1 3317 157 HISTOLOGICAL TRANSFORMATION TO SIGNET-RING CELL CARCINOMA IN A PATIENT WITH CLINICALLY AGGRESSIVE POORLY DIFFERENTIATED ADENOCARCINOMA OF THE ASCENDING COLON AFTER RESPONSE TO CHEMOTHERAPY PLUS CETUXIMAB: A CASE REPORT. BACKGROUND: ALTERATION OF CHEMOSENSITIVITY OR TUMOR AGGRESSIVENESS IN RESPONSE TO CHEMOTHERAPY HAS BEEN REPORTED, AND LIQUID BIOPSY ASSESSMENT DURING CHEMOTHERAPY FOR COLORECTAL CANCERS HAS CONFIRMED THE ACQUISITION OF MUTATIONS IN VARIOUS ONCOGENES. HOWEVER, THE OCCURRENCE OF HISTOLOGICAL TRANSFORMATION SEEMS TO BE EXTREMELY RARE IN COLORECTAL CANCERS, AND THE FEW EXISTING CASE REPORTS OF THIS TRANSFORMATION ARE FROM LUNG CANCER AND BREAST CANCER. IN THIS REPORT, WE DESCRIBE THE HISTOLOGICAL TRANSFORMATION OF CLINICALLY AGGRESSIVE SCIRRHOUS-TYPE POORLY DIFFERENTIATED ADENOCARCINOMA OF THE ASCENDING COLON TO SIGNET-RING CELL CARCINOMA IN ALMOST ALL RECURRENT TUMORS THAT WERE CONFIRMED BY AUTOPSY AFTER RESPONSE TO CHEMOTHERAPY PLUS CETUXIMAB. CASE PRESENTATION: A 59-YEAR-OLD WOMAN VISITED OUR HOSPITAL WITH WHOLE ABDOMINAL PAIN AND BODY WEIGHT LOSS AND WAS DIAGNOSED WITH SCIRRHOUS-TYPE POORLY DIFFERENTIATED ADENOCARCINOMA OF THE ASCENDING COLON WITH AGGRESSIVE LYMPH NODE METASTASES. THE INTRINSIC CHEMOSENSITIVITY OF THE TUMORS WAS EVIDENT UPON INITIATION OF MFOLFOX6 PLUS CETUXIMAB THERAPY, AND RIGHT HEMICOLECTOMY WAS PERFORMED, AND THE TUMOR OBVIOUSLY REMAINED IN THE PERIPANCREATIC AREA, PARAAORTIC REGION, OR OTHER RETROPERITONEAL AREAS. THE ASCENDING COLON TUMORS MAINLY CONSISTED OF POORLY DIFFERENTIATED ADENOCARCINOMA AND WERE NOT ASSOCIATED WITH SIGNET-RING CELL COMPONENTS EXCEPT FOR MINUTE CLUSTERS IN A FEW LYMPHATIC EMBOLI IN THE MAIN TUMOR. CHEMOTHERAPY WAS CONTINUED, AND METASTASES WERE ELIMINATED AT 8 MONTHS AFTER THE OPERATION; THIS RESPONSE WAS MAINTAINED FOR AN ADDITIONAL 4 MONTHS. DISCONTINUATION OF CHEMOTHERAPY PLUS CETUXIMAB RESULTED IN IMMEDIATE TUMOR RECURRENCE AND RAPID EXPANSION, AND THE PATIENT DIED OF THE RECURRENT TUMOR 1 YEAR AND 2 MONTHS AFTER THE OPERATION. AUTOPSY SPECIMENS REVEALED THAT ALMOST ALL OF THE RECURRENT TUMORS EXHIBITED TRANSFORMATION AND CONSISTED OF SIGNET-RING CELL HISTOLOGY. CONCLUSION: THIS CASE MIGHT SUGGEST THAT VARIOUS ONCOGENE MUTATIONS OR EPIGENETIC CHANGES RESULTING FROM CHEMOTHERAPY, ESPECIALLY REGIMENS THAT INCLUDE CETUXIMAB, CONTRIBUTE TO THE TRANSFORMATION OF NON-SIGNET-RING CELL COLORECTAL CARCINOMA TO SIGNET-RING CELL CARCINOMA HISTOLOGY AND CAN PROMOTE THE AGGRESSIVE CLINICAL PROGRESSION CHARACTERISTIC OF SIGNET-RING CELL CARCINOMA. 