% IN PERIPHERAL BLOOD AND 7.3% IN BONE MARROW. THERE WAS NO ADDITIONAL CHROMOSOMAL ABNORMALITY EXCEPT FOR T(9;22)(Q34;Q11.2) BY CHROMOSOMAL ANALYSIS. AT ONSET, THE SOKAL SCORE WAS 1.4, INDICATING HIGH RISK. THE PATIENT RECEIVED TYROSINE KINASE INHIBITOR (TKI) THERAPY, COMPRISING NILOTINIB APPROXIMATELY 600 MG/DAY, BOSUTINIB APPROXIMATELY 600 MG/DAY, PONATINIB APPROXIMATELY 45 MG/DAY, AND DASATINIB APPROXIMATELY 100 MG/DAY. NEVERTHELESS, AFTER 1.5 YEARS OF CONTINUOUS TKI THERAPY, THE BEST OUTCOME WAS A HEMATOLOGICAL RESPONSE. ALTHOUGH ADDITIONAL CHROMOSOMAL ABERRATIONS AND ABL1 KINASE MUTATIONS WERE ANALYZED REPEATEDLY BEFORE AND DURING TKI THERAPY, KNOWN GENETIC ABNORMALITIES WERE NOT DETECTED. THEREAFTER, THE PATIENT UNDERWENT BONE MARROW TRANSPLANTATION FROM AN HLA 7/8 MATCHED UNRELATED DONOR (HLA-CW 1 LOCUS MISMATCH, GRAFT-VERSUS-HOST DIRECTION). THE PATIENT ACHIEVED NEUTROPHIL ENGRAFTMENT, 18 DAYS AFTER TRANSPLANTATION, LEADING TO COMPLETE REMISSION WITH AN UNDETECTABLE LEVEL OF BCR-ABL1 MRNA. THE PATIENT, HOWEVER, DIED FROM GRAFT-VERSUS-HOST DISEASE AND THROMBOTIC MICROANGIOPATHY AFTER 121 DAYS. GENE SEQUENCE ANALYSIS OF HIS CML CELL BEFORE STEM CELL TRANSPLANTATION REVEALED ASXL1 MUTATIONS. PHYSIOLOGICALLY, ASXL1 CONTRIBUTES TO EPIGENETIC REGULATION. IN THE CML-CP PATIENT IN THIS CASE REPORT, ASXL1 MUTATION CONFERRED RESISTANCE TO TKI THROUGH OBSCURE RESISTANCE MECHANISMS. EVEN THOUGH A MOLECULAR MECHANISM FOR TKI RESISTANCE IN ASXL1 MUTATION IN CML HAS REMAINED OBSCURE, EPIGENETIC MODULATION IS A PLAUSIBLE MODE OF CML DISEASE PROGRESSION. THE CLINICAL IMPACT INCLUDING PROGNOSIS OF ASXL1 FOR CML IS UNDERSCORED. AND THE TREATMENT STRATEGY OF CML WITH ASXL1 MUTATION HAS NOT BEEN ESTABLISHED. A DISCUSSION OF THIS CASE WAS EXPECTED TO FACILITATE TREATMENT OPTIONS. 2020 11 3575 38 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 12 5284 38 PROPOSALS FOR CLINICAL TRIALS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGIC MALIGNANCY OF MOSTLY OLDER INDIVIDUALS THAT EXHIBITS BOTH MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES. CMML PRESENTATION AND OUTCOME ARE VARIABLE, REFLECTING GENETIC AND CLINICAL HETEROGENEITY. HYPOMETHYLATING AGENTS ARE THE MAINSTAY OF THERAPY BUT INDUCE COMPLETE REMISSIONS IN LESS THAN 20% OF PATIENTS AND DO NOT PROLONG SURVIVAL COMPARED TO HYDROXYUREA. ALLOGENEIC STEM CELL TRANSPLANT (ASCT) IS POTENTIALLY CURATIVE, BUT FEW PATIENTS QUALIFY DUE TO ADVANCED AGE AND/OR COMORBIDITIES. WORK OF THE PAST SEVERAL YEARS HAS IDENTIFIED KEY MOLECULAR PATHWAYS THAT