1  5044 126 PHARMACOKINETICS AND PHARMACODYNAMICS WITH EXTENDED DOSING OF CC-486 IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN DEVELOPMENT FOR PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA. IN PART 1 OF THIS TWO-PART STUDY, A 7-DAY CC-486 DOSING SCHEDULE SHOWED CLINICAL ACTIVITY, WAS GENERALLY WELL TOLERATED, AND REDUCED DNA METHYLATION. EXTENDING DOSING OF CC-486 BEYOND 7 DAYS WOULD INCREASE DURATION OF AZACITIDINE EXPOSURE. WE HYPOTHESIZED THAT EXTENDED DOSING WOULD THEREFORE PROVIDE MORE SUSTAINED EPIGENETIC ACTIVITY. REPORTED HERE ARE THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROFILES OF CC-486 EXTENDED DOSING SCHEDULES IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) OR ACUTE MYELOID LEUKEMIA (AML) FROM PART 2 OF THIS STUDY. PK AND/OR PD DATA WERE AVAILABLE FOR 59 PATIENTS WHO WERE SEQUENTIALLY ASSIGNED TO 1 OF 4 EXTENDED CC-486 DOSING SCHEDULES: 300MG ONCE-DAILY OR 200MG TWICE-DAILY FOR 14 OR 21 DAYS PER 28-DAY CYCLE. BOTH 300MG ONCE-DAILY SCHEDULES AND THE 200MG TWICE-DAILY 21-DAY SCHEDULE SIGNIFICANTLY (ALL P < .05) REDUCED GLOBAL DNA METHYLATION IN WHOLE BLOOD AT ALL MEASURED TIME POINTS (DAYS 15, 22, AND 28 OF THE TREATMENT CYCLE), WITH SUSTAINED HYPOMETHYLATION AT CYCLE END COMPARED WITH BASELINE. CC-486 EXPOSURES AND REDUCED DNA METHYLATION WERE SIGNIFICANTLY CORRELATED. PATIENTS WHO HAD A HEMATOLOGIC RESPONSE HAD SIGNIFICANTLY GREATER METHYLATION REDUCTIONS THAN NON-RESPONDING PATIENTS. THESE DATA DEMONSTRATE THAT EXTENDED DOSING OF CC-486 SUSTAINS EPIGENETIC EFFECTS THROUGH THE TREATMENT CYCLE. TRIAL REGISTRATION: CLINICALTRIALS.GOV NCT00528983.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2   765  51 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  2769  55 EXTENDED DOSING WITH CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH MYELOID MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN CLINICAL DEVELOPMENT FOR TREATMENT OF HEMATOLOGICAL CANCERS. THIS STUDY OF EXTENDED CC-486 DOSING INCLUDED PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDSS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), OR ACUTE MYELOID LEUKEMIA (AML). AFTER A PHARMACOKINETIC ASSESSMENT PERIOD, 31 PATIENTS (MDS N = 18, CMML N = 4, AND AML N = 9) ENTERED A CLINICAL PHASE IN WHICH THEY RECEIVED CC-486 300 MG ONCE-DAILY FOR 21 DAYS OF REPEATED 28-DAY CYCLES. MEDIAN AGE WAS 71 YEARS (RANGE: 53-93); 42% OF PATIENTS WERE AGED >/=75 YEARS. A TOTAL OF 5 PATIENTS WITH AML (63%) HAD PRIOR MDS. MEDIAN NUMBER OF CC-486 TREATMENT CYCLES WAS 4 (RANGE: 1-32). THE MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) WERE GASTROINTESTINAL (84% OF PATIENTS) AND HEMATOLOGIC (81%). MOST COMMON GRADE 3-4 TEAES WERE NEUTROPENIA (N = 13, 42%) AND ANEMIA (N = 9, 29%). TEN PATIENTS EXPERIENCED GRADE 4 NEUTROPENIA. INFREQUENTLY, CC-486 DOSE WAS INTERRUPTED OR REDUCED DUE TO GASTROINTESTINAL (N = 5, 16%) OR HEMATOLOGIC (N = 6, 19%) TEAES. OVERALL RESPONSE RATE (COMPLETE REMISSION [CR], CR WITH INCOMPLETE HEMATOLOGICAL RECOVERY [CRI], PARTIAL REMISSION [PR], MARROW CR) IN THE MDS/CMML SUBGROUPS WAS 32% AND IN THE AML SUBGROUP (CR/CRI/PR) WAS 22%. RED BLOOD CELL TRANSFUSION INDEPENDENCE RATES IN THE MDS/CMML AND AML SUBGROUPS WERE 33% AND 25%, RESPECTIVELY, AND 2 MDS/CMML PATIENTS ATTAINED HEMATOLOGIC IMPROVEMENT AS A BEST RESPONSE ON-STUDY. NO BASELINE GENE MUTATION WAS PREDICTIVE OF RESPONSE/NONRESPONSE. CC-486 ALLOWS FLEXIBLE DOSING AND SCHEDULES TO IMPROVE TOLERABILITY OR RESPONSE. NEUTROPENIA IN EARLY TREATMENT CYCLES DESERVES SCRUTINY AND MAY WARRANT INITIATION OF PROPHYLACTIC ANTIBIOTICS. KEY POINTS: THE