2023 2 4918 29 PANCREATIC CANCER: FROM BENCH TO 5-YEAR SURVIVAL. PANCREATIC DUCTAL ADENOCARCINOMA IS ONE OF THE MOST AGGRESSIVE HUMAN MALIGNANCIES, WITH AN OVERALL 5-YEAR SURVIVAL RATE OF LESS THAN 4%. ON THE MOLECULAR LEVEL, AN INCREASING NUMBER OF GENETIC AND EPIGENETIC ALTERATIONS HAVE BEEN DISCOVERED, WITH A PARTICULAR FOCUS ON GROWTH FACTORS AND RELATED PATHWAYS. SMALL-MOLECULE TYROSINE KINASE INHIBITORS, ANTIBODIES, AND OTHER APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS TO TARGET THESE SIGNAL TRANSDUCTION PATHWAYS, AND FIRST CLINICAL TRIALS SHOW ENCOURAGING RESULTS. IN ADDITION, MOLECULAR ALTERATIONS HAVE BEEN IDENTIFIED THAT ENABLE THE CANCER CELLS TO INVADE THE PERINEURIUM AND THE RETROPERITONEAL SPACE, THUS EXPLAINING AT LEAST IN PART THE HIGH RATE OF LOCAL RECURRENCE AND THE SEVERE PAIN SYNDROME. TECHNICALLY, PANCREATIC SURGERY HAS ADVANCED, WITH ACCEPTABLE MORBIDITY AND MORTALITY RATES IN HIGH-VOLUME CENTERS. RANDOMIZED CONTROLLED TRIALS ARE INCREASINGLY CARRIED OUT TO DEFINE THE BEST PALLIATIVE AND ADJUVANT THERAPY FOR THIS DISEASE. TRANSLATIONAL RESEARCH COMBINED WITH CLINICAL TRIALS WILL HOPEFULLY LEAD TO IMPROVED SURVIVAL AND BETTER QUALITY OF LIFE FOR PANCREATIC CANCER PATIENTS IN THE FUTURE. 2006 3 3872 33 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 4 4760 24 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS. 2020 5 261 35 ADVANCES IN TARGET THERAPY FOR LUNG CANCER. RECENT PROGRESS IN MOLECULAR BIOLOGY HAS SHOWN THAT CANCER CELLS ACQUIRE COMMON PHENOTYPES SUCH AS SELF-SUFFICIENCY OF GROWTH SIGNALS, RESISTANCE TO ANTI-PROLIFERATIVE AND APOPTOTIC SIGNALS THROUGH THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES. RECENTLY DEVELOPED ANTICANCER DRUGS TARGET THESE MOLECULAR MECHANISMS AND GOOD RESULTS HAVE BEEN REPORTED FOR VARIOUS CANCER TYPES. IN LUNG CANCER, TYROSINE KINASE INHIBITORS SPECIFIC FOR THE EPIDERMAL GROWTH FACTOR RECEPTOR SUCH AS GEFITINIB AND ERLOTINIB HAVE CHANGED CLINICAL PRACTICE DRAMATICALLY. ABOUT HALF OF THE JAPANESE PATIENTS WITH LUNG CANCERS HARBOR AN ACTIVATING MUTATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR GENE AND THEY ARE VERY SENSITIVE TO EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS. PROGRESSION-FREE SURVIVAL OF SUCH PATIENTS IS APPROXIMATELY 10 MONTHS WHEN TREATED WITH GEFITINIB, WHEREAS THE SURVIVAL FOR THOSE TREATED WITH PLATINUM DOUBLET THERAPY IS APPROXIMATELY 6 MONTHS. TARGET THERAPIES AGAINST ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 4-ANAPLASTIC LYMPHOMA KINASE FUSION PROTEIN OR A MUTATED ERBB2 (V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOGUE 2) PRESENT IN APPROXIMATELY 5% AND APPROXIMATELY 3% OF THE JAPANESE PATIENTS WITH ADENOCARCINOMAS, RESPECTIVELY, ARE CURRENTLY UNDER DEVELOPMENT. ADDITION OF AN ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY, CETUXIMAB, OR ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY, BEVACIZUMAB, TO