DRIVE DISEASE PROLIFERATION AND TRANSFORMATION TO ACUTE LEUKEMIA, INCLUDING JAK/STAT AND MAPK SIGNALING AND EPIGENETIC DYSREGULATION. THERE IS INCREASINGLY COMPELLING EVIDENCE THAT INFLAMMATION IS A MAJOR DRIVER OF CMML PROGRESSION. THUS FAR HOWEVER, THIS MECHANISTIC KNOWLEDGE HAS NOT YET BEEN TRANSLATED INTO IMPROVED OUTCOMES, SUGGESTING THAT FUNDAMENTALLY NEW APPROACHES ARE REQUIRED. IN THIS REVIEW, WE DISCUSS THE DISEASE COURSE, NEW CLASSIFICATIONS, AND CURRENT TREATMENT LANDSCAPE OF CMML. WE REVIEW ONGOING CLINICAL STUDIES AND DISCUSS OPTIONS FOR RATIONALLY BASED FUTURE CLINICAL TRIALS. 2023 13 6653 30 UPDATE ON PANCREATIC CANCER AND ALCOHOL-ASSOCIATED RISK. DUCTAL ADENOCARCINOMA OF THE PANCREAS IS CHARACTERIZED BY EXTREMELY AGGRESSIVE BEHAVIOR, WITH AN OVERALL 5-YEAR SURVIVAL OF <4%. BECAUSE CONVENTIONAL AND SPECIFICALLY TAILORED THERAPEUTIC REGIMENS HAVE LITTLE IMPACT ON PATIENT SURVIVAL, EPIDEMIOLOGICAL AND MOLECULAR RESEARCH AIMS AT IDENTIFYING AND REDUCING RISK FACTORS. CIGARETTE SMOKING, OBESITY, DIABETES MELLITUS, AND CHRONIC PANCREATITIS ARE AMENABLE TO MEDICAL PREVENTION OR THERAPY. HEAVY ALCOHOL CONSUMPTION IS AN INCONSISTENT SINGLE RISK FACTOR FOR PANCREATIC CANCER BUT MAY PROMOTE CARCINOGENESIS BY INCREASING THE RISK OF DIABETES MELLITUS OR CHRONIC PANCREATITIS. FOR VARIOUS AGENTS, THE KEY CARCINOGENIC EFFECT IS PROBABLY AN INFLAMMATORY RESPONSE IN THE PANCREATIC TISSUE. ON THE MOLECULAR LEVEL, MUTATIONS OF ONCOGENES AND TUMOR SUPPRESSOR GENES, AS WELL AS VARIOUS EPIGENETIC ALTERATIONS, SUCH AS OVEREXPRESSION OF GROWTH FACTORS AND THEIR RECEPTORS, ARE IMPORTANT IN TUMORIGENESIS. COMPLETE AND SAFE SURGICAL RESECTION, TOGETHER WITH ADJUVANT THERAPY, OFFERS PROLONGED SURVIVAL, WITH 5-YEAR SURVIVAL RATES OF APPROXIMATELY 25%. HOWEVER, FOR UNRESECTABLE OR DISSEMINATED DISEASE, WHICH CONSTITUTES THE VAST MAJORITY OF CASES, TREATMENT IS PALLIATIVE. DESPITE INCREASING KNOWLEDGE ABOUT THE MOLECULAR PATHOLOGY OF PANCREATIC CANCER AND DESPITE ADVANCES IN TREATMENT, THE OVERALL COURSE OF THE DISEASE IS DISMAL, AND REINFORCED EFFORTS TO REDUCE INCIDENCE AND IMPROVE OUTCOME ARE NEEDED DESPERATELY. 2006 14 667 34 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 15 4859 26 ORAL SQUAMOUS CELL CARCINOMA: DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS. OSCC IS THE MOST FREQUENT MALIGNANT TUMOUR OF THE ORAL CAVITY, ACCOUNTING FOR MORE THAN 90% OF MALIGNANT TUMOURS OF THIS ANATOMIC REGION AND IT OFTEN ARISES FROM PRECURSOR LESIONS. ASIDE FROM TOBACCO AND ALCOHOL CONSUMPTION, FURTHER