SAFETY PROFILE OF ORAL CC-486 WAS COMPARABLE TO THAT OF INJECTABLE AZACITIDINE; MOST ADVERSE EVENTS WERE HEMATOLOGICAL AND GASTROINTESTINAL. EXTENDED (21-DAY/CYCLE) CC-486 DOSING INDUCED RESPONSES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES, MANY OF WHOM HAD PRIOR DNMTI FAILURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  5478  42 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  5613  41 SAFETY AND EFFICACY OF ABEXINOSTAT, A PAN-HISTONE DEACETYLASE INHIBITOR, IN NON-HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PHASE II STUDY. HISTONE DEACETYLASE INHIBITORS ARE MEMBERS OF A CLASS OF EPIGENETIC DRUGS THAT HAVE PROVEN ACTIVITY IN T-CELL MALIGNANCIES, BUT LITTLE IS KNOWN ABOUT THEIR EFFICACY IN B-CELL LYMPHOMAS. ABEXINOSTAT IS AN ORALLY AVAILABLE HYDROXAMATE-CONTAINING HISTONE DEACETYLASE INHIBITOR THAT DIFFERS FROM APPROVED INHIBITORS; ITS UNIQUE PHARMACOKINETIC PROFILE AND ORAL DOSING SCHEDULE, TWICE DAILY FOUR HOURS APART, ALLOWS FOR CONTINUOUS EXPOSURE AT CONCENTRATIONS REQUIRED TO EFFICIENTLY KILL TUMOR CELLS. IN THIS PHASE II STUDY, PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVED ORAL ABEXINOSTAT AT 80 MG BID FOR 14 DAYS OF A 21-DAY CYCLE AND CONTINUED UNTIL PROGRESSIVE DISEASE OR UNACCEPTABLE TOXICITY. A TOTAL OF 100 PATIENTS WITH B-CELL MALIGNANCIES AND T-CELL LYMPHOMAS WERE ENROLLED BETWEEN OCTOBER 2011 AND JULY 2014. ALL PATIENTS RECEIVED AT LEAST ONE DOSE OF STUDY DRUG. PRIMARY REASONS FOR DISCONTINUATION INCLUDED PROGRESSIVE DISEASE (56%) AND ADVERSE EVENTS (25%). GRADE 3 OR OVER ADVERSE EVENTS AND ANY SERIOUS ADVERSE EVENTS WERE REPORTED IN 88% AND 73% OF PATIENTS, RESPECTIVELY. THE MOST FREQUENTLY REPORTED GRADE 3 OR OVER TREATMENT-EMERGENT RELATED ADVERSE EVENTS WERE THROMBOCYTOPENIA (80%), NEUTROPENIA (27%), AND ANEMIA (12%). AMONG THE 87 PATIENTS EVALUABLE FOR EFFICACY, OVERALL RESPONSE RATE WAS 28% (COMPLETE RESPONSE 5%), WITH HIGHEST RESPONSES OBSERVED IN PATIENTS WITH FOLLICULAR LYMPHOMA (OVERALL RESPONSE RATE 56%), T-CELL LYMPHOMA (OVERALL RESPONSE RATE 40%), AND DIFFUSE LARGE B-CELL LYMPHOMA (OVERALL RESPONSE RATE 31%). FURTHER INVESTIGATION OF THE SAFETY AND EFFICACY OF ABEXINOSTAT IN FOLLICULAR LYMPHOMA, T-CELL LYMPHOMA, AND DIFFUSE LARGE B-CELL LYMPHOMA IMPLEMENTING A LESS DOSE-INTENSE WEEK-ON-WEEK-OFF SCHEDULE IS WARRANTED. (TRIAL REGISTERED AT: EUDRACT-2009-013691-47).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  5283  37 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  5612  46 SAFETY AND ACTIVITY OF RRX-001 IN PATIENTS WITH ADVANCED CANCER: A FIRST-IN-HUMAN, OPEN-LABEL, DOSE-ESCALATION PHASE 1 STUDY. BACKGROUND: EPIGENETIC ALTERATIONS HAVE BEEN STRONGLY ASSOCIATED WITH TUMOUR FORMATION AND RESISTANCE TO CHEMOTHERAPEUTIC DRUGS, AND EPIGENETIC MODIFICATIONS ARE AN ATTRACTIVE TARGET IN CANCER RESEARCH. RRX-001 IS ACTIVATED BY HYPOXIA AND INDUCES THE GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES THAT CAN EPIGENETICALLY MODULATE DNA METHYLATION, HISTONE DEACETYLATION, AND LYSINE DEMETHYLATION. THE AIM OF THIS PHASE 1 STUDY WAS TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF RRX-001. METHODS: IN THIS OPEN-LABEL, DOSE-ESCALATION, PHASE 1 STUDY, WE RECRUITED ADULT PATIENTS (AGED >18 YEARS) WITH HISTOLOGICALLY OR CYTOLOGICALLY CONFIRMED DIAGNOSIS OF ADVANCED, MALIGNANT, INCURABLE SOLID TUMOURS FROM UNIVERSITY OF CALIFORNIA AT SAN DIEGO, CA, USA, AND SARAH CANNON RESEARCH INSTITUTE, NASHVILLE, TN, USA. KEY ELIGIBILITY CRITERIA INCLUDED EVALUABLE DISEASE, EASTERN COOPERATIVE GROUP PERFORMANCE STATUS OF 2 OR LESS, AN ESTIMATED LIFE EXPECTANCY OF AT LEAST 