PLATINUM DOUBLET THERAPY SIGNIFICANTLY BUT MODESTLY PROLONGED THE SURVIVAL IN RECENT CLINICAL TRIALS. HOWEVER, CLINICAL DEVELOPMENT OF SMALL MOLECULE MULTI-KINASE INHIBITORS INCLUDING THOSE TARGETING VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS, SUCH AS VANDETANIB, SUNITINIB AND SORAFENIB, HAS NOT BEEN VERY SUCCESSFUL. THROUGH THESE COLLABORATIONS AMONG CLINICIANS, BASIC RESEARCHERS AND PHARMACEUTICAL COMPANIES, IT SHOULD BE POSSIBLE TO INDIVIDUALIZE LUNG CANCER TREATMENT TO TURN THIS FATAL DISEASE INTO A CHRONIC DISORDER AND, EVENTUALLY, TO CURE IT. 2010 6 765 31 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 7 5245 28 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS. 2018 8 6437 23 THERAPEUTIC ADVANCES IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME OVER THE PAST 40 YEARS. MAJOR THERAPEUTIC PROGRESS HAS BEEN ACCOMPLISHED IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME (MDS) OVER THE PAST 40 YEARS, WHICH MAY NOT BE FULLY APPRECIATED BY THE LARGER MEDICAL COMMUNITY. THE OBJECTIVE OF THIS REVIEW WAS TO BRIEFLY HIGHLIGHT THE TREATMENT BREAKTHROUGHS IN LEUKEMIA AND MDS. THERAPEUTIC PROGRESS HAPPENED THROUGH BETTER UNDERSTANDING OF DISEASE PATHOPHYSIOLOGIES AND RATIONAL DEVELOPMENT OF TARGETED AGENTS, LIKE IMATINIB MESYLATE IN CHRONIC MYELOID LEUKEMIA (CML), AND THROUGH ASTUTE, EMPIRICAL DISCOVERIES IN THE CLINIC, LIKE ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN ACUTE PROMYELOCYTIC LEUKEMIA (APL) AND CHLORODEOXYADENOSINE IN HAIRY CELL LEUKEMIA (HCL). TODAY, THE 5- TO 10-YEAR SURVIVAL RATES IN PATIENTS WITH APL AND HCL EXCEED 80%. IN PATIENTS WITH CML, IMATINIB THERAPY HAS BEEN ASSOCIATED WITH ESTIMATED 5- TO 7-YEAR SURVIVAL RATES FROM 85% TO 90%. IN PATIENTS WITH ADULT ACUTE LYMPHOCYTIC LEUKEMIA, MODERN INTENSIVE REGIMENS HAVE IMPROVED THE 5-YEAR SURVIVAL RATES FROM 20% UP TO 40%. IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA, CHEMOIMMUNOTHERAPY RECENTLY PRODUCED HIGH RATES OF QUALITY RESPONSES AND IMPROVED LONG-TERM OUTCOME. IN YOUNGER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML), THE 5-YEAR SURVIVAL RATES RANGE FROM 40% TO 50%, ALTHOUGH ELDERLY AML REMAINS A THERAPEUTIC CHALLENGE. IN PATIENTS WITH MDS, IT WAS RECENTLY DEMONSTRATED THAT EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENTS IMPROVED SURVIVAL. MUCH THERAPEUTIC PROGRESS HAS BEEN WITNESSED IN LEUKEMIA AND MDS, AND MUCH MORE IS EXPECTED TO OCCUR SOON. 2008 9 791 28 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 10 6574 27 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 11 6653 31 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 12 6857 31 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 13 5127 37 POSTMENOPAUSAL