DETERMINANTS HAVE BEEN CONSIDERED TO INCREASE THE RISK OF OSCC DEVELOPMENT, SUCH AS MICRONUTRIENT DEFICIENCIES, CHRONIC TRAUMATISM, POOR ORAL HYGIENE AND VIRUSES. RECURRENCE, SURVIVAL AND CONVERSELY, MORTALITY DEPENDS ON NUMEROUS AND DIFFERENT BIOLOGICAL, HISTOLOGICAL, MACROSCOPIC AND MICROSCOPIC FACTORS THAT HAVE BEEN INVESTIGATED IN ORDER TO DEFINE CAUSES, TO HELP DIAGNOSIS AND TO REFINE APPROPRIATE TREATMENTS THAT PERFECTLY FIT WITH THE DIFFERENT FEATURES OF OSCCS. FOR THIS PURPOSE, DURING THE LAST DECADES, THE IMPROVEMENT OF SCIENTIFIC TECHNOLOGIES AND MOLECULAR ANALYSES HAVE ALLOWED TO INVESTIGATE MARKERS AND GENETIC AND EPIGENETIC FACTORS, IN ORDER TO CLARIFY THEIR RESPONSIBILITIES RELATED TO EARLY DIAGNOSIS AND OSCC PROGRESSION AND PROGNOSIS IN ORDER TO ADDRESS THEM AS TARGETS IN FUTURE SELECTIVE AND INDIVIDUALLY-SHAPED THERAPIES. THIS REVIEW WILL FOCUS ON THE ETIOLOGY, ADVANCES IN DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS FOR ORAL CANCERS. 2016 16 933 32 CHRONIC KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE (CKD) HAVE EVOLVED OVER TIME, BUT CURRENT INTERNATIONAL GUIDELINES DEFINE THIS CONDITION AS DECREASED KIDNEY FUNCTION SHOWN BY GLOMERULAR FILTRATION RATE (GFR) OF LESS THAN 60 ML/MIN PER 1.73 M(2), OR MARKERS OF KIDNEY DAMAGE, OR BOTH, OF AT LEAST 3 MONTHS DURATION, REGARDLESS OF THE UNDERLYING CAUSE. DIABETES AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ALL HIGH-INCOME AND MIDDLE-INCOME COUNTRIES, AND ALSO IN MANY LOW-INCOME COUNTRIES. INCIDENCE, PREVALENCE, AND PROGRESSION OF CKD ALSO VARY WITHIN COUNTRIES BY ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH, POSSIBLY THROUGH EPIGENETIC INFLUENCE. MANY PEOPLE ARE ASYMPTOMATIC OR HAVE NON-SPECIFIC SYMPTOMS SUCH AS LETHARGY, ITCH, OR LOSS OF APPETITE. DIAGNOSIS IS COMMONLY MADE AFTER CHANCE FINDINGS FROM SCREENING TESTS (URINARY DIPSTICK OR BLOOD TESTS), OR WHEN SYMPTOMS BECOME SEVERE. THE BEST AVAILABLE INDICATOR OF OVERALL KIDNEY FUNCTION IS GFR, WHICH IS MEASURED EITHER VIA EXOGENOUS MARKERS (EG, DTPA, IOHEXOL), OR ESTIMATED USING EQUATIONS. PRESENCE OF PROTEINURIA IS ASSOCIATED WITH INCREASED RISK OF PROGRESSION OF CKD AND DEATH. KIDNEY BIOPSY SAMPLES CAN SHOW DEFINITIVE EVIDENCE OF CKD, THROUGH COMMON CHANGES SUCH AS GLOMERULAR SCLEROSIS, TUBULAR ATROPHY, AND INTERSTITIAL FIBROSIS. COMPLICATIONS INCLUDE ANAEMIA DUE TO REDUCED PRODUCTION OF ERYTHROPOIETIN BY THE KIDNEY; REDUCED RED BLOOD CELL SURVIVAL AND IRON DEFICIENCY; AND MINERAL BONE DISEASE CAUSED BY DISTURBED VITAMIN D, CALCIUM, AND