12 WEEKS, ADEQUATE LABORATORY PARAMETERS, DISCONTINUATION OF ALL PREVIOUS ANTINEOPLASTIC THERAPIES AT LEAST 6 WEEKS BEFORE INTERVENTION, AND NO RESIDUAL SIDE-EFFECTS FROM PREVIOUS THERAPIES. PATIENTS WERE ASSIGNED TO RECEIVE INTRAVENOUS INFUSIONS OF RRX-001 AT INCREASING DOSES (10 MG/M(2), 16.7 MG/M(2), 24.6 MG/M(2), 33 MG/M(2), 55 MG/M(2), AND 83 MG/M(2)) EITHER ONCE OR TWICE-WEEKLY FOR AT LEAST 4 WEEKS, WITH AT LEAST THREE PATIENTS PER DOSE COHORT AND ALLOWING A 2-WEEK OBSERVATION PERIOD BEFORE DOSE ESCALATION. SAMPLES FOR SAFETY AND PHARMACOKINETICS ANALYSIS, INCLUDING STANDARD CHEMISTRY AND HAEMATOLOGICAL PANELS, WERE TAKEN ON EACH TREATMENT DAY. THE PRIMARY OBJECTIVE WAS TO ASSESS SAFETY, TOLERABILITY, AND DOSE-LIMITING TOXIC EFFECTS OF RRX-001, TO DETERMINE SINGLE-DOSE PHARMACOKINETICS, AND TO IDENTIFY A RECOMMENDED DOSE FOR PHASE 2 TRIALS. ALL ANALYSES WERE DONE PER PROTOCOL. ACCRUAL IS COMPLETE AND FOLLOW-UP IS STILL ON-GOING. THIS TRIAL IS REGISTERED WITH CLINICALTRIALS.GOV, NUMBER NCT01359982. FINDINGS: BETWEEN OCT 10, 2011, AND MARCH 18, 2013, WE ENROLLED 25 PATIENTS AND TREATED SIX PATIENTS IN THE 10 MG/M(2) COHORT, THREE PATIENTS IN THE 16.7 MG/M(2) COHORT, THREE PATIENTS IN THE 24.6 MG/M(2) COHORT, FOUR PATIENTS IN THE 33 MG/M(2) COHORT, THREE PATIENTS IN THE 55 MG/M(2), AND SIX PATIENTS IN THE 83 MG/M(2) COHORT. PAIN AT THE INJECTION SITE, MOSTLY GRADE 1 AND GRADE 2, WAS THE MOST COMMON ADVERSE EVENT RELATED TO TREATMENT, EXPERIENCED BY 21 (84%) PATIENTS. OTHER COMMON DRUG-RELATED ADVERSE EVENTS INCLUDED ARM SWELLING OR OEDEMA (EIGHT [32%] PATIENTS), AND VEIN HARDENING (SEVEN [28%] PATIENTS). NO DOSE-LIMITING TOXICITIES WERE OBSERVED. TIME CONSTRAINTS RELATED TO MANAGEMENT OF INFUSION PAIN FROM RRX-001 RESULTED IN A MAXIMALLY FEASIBLE DOSE OF 83 MG/M(2). OF THE 21 EVALUABLE PATIENTS, ONE (5%) PATIENT HAD A PARTIAL RESPONSE, 14 (67%) PATIENTS HAD STABLE DISEASE, AND SIX (29%) PATIENTS HAD PROGRESSIVE DISEASE; ALL RESPONSES WERE ACROSS A VARIETY OF TUMOUR TYPES. FOUR PATIENTS WHO HAD RECEIVED RRX-001 WERE SUBSEQUENTLY RECHALLENGED WITH A TREATMENT THAT THEY HAD BECOME REFRACTORY TO; ALL FOUR RESPONDED TO THE RECHALLENGE. INTERPRETATION: RRX-001 IS A WELL-TOLERATED NOVEL COMPOUND WITHOUT CLINICALLY SIGNIFICANT TOXIC EFFECTS AT THE TESTED DOSES. PRELIMINARY EVIDENCE OF ACTIVITY IS PROMISING AND, ON THE BASIS OF ALL FINDINGS, A DOSE OF 16.7 MG/M(2) WAS RECOMMENDED AS THE TARGETED DOSE FOR PHASE 2 TRIALS. FUNDING: EPICENTRX (FORMERLY RADIORX).	2015	

8  2822  46 FIRST-IN-HUMAN STUDY OF INHALED AZACITIDINE IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER. BACKGROUND: AEROSOLIZED AZACITIDINE HAS BEEN SHOWN TO INHIBIT ORTHOTOPIC LUNG CANCER GROWTH AND INDUCE RE-EXPRESSION OF METHYLATED TUMOR SUPPRESSOR GENES IN MURINE MODELS. WE HYPOTHESIZED THAT INHALED AZACITIDINE IS SAFE AND EFFECTIVE IN REVERSING EPIGENETIC CHANGES IN THE BRONCHIAL EPITHELIUM SECONDARY TO CHRONIC SMOKING. PATIENTS AND METHODS: WE REPORT THE FIRST IN HUMAN STUDY OF INHALED AZACITIDINE. AZACITIDINE IN AQUEOUS SOLUTION WAS USED TO GENERATE AN AEROSOL SUSPENSION OF 0.25-5 MUM PARTICLE SIZE. MAIN INCLUSION CRITERIA: STAGE IV OR RECURRENT NSCLC WITH PREDOMINANTLY LUNG INVOLVEMENT, >/=1 PRIOR SYSTEMIC THERAPY, ECOG PS 0-1, AND ADEQUATE PULMONARY FUNCTION. PATIENTS RECEIVED INHALED AZACITIDINE DAILY ON DAYS 1-5 AND 15-19 OF 28-DAY CYCLES, AT 3 ESCALATING DOSES (15, 30 AND 45 MG/M(2) DAILY). THE PRIMARY OBJECTIVE WAS TO DETERMINE THE FEASIBILITY AND TOLERABILITY OF THIS NEW THERAPEUTIC MODALITY. THE KEY SECONDARY OBJECTIVES INCLUDED PHARMACOKINETICS, METHYLATION