UTERINE LEIOMYOMAS AND CHRONIC LYMPHADENOPATHY: EXPLORING EPIGENETIC CHANGES AND PATHOPHYSIOLOGY. UTERINE LEIOMYOMAS (LM) ARE TUMORS ARISING FROM THE NON-NEOPLASTIC PROLIFERATION OF SMOOTH MUSCLE CELLS WITHIN THE MYOMETRIUM. LIKE BENIGN TUMORS, LM ARE NOT GENERALLY SPREAD THROUGH THE LYMPHATIC SYSTEM, AND THEREFORE SHOULD NOT BE ASSOCIATED WITH LYMPHADENOPATHY. HEREIN, WE PRESENT A CASE OF A 60-YEAR-OLD FEMALE WHO PRESENTED TO THE CLINIC WITH POSTMENOPAUSAL BLEEDING IN THE SETTING OF SONOGRAPHICALLY EVIDENT UTERINE LM AND ABDOMINAL LYMPHADENOPATHY. A LYMPH NODE BIOPSY REVEALED PLASMA CELLS AND AN EOSINOPHILIC MATERIAL PRESUMPTIVELY DIAGNOSED AS AMYLOID. SHE THEN UNDERWENT AN ABDOMINAL HYSTERECTOMY FOR DEFINITIVE TREATMENT OF LM. SURGICAL PATHOLOGY CONFIRMED THE CLINICAL DIAGNOSIS OF UTERINE AND CERVICAL LEIOMYOMA. CURRENT LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC ABNORMALITIES CONTRIBUTE TO THE PATHOGENESIS OF LM IN ADDITION TO HORMONAL SIGNALS SUCH AS ESTROGEN AND PROGESTERONE. IT IS UNUSUAL FOR LM TO OCCUR IN POST-MENOPAUSAL WOMEN DUE TO REDUCED HORMONAL INFLUENCE. THEREFORE, THIS CASE EXPLORED AN ALTERNATIVE MECHANISM OF TUMOR PROLIFERATION. THIS CASE HYPOTHESIZES THAT GENETIC MUTATIONS AND EPIGENETIC CHANGES RESULTING FROM CHRONIC INFLAMMATORY OFFENSES CONTRIBUTED TO LM GROWTH AND LYMPHADENOPATHY. 2021 14 5969 34 TERT PROMOTER MUTATIONS IN PRIMARY LIVER TUMORS. NEXT-GENERATION SEQUENCING HAS DRAWN THE GENETIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA AND SEVERAL SIGNALING PATHWAYS ARE ALTERED AT THE DNA LEVEL IN TUMORS: WNT/BETA-CATENIN, CELL CYCLE REGULATOR, EPIGENETIC MODIFIER, HISTONE METHYLTRANSFERASE, OXIDATIVE STRESS, RAS/RAF/MAP KINASE AND AKT/MTOR PATHWAYS. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS STARTING WITH THE EXPOSURE TO DIFFERENT RISK FACTORS, FOLLOWED BY THE DEVELOPMENT OF A CHRONIC LIVER DISEASE AND CIRRHOSIS PRECEDE IN THE VAST MAJORITY OF THE CASES THE DEVELOPMENT OF HCC. SEVERAL LINES OF EVIDENCE HAVE UNDERLINED THE PIVOTAL ROLE OF TELOMERE MAINTENANCE IN BOTH CIRRHOSIS AND HCC PATHOGENESIS. TERT PROMOTER MUTATIONS WERE IDENTIFIED AS THE MOST FREQUENT GENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH AN OVERALL FREQUENCY AROUND 60%. MOREOVER, IN CIRRHOSIS, TERT PROMOTER MUTATIONS ARE OBSERVED AT THE EARLY STEPS OF HEPATOCARCINOGENESIS SINCE THEY ARE RECURRENTLY IDENTIFIED IN LOW-GRADE AND HIGH-GRADE DYSPLASTIC NODULES. IN CONTRAST, ACQUISITION OF GENOMIC DIVERSITY THROUGH MUTATIONS OF CLASSICAL ONCOGENES AND TUMOR SUPPRESSOR GENES (TP53, CTNNB1, ARID1A...) OCCURRED ONLY IN PROGRESSED HCC. IN NORMAL LIVER, A SUBSET OF HCC CAN DERIVED FROM THE MALIGNANT TRANSFORMATION OF HEPATOCELLULAR ADENOMA (HCA). IN HCA, CTNNB1 MUTATIONS PREDISPOSE TO TRANSFORMATION OF HCA IN HCC AND TERT PROMOTER MUTATIONS ARE REQUIRED IN MOST OF THE CASES AS A SECOND HIT FOR A FULL MALIGNANT TRANSFORMATION. ALL THESE FINDINGS HAVE REFINED OUR KNOWLEDGE OF HCC PATHOGENESIS AND HAVE POINTED TELOMERASE AS A TARGET FOR TAILORED THERAPY IN THE FUTURE. 