PHOSPHATE METABOLISM. PEOPLE WITH CKD ARE FIVE TO TEN TIMES MORE LIKELY TO DIE PREMATURELY THAN THEY ARE TO PROGRESS TO END STAGE KIDNEY DISEASE. THIS INCREASED RISK OF DEATH RISES EXPONENTIALLY AS KIDNEY FUNCTION WORSENS AND IS LARGELY ATTRIBUTABLE TO DEATH FROM CARDIOVASCULAR DISEASE, ALTHOUGH CANCER INCIDENCE AND MORTALITY ARE ALSO INCREASED. HEALTH-RELATED QUALITY OF LIFE IS SUBSTANTIALLY LOWER FOR PEOPLE WITH CKD THAN FOR THE GENERAL POPULATION, AND FALLS AS GFR DECLINES. INTERVENTIONS TARGETING SPECIFIC SYMPTOMS, OR AIMED AT SUPPORTING EDUCATIONAL OR LIFESTYLE CONSIDERATIONS, MAKE A POSITIVE DIFFERENCE TO PEOPLE LIVING WITH CKD. INEQUITY IN ACCESS TO SERVICES FOR THIS DISEASE DISPROPORTIONALLY AFFECTS DISADVANTAGED POPULATIONS, AND HEALTH SERVICE PROVISION TO INCENTIVISE EARLY INTERVENTION OVER PROVISION OF CARE ONLY FOR ADVANCED CKD IS STILL EVOLVING IN MANY COUNTRIES. 2017 17 536 33 ASXL1 MUTATIONS PREDICT INFERIOR MOLECULAR RESPONSE TO NILOTINIB TREATMENT IN CHRONIC MYELOID LEUKEMIA. GENE MUTATIONS INDEPENDENT OF BCR::ABL1 HAVE BEEN IDENTIFIED IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) IN CHRONIC PHASE, WHEREBY MUTATIONS IN EPIGENETIC MODIFIER GENES WERE MOST COMMON. THESE FINDINGS PROMPTED THE SYSTEMATIC ANALYSIS OF PREVALENCE, DYNAMICS, AND PROGNOSTIC SIGNIFICANCE OF SUCH MUTATIONS, IN A CLINICALLY WELL-CHARACTERIZED PATIENT POPULATION OF 222 CML PATIENTS FROM THE TIGER STUDY (CML-V) BY TARGETED NEXT-GENERATION SEQUENCING COVERING 54 MYELOID LEUKEMIA-ASSOCIATED GENES. IN TOTAL, 53/222 CML PATIENTS (24%) CARRIED 60 MUTATIONS AT DIAGNOSIS WITH ASXL1 BEING MOST COMMONLY AFFECTED (N = 20). TO STUDY MUTATION DYNAMICS, LONGITUDINAL DEEP SEQUENCING ANALYSIS OF SERIAL SAMPLES WAS PERFORMED IN 100 PATIENTS AFTER 12, 24, AND 36 MONTHS OF THERAPY. TYPICAL PATTERNS OF CLONAL EVOLUTION INCLUDED ERADICATION, PERSISTENCE, AND EMERGENCE OF MUTATED CLONES. PATIENTS CARRYING AN ASXL1 MUTATION AT DIAGNOSIS SHOWED A LESS FAVORABLE MOLECULAR RESPONSE TO NILOTINIB TREATMENT, AS A MAJOR MOLECULAR RESPONSE (MMR) WAS ACHIEVED LESS FREQUENTLY AT MONTH 12, 18, AND 24 COMPARED TO ALL OTHER PATIENTS. PATIENTS WITH ASXL1 MUTATIONS WERE ALSO YOUNGER AND MORE FREQUENTLY FOUND IN THE HIGH RISK CATEGORY, SUGGESTING A CENTRAL ROLE OF CLONAL EVOLUTION ASSOCIATED WITH ASXL1 MUTATIONS IN CML PATHOGENESIS. 2022 18 2205 23 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES. 2006 19 3265 28 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018 20 3560 38 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