PROFILES AND EFFICACY. RESULTS: FROM 3/2015 TO 2/2018, EIGHT PATIENTS RECEIVED A MEDIAN NUMBER OF 2 (IQR = 1) CYCLES OF INHALED AZACITIDINE. NO CLINICALLY SIGNIFICANT ADVERSE EVENTS WERE OBSERVED, EXCEPT ONE PATIENT TREATED AT THE HIGHEST DOSE DEVELOPED AN ASYMPTOMATIC GRADE 2 DECREASED DLCO WHICH RESOLVED SPONTANEOUSLY. ONE PATIENT RECEIVING 12 CYCLES OF THERAPY HAD AN OBJECTIVE AND DURABLE PARTIAL RESPONSE, AND TWO PATIENTS HAD STABLE DISEASE. PLASMA AZACITIDINE WAS ONLY BRIEFLY DETECTABLE IN PATIENTS TREATED AT THE HIGHER DOSES. MOREOVER, IN 2 OF 3 PARTICIPANTS WHO AGREED AND UNDERWENT PRE- AND POST-TREATMENT BRONCHOSCOPY, THE GLOBAL DNA METHYLATION IN THE BRONCHIAL EPITHELIUM DECREASED BY 24 % AND 79 % POST-THERAPY, RESPECTIVELY. THE INTERVAL BETWEEN LAST INHALED TREATMENT AND BRONCHOSCOPY WAS 3 DAYS. CONCLUSIONS: INHALED AZACITIDINE RESULTED IN NEGLIGIBLE PLASMA LEVELS COMPARED TO THE PREVIOUSLY REPORTED SUBCUTANEOUS ADMINISTRATION AND WAS WELL-TOLERATED. THE RESULTS JUSTIFY THE CONTINUED DEVELOPMENT OF INHALED AZACITIDINE AT NON-CYTOTOXIC DOSES FOR PATIENTS WITH LUNG-CONFINED MALIGNANT AND/OR PREMALIGNANT LESIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  3178  29 HAEMATOLOGIC MALIGNANCIES WITH UNFAVOURABLE GENE MUTATIONS BENEFIT FROM DONOR LYMPHOCYTE INFUSION WITH/WITHOUT DECITABINE FOR PROPHYLAXIS OF RELAPSE AFTER ALLOGENEIC HSCT: A PILOT STUDY. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE FOR LEUKAEMIA PATIENTS WITH UNFAVOURABLE GENE MUTATIONS WHO RECEIVE ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT). THERE IS NO CONSENSUS ON THE INDICATION OF DONOR LYMPHOCYTE INFUSION (DLI) FOR PROPHYLAXIS OF RELAPSE AFTER ALLO-HSCT. TO EVALUATE THE TOLERANCE AND EFFICACY OF PROPHYLACTIC DLI IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS SUCH AS FLT3-ITD, TP53, ASXL1, DNMT3A OR TET2, WE PERFORMED A PROSPECTIVE, SINGLE-ARM STUDY. PROPHYLACTIC USE OF DECITABINE FOLLOWED BY DLI WAS PLANNED IN PATIENTS WITH TP53 OR EPIGENETIC MODIFIER GENE MUTATIONS. THE PROPHYLAXIS WAS PLANNED IN 46 RECIPIENTS: IT WAS ADMINISTERED IN 28 PATIENTS AND IT WAS NOT ADMINISTERED IN 18 PATIENTS DUE TO CONTRAINDICATIONS. NO DLI-ASSOCIATED PANCYTOPENIA WAS OBSERVED. THE CUMULATIVE INCIDENCES OF GRADE II-IV AND III-IV ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD) AT 100 DAYS POST-DLI WERE 25.8% AND 11.0%, RESPECTIVELY. THE RATES OF CHRONIC GVHD, NON-RELAPSE MORTALITY AND RELAPSE AT 3 YEARS POST-DLI WERE 21.6%, 25.0% AND 26.1%, RESPECTIVELY. THE 3-YEAR RELAPSE-FREE SURVIVAL AND OVERALL SURVIVAL (OS) RATES WERE 48.9% AND 48.2%, RESPECTIVELY. ACUTE GVHD (HR: 2.30, P = 0.016) AND RELAPSE (HR: 2.46, P = 0.003) AFTER DLI WERE INDEPENDENTLY ASSOCIATED WITH INFERIOR OS. DATA IN THE CURRENT STUDY SHOWED THE FEASIBILITY OF PROPHYLACTIC DLI WITH/WITHOUT DECITABINE IN THE EARLY STAGE AFTER ALLO-HSCT IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  1818  28 EFFECTS OF CHRONIC METHAMPHETAMINE EXPOSURE ON REWARDING BEHAVIOR AND NEURODEGENERATION MARKERS IN ADULT MICE. RECREATIONAL AND MEDICAL USE OF STIMULANTS AMONG YOUNG ADULTS HAVE GAINED POPULARITY IN THE UNITED STATES OVER THE LAST DECADE AND THEIR USE MAY INCREASE VULNERABILITY TO BRAIN BIOCHEMICAL CHANGES AND ADDICTIVE BEHAVIORS. THE LONG-TERM EFFECTS OF CHRONIC STIMULANT EXPOSURE IN LATER ADULTHOOD HAVE NOT BEEN FULLY ELUCIDATED.OUR STUDY INVESTIGATED WHETHER CHRONIC EXPOSURE TO METHAMPHETAMINE (METH), AT A DOSE DESIGNED TO EMULATE HUMAN THERAPEUTIC DOSING FOR ADHD, WOULD PROMOTE BIOCHEMICAL ALTERATIONS AND AFFECT SENSITIVITY TO THE REWARDING EFFECTS OF SUBSEQUENT METH DOSING.GROUPS OF 