2016 15 953 26 CHRONIC MYELOID LEUKEMIA STEM CELLS. ALTHOUGH RARE, CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE MOLECULAR EVENTS LEADING TO MALIGNANT TRANSFORMATION OF PRIMITIVE HEMATOPOIETIC PROGENITORS. CML WAS THE FIRST CANCER TO BE ASSOCIATED WITH A DEFINED GENETIC ABNORMALITY, BCR-ABL, THAT IS NECESSARY AND SUFFICIENT FOR INITIATING CHRONIC PHASE DISEASE AS WELL AS THE FIRST CANCER TO BE TREATED WITH MOLECULAR TARGETED THERAPY. MALIGNANT PROGENITORS OR LEUKEMIA STEM CELLS (LSCS) EVOLVE AS A RESULT OF BOTH EPIGENETIC AND GENETIC EVENTS THAT ALTER HEMATOPOIETIC PROGENITOR DIFFERENTIATION, PROLIFERATION, SURVIVAL, AND SELF-RENEWAL. LSCS ARE RARE AND DIVIDE LESS FREQUENTLY, AND THUS, REPRESENT A RESERVOIR FOR RELAPSE AND RESISTANCE TO A MOLECULARLY TARGETED SINGLE AGENT. ON SUBVERTING DEVELOPMENTAL PROCESSES NORMALLY RESPONSIBLE FOR MAINTAINING ROBUST LIFE-LONG HEMATOPOIESIS, THE LSCS ARE ABLE TO EVADE THE MAJORITY OF CURRENT CANCER TREATMENTS THAT TARGET RAPIDLY DIVIDING CELLS. ENTHUSIASM FOR THE ENORMOUS SUCCESS OF TYROSINE KINASE INHIBITORS AT CONTROLLING THE CHRONIC PHASE DISEASE IS TEMPERED SOMEWHAT BY THE PERSISTENCE OF THE LSC POOL IN THE MAJORITY OF THE PATIENTS. COMBINED THERAPIES TARGETING ABERRANT PROPERTIES OF LSC MAY OBVIATE THERAPEUTIC RESISTANCE AND RELAPSE IN ADVANCED PHASE AND THERAPEUTICALLY RECALCITRANT CML. 2008 16 1445 37 DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA ARISING IN AN OVARIAN MATURE CYSTIC TERATOMA. IMMATURE NEUROECTODERMAL TISSUE CAN BE FOUND IN THE OVARY AS PART OF AN IMMATURE TERATOMA OR AS PART OF A TERATOMA WITH MALIGNANT NEUROECTODERMAL TRANSFORMATION. SUCH LESIONS MAY CLOSELY RESEMBLE CENTRAL NERVOUS SYSTEM TUMORS, BUT THEIR BIOLOGIC SIMILARITY IS UNCLEAR. WE DESCRIBE AN 18-YR-OLD FEMALE WHO PRESENTED WITH ABDOMINAL PAIN CAUSED BY AN OVARIAN MASS WITH WIDESPREAD METASTASES. HISTOLOGY SHOWED A PRIMITIVE, HIGH-GRADE TUMOR ARISING IN THE BACKGROUND OF A MATURE TERATOMA. THE TUMOR WAS SOX10 POSITIVE, WITH FOCAL EXPRESSION OF GFAP, S100, NSE, AND SYNAPTOPHYSIN. MOLECULAR ANALYSIS DEMONSTRATED CO-AMPLIFICATION OF PDGFRA AND KIT, ALTERATIONS COMMON IN HIGH-GRADE GLIOMAS. BY WHOLE-GENOME METHYLATION PROFILING, IT CLUSTERED INTO THE "DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA, RTK1 SUBTYPE, SUBCLASS C" GROUP. DESPITE PROGRESSING THROUGH 2 LINES OF CHEMOTHERAPY WITH WIDESPREAD METASTATIC DISEASE, SHE ACHIEVED AN EXCELLENT