3.5-MONTH-OLD MALE AND FEMALE C57BL/6J MICE WERE ADMINISTERED NON-CONTINGENT INTRAPERITONEAL INJECTIONS OF EITHER SALINE OR METH (1.4 MG/KG) TWICE A DAY FOR 1 MONTH (5 DAYS/WEEK). METH (0.5 MG/KG)-INDUCED CONDITIONED PLACE PREFERENCE (CPP) WAS TESTED IN MICE TO DETERMINE THE EFFECTS OF PREVIOUS METH EXPOSURE ON REWARD-RELATED BEHAVIOR. MICE WERE RANDOMLY ASSIGNED TO EXPERIMENT I (MALES AND FEMALES) OR EXPERIMENT II (FEMALES ONLY) IN WHICH CPP TESTING WAS RESPECTIVELY PERFORMED EITHER 0.5 OR 5 MONTHS AFTER THE END OF METH INJECTIONS, AT ~5 OR 10 MONTHS OLD RESPECTIVELY. THE MIDBRAIN AND STRIATUM, REGIONS INVOLVED IN REWARD CIRCUIT, WERE ASSESSED FOR MARKERS ASSOCIATED WITH NEUROTOXICITY, DOPAMINERGIC FUNCTION, NEUROINFLAMMATION AND EPIGENETIC CHANGES AFTER BEHAVIORAL TESTING.PREVIOUS EXPOSURE TO CHRONIC METH DID NOT HAVE SIGNIFICANT SHORT-TERM EFFECTS ON CPP RESPONSE BUT LED TO A DECREASED CPP RESPONSE IN 10-MONTH-OLD FEMALES. PREVIOUS EXPOSURE TO METH INDUCED SOME SHORT-TERM CHANGES TO BIOCHEMICAL MARKERS MEASURED IN A BRAIN REGION AND SEX-DEPENDENT MANNER, WHILE LONG-TERM CHANGES WERE ONLY OBSERVED WITH GFAP AND KDM5C.IN CONCLUSION, OUR DATA SUGGEST SEX- AND POST-EXPOSURE DURATION-DEPENDENT OUTCOMES AND WARRANT FURTHER EXPLORATION OF THE LONG-TERM NEUROBEHAVIORAL CONSEQUENCES OF PSYCHOSTIMULANT USE IN BOTH SEXES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  4264  22 MICRO-OPIOID RECEPTOR GENE VARIANT OPRM1 118 A>G: A SUMMARY OF ITS MOLECULAR AND CLINICAL CONSEQUENCES FOR PAIN. THE HUMAN MICRO-OPIOID RECEPTOR VARIANT 118 A>G (RS1799971) HAS BECOME ONE OF THE MOST ANALYZED GENETIC VARIANTS IN THE PAIN FIELD. AT THE MOLECULAR LEVEL, THE VARIANT REDUCES OPIOID RECEPTOR SIGNALING EFFICIENCY AND EXPRESSION, THE LATTER PROBABLY VIA A GENETIC-EPIGENETIC INTERACTION. IN EXPERIMENTAL SETTINGS, THE VARIANT WAS REPRODUCIBLY ASSOCIATED WITH DECREASED EFFECTS OF EXOGENOUS OPIOIDS. HOWEVER, THIS TRANSLATES INTO VERY SMALL CLINICAL EFFECTS (META-ANALYSIS OF 14 STUDIES: COHEN'S D = 0.096; P = 0.008), CONSISTING OF SLIGHTLY HIGHER OPIOID DOSING REQUIREMENTS IN PERI- AND POST-OPERATIVE SETTINGS. AN EFFECT CAN NEITHER BE MAINTAINED FOR CHRONIC ANALGESIC THERAPY NOR FOR OPIOID SIDE EFFECTS. IT SEEMS UNLIKELY THAT FURTHER STUDIES WILL REVEAL LARGER EFFECT SIZES AND, THEREFORE, FURTHER ANALYSES APPEAR UNWARRANTED. THUS, DUE TO ITS SMALL EFFECT SIZE, THE SNP IS WITHOUT MAJOR CLINICAL RELEVANCE AS A SOLITARY VARIANT, BUT SHOULD BE REGARDED AS A PART OF COMPLEX GENOTYPES UNDERLYING PAIN AND ANALGESIA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  6582  30 TRICHOSTATIN A, A HISTONE DEACETYLASE INHIBITOR, ALLEVIATES THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. RECENT REPORTS HAVE IMPLIED THAT ABERRANT BIOCHEMICAL PROCESSES IN THE BRAIN ARE FREQUENTLY ACCOMPANIED BY SUBTLE SHIFTS IN THE CELLULAR EPIGENETIC PROFILE THAT MIGHT UNDERLIE THE PATHOGENIC PROGRESSION OF PSYCHIATRIC DISORDERS. THE AIM OF THE PRESENT STUDY WAS TO EXAMINE THE EFFECT OF TRICHOSTATIN A (TSA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, ON THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. MICE WERE EXPOSED TO REPEATED RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS. WE APPLIED DOSING SCHEDULES. IN ONE SCHEDULE, FROM THE 3RD DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA (1650 MUM/4 MUL, I.C.V.) IMMEDIATELY AFTER THE DAILY EXPOSURE TO RESTRAINT STRESS. IN THE OTHER SCHEDULE, FROM THE 1ST DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA 2 H BEFORE EXPOSURE TO RESTRAINT STRESS. AFTER THE FINAL EXPOSURE TO RESTRAINT STRESS, THE EMOTIONALITY OF MICE WAS EVALUATED USING THE HOLE-BOARD TEST. MICE THAT WERE EXPOSED TO RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS SHOWED A DECREASE IN HEAD-DIPPING BEHAVIOR. THIS DECREASED EMOTIONALITY OBSERVED IN STRESS-MALADAPTIVE MICE WAS SIGNIFICANTLY RECOVERED BY CHRONIC TREATMENT WITH TSA 2 H BEFORE DAILY EXPOSURE TO RESTRAINT STRESS, WHICH CONFIRMED THE DEVELOPMENT OF STRESS ADAPTATION. ON THE OTHER HAND, NO SUCH STRESS ADAPTATION WAS OBSERVED UNDER CHRONIC TREATMENT WITH TSA IMMEDIATELY AFTER DAILY STRESS EXPOSURE. A BIOCHEMICAL STUDY SHOWED THAT TRYPTOPHAN HYDROXYLASE, THE RATE-LIMITING ENZYME IN SEROTONIN (5-HT) SYNTHESIS, WAS INCREASED IN MIDBRAIN CONTAINING RAPHE NUCLEI OBTAINED FROM STRESS-ADAPTED MICE THAT WERE CHRONICALLY TREATED WITH TSA 2 H BEFORE DAILY STRESS EXPOSURE. THESE FINDINGS SUGGEST THAT AN HDAC INHIBITOR MAY HAVE A BENEFICIAL EFFECT ON STRESS ADAPTATION BY AFFECTING 5-HT NEURAL FUNCTION IN THE BRAIN AND ALLEVIATE THE EMOTIONAL ABNORMALITY UNDER CONDITIONS OF EXCESSIVE STRESS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  1046  38 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  5499  33 REVIEW: RECENT CLINICAL TRIALS IN EPIGENETIC THERAPY. EPIGENETIC FACTORS SUCH AS DNA METHYLATION AND HISTONE DEACETYLATION ARE KNOWN TO CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF CELLS BY SILENCING CRITICAL GENES. DRUGS THAT INHIBIT DNA METHYLTRANSFERASES OR HISTONE DEACETYLASES WERE SHOWN TO HAVE THE POTENTIAL TO REACTIVATE SILENCED GENES AND INDUCE DIFFERENTIATION OR APOPTOSIS OF MALIGNANT CELLS. THE MOST INTENSIVELY STUDIED CLASS OF SUCH AGENTS IS DNA METHYLTRANSFERASE INHIBITORS, INCLUDING 5-AZACYTIDINE (AZACITIDINE) AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE). IN 2004, AZACITIDINE WAS APPROVED FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME ON THE BASIS OF PHASE II AND III STUDIES THAT SHOWED A RESPONSE RATE (COMPLETE AND PARTIAL RESPONSES) OF 15%. AZACITIDINE IS ALSO BEING EVALUATED IN CLINICAL TRIALS FOR OTHER MALIGNANT DISEASES. DECITABINE HAS RESPONSE RATES OF 17-49% IN MYELODYSPLASTIC SYNDROME IN MULTIPLE PHASE II AND III STUDIES AND ALSO ACTIVITY IN ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA. HISTONE DEACETYLASE INHIBITORS BELONG TO ANOTHER CLASS OF EPIGENETIC MODIFYING AGENTS THAT INCLUDE DEPSIPEPTIDE, BUTYRATE DERIVATIVES, SUBEROYLANILIDE HYDROXAMIC ACID AND VALPROIC ACID. NO AGENT IN THIS CLASS HAS BEEN STUDIED IN A PHASE III TRIAL, BUT SEVERAL AGENTS HAVE BEEN OR ARE BEING STUDIED IN PHASE II TRIALS. FURTHER RESEARCH IS NEEDED TO DETERMINE THE APPROPRIATE PATIENT SELECTION AND DOSING SCHEDULES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  6617  24 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  4847  30 OPIOID DEPENDENCE AND PREGNANCY: MINIMIZING STRESS ON THE FETAL BRAIN. INCREASE IN THE NUMBER OF OPIOID-DEPENDENT PREGNANT WOMEN DELIVERING BABIES AT RISK FOR NEONATAL ABSTINENCE SYNDROME PROMPTED A US GOVERNMENT ACCOUNTABILITY OFFICE REPORT DOCUMENTING DEFICITS IN RESEARCH AND PROVIDER KNOWLEDGE ABOUT CARE OF THE MATERNAL/FETAL UNIT AND THE NEONATE. THERE ARE 3 GENERAL SOURCES OF DEPENDENCE: UNTREATED OPIOID USE DISORDER, PAIN MANAGEMENT, AND MEDICATION-ASSISTED TREATMENT WITH METHADONE OR BUPRENORPHINE. A SURVEY OF METHADONE PATIENTS' EXPERIENCES WHEN TELLING A PHYSICIAN OF THEIR PREGNANCY AND OPIOID DEPENDENCE DEMONSTRATED PHYSICIAN CONFUSION ABOUT PROPER CARE, FREQUENT NEGATIVE INTERACTIONS WITH THE MOTHER, AND FAILURES TO PROVIDE APPROPRIATE REFERRAL. PATIENTS IN PAIN MANAGEMENT WERE DISCHARGED WITHOUT REFERRAL WHEN THE PHYSICIAN WAS TOLD OF THE PREGNANCY. METHADONE AND BUPRENORPHINE WERE FREQUENTLY SEEN NEGATIVELY BECAUSE THEY "CAUSED" NEONATAL ABSTINENCE SYNDROME. MOST MOTHERS SURVEYED HAD TO FIND OPIOID TREATMENT ON THEIR OWN. HOW DEPENDENCE IS MANAGED MEDICALLY IS A CRITICAL DETERMINANT OF THE LEVEL OF STRESS ON BOTH MOTHER AND FETUS, AND THEREFORE ANOTHER DETERMINANT OF NEONATAL HEALTH. THE EFFECTS OF BOTH OPIOID WITHDRAWAL STRESS AND MATERNAL EMOTIONAL STRESS ON NEONATAL AND DEVELOPMENTAL OUTCOMES ARE REVIEWED. CURRENTLY, THERE HAVE BEEN EFFORTS TO CRIMINALIZE MATERNAL OPIOID DEPENDENCE AND TO ENCOURAGE OR COERCE PREGNANT WOMEN TO UNDERGO WITHDRAWAL. THIS PRACTICE POSES BOTH ACUTE RISKS OF FETAL HYPOXIA AND LONG-TERM RISKS OF ADVERSE EPIGENETIC PROGRAMMING RELATED TO CATECHOLAMINE AND CORTICOSTEROID SURGES DURING WITHDRAWAL. CONTEMPORARY STUDIES OF THE EFFECTS OF WITHDRAWAL STRESS ON THE DEVELOPING FETAL BRAIN ARE URGENTLY NEEDED TO ELUCIDATE AND QUANTIFY THE RISKS OF SUCH PRACTICES. AT BIRTH, INCONSISTENCIES IN THE HOSPITAL MANAGEMENT OF NEONATES AT RISK FOR NEONATAL ABSTINENCE SYNDROME HAVE BEEN OBSERVED. NEGLECT OF THE CRITICAL ROLE OF MATERNAL COMFORTING IN NEONATAL ABSTINENCE SYNDROME MANAGEMENT IS AN IATROGENIC AND PREVENTABLE CAUSE OF POOR OUTCOMES AND LONG HOSPITALIZATIONS. ROOMING-IN ALLOWS FOR CONTINUOUS CARE OF THE BABY AND MATERNAL/NEONATAL ATTACHMENT, OFTEN UNWITTINGLY DISRUPTED BY THE NEONATAL INTENSIVE CARE UNIT ENVIRONMENT. RECOMMENDATIONS ARE MADE FOR FURTHER RESEARCH INTO PHYSICIAN/PATIENT INTERACTIONS AND INTO OPTIMAL DOSING OF METHADONE AND BUPRENORPHINE TO MINIMIZE MATERNAL/FETAL WITHDRAWAL.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  6574  31 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  5056  30 PHASE I TRIAL OF LOW DOSE DECITABINE TARGETING DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA AND NON-HODGKIN LYMPHOMA: DOSE-LIMITING MYELOSUPPRESSION WITHOUT EVIDENCE OF DNA HYPOMETHYLATION. TARGETING ABERRANT DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN LYMPHOMA (NHL) WITH DECITABINE MAY REVERSE EPIGENETIC SILENCING IN B-CELL MALIGNANCIES. TWENTY PATIENTS WERE ENROLLED IN TWO PHASE I TRIALS TO DETERMINE THE MINIMUM EFFECTIVE PHARMACOLOGICAL DOSE OF DECITABINE IN PATIENTS WITH RELAPSED/REFRACTORY CLL (N = 16) AND NHL (N = 4). PATIENTS RECEIVED 1-3 CYCLES OF DECITABINE. DOSE-LIMITING TOXICITY (DLT) WAS OBSERVED IN 2 OF 4 CLL AND 2 OF 2 NHL PATIENTS RECEIVING DECITABINE AT 15 MG/M(2) PER D DAYS 1-10, CONSISTING OF GRADE 3-4 THROMBOCYTOPENIA AND HYPERBILIRUBINAEMIA. SIX PATIENTS WITH CLL RECEIVED DECITABINE AT 10 MG/M(2) PER D DAYS 1-10 WITHOUT DLT; HOWEVER, RE-EXPRESSION OF METHYLATED GENES OR CHANGES IN GLOBAL DNA METHYLATION WERE NOT OBSERVED. THEREFORE, A 5-DAY DECITABINE SCHEDULE WAS EXAMINED. WITH 15 MG/M(2) PER D DECITABINE DAYS 1-5, DLT OCCURRED IN 2 OF 6 CLL AND 2 OF 2 NHL PATIENTS, CONSISTING OF GRADE 3-4 NEUTROPENIA, THROMBOCYTOPENIA, AND FEBRILE NEUTROPENIA. EIGHT PATIENTS HAD STABLE DISEASE. IN 17 PATIENTS, THERE WERE NO SIGNIFICANT CHANGES IN GENOME-WIDE METHYLATION OR IN TARGET GENE RE-EXPRESSION. IN CONCLUSION, DOSE-LIMITING MYELOSUPPRESSION AND INFECTIOUS COMPLICATIONS PREVENTED DOSE ESCALATION OF DECITABINE TO LEVELS ASSOCIATED WITH CHANGES IN GLOBAL METHYLATION OR GENE RE-EXPRESSION IN CLL AND NHL.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  6689  39 VALPROIC ACID AT THERAPEUTIC PLASMA LEVELS MAY INCREASE 5-AZACYTIDINE EFFICACY IN HIGHER RISK MYELODYSPLASTIC SYNDROMES. PURPOSE: EPIGENETIC CHANGES PLAY A ROLE AND COOPERATE WITH GENETIC ALTERATIONS IN THE PATHOGENESIS OF MYELODYSPLASTIC SYNDROMES (MDS). WE CONDUCTED A PHASE II MULTICENTER STUDY ON THE COMBINATION OF THE DNA-METHYLTRANSFERASE INHIBITOR 5-AZACYTIDINE (5-AZA) AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID (VPA) IN PATIENTS WITH HIGHER RISK MDS. EXPERIMENTAL DESIGN: WE ENROLLED 62 PATIENTS WITH MDS (REFRACTORY ANEMIA WITH EXCESS BLASTS, 39 PATIENTS; REFRACTORY ANEMIA WITH EXCESS BLASTS IN TRANSFORMATION, 19 PATIENTS; AND CHRONIC MYELOMANOCYTIC LEUKEMIA (CMML), 4 PATIENTS) AND AN INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS) RATING OF INTERMEDIATE-2 (42 PATIENTS) OR HIGH (20 PATIENTS). VPA WAS GIVEN TO REACH A PLASMA CONCENTRATION OF >50 MICROG/ML, THEN 5-AZA WAS ADDED S.C. AT 75 MG/M(2) FOR 7 DAYS IN EIGHT MONTHLY CYCLES. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS 14.4 MONTHS. AT A MEDIAN FOLLOW-UP OF 12 MONTHS (RANGE, 0.7-21.0), THE DISEASE PROGRESSED IN 20 PATIENTS, WITH 21% CUMULATIVE INCIDENCE OF PROGRESSION. OF 26 PATIENTS WHO COMPLETED EIGHT CYCLES, 30.7% OBTAINED COMPLETE OR PARTIAL REMISSION, 15.4% HAD A MAJOR HEMATOLOGIC IMPROVEMENT, WHEREAS 38.5% SHOWED STABLE DISEASE. DRUG-RELATED TOXICITY WAS MILD. FAVORABLE PROGNOSTIC FACTORS FOR SURVIVAL WERE IPSS INTERMEDIATE-2 AND PLASMA VPA OF > OR =50 MICROG/ML (LOG RANK = 0.013 AND 0.007, RESPECTIVELY). ANALYSIS OF POLYMORPHISMS IMPORTANT FOR THE METABOLISM OF THE DRUGS USED IN THE TRIAL SHOWED THAT CARRIERS OF THE CYP2C19*2 VARIANT OF CYTOCHROME P450 REQUIRED HIGHER VPA DOSES TO ACHIEVE THE TARGET VPA PLASMA CONCENTRATION OF 50 MICROG/ML ON DAY 1 OF 5-AZA TREATMENT (P = 0.0021). CONCLUSION: OUR DATA SHOW THAT THE 5-AZA/VPA COMBINATION IS ACTIVE AND SAFE IN PATIENTS WITH MDS WITH A POOR PROGNOSIS. ACHIEVEMENT OF VPA THERAPEUTIC LEVELS MAY INDEED INCREASE 5-AZA EFFICACY.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20    87  44 A PHASE 1 STUDY OF AZACITIDINE WITH HIGH-DOSE CYTARABINE AND MITOXANTRONE IN HIGH-RISK ACUTE MYELOID LEUKEMIA. IN THIS PHASE 1 STUDY, AZACITIDINE (AZA) WAS GIVEN BEFORE HIGH-DOSE CYTARABINE (HIDAC) AND MITOXANTRONE (MITO) BASED ON THE HYPOTHESIS THAT EPIGENETIC PRIMING WITH A HYPOMETHYLATING AGENT BEFORE CYTOTOXIC CHEMOTHERAPY WOULD IMPROVE RESPONSE RATES IN PATIENTS WITH HIGH-RISK ACUTE MYELOID LEUKEMIA (AML), INCLUDING RELAPSED/REFRACTORY DISEASE. THE PRIMARY OBJECTIVE WAS TO ESTABLISH THE RECOMMENDED PHASE 2 DOSE OF AZA GIVEN BEFORE STANDARD HIDAC/MITO. IN A DOSE ESCALATION SCHEME, 46 PATIENTS (MEDIAN AGE, 66 YEARS) RECEIVED AZA AT 37.5, 50, OR 75 MG/M2 SUBCUTANEOUSLY OR IV ONCE DAILY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10 (THE HIDAC/MITO DOSE WAS REDUCED 33% IN ELDERLY SUBJECTS). TWO DOSE-LIMITING TOXICITIES OCCURRED (BOTH IN THE SAME PATIENT): ACUTE LIVER FAILURE AND KIDNEY INJURY AT THE 50 MG/M2 DOSE. THE 30-DAY INDUCTION DEATH RATE WAS 2.2% (1 OF 46). THE OVERALL RESPONSE RATE, INCLUDING COMPLETE REMISSION AND COMPLETE REMISSION WITH INCOMPLETE COUNT RECOVERY, WAS 61% (28 OF 46). PREVIOUSLY UNTREATED PATIENTS AGED >/=60 YEARS WITH THERAPY-RELATED AML AND DE NOVO AML WERE MORE LIKELY TO RESPOND THAN UNTREATED PATIENTS WITH AML PROGRESSING FROM AN ANTECEDENT HEMATOLOGIC DISORDER (MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA). PATIENTS WITH FAVORABLE EUROPEAN LEUKEMIA NETWORK RISK (P = .008), NPM1 MUTATIONS (P = .007), OR IDH2 MUTATIONS (P = .03) WERE MORE LIKELY TO RESPOND, AND THOSE WITH TP53 MUTATIONS (P = .03) WERE LESS LIKELY TO RESPOND. THE RECOMMENDED PHASE 2 DOSE OF AZA IS 75 MG/M2 PER DAY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10. THIS TRIAL WAS REGISTERED AT WWW.CLINICALTRIALS.GOV AS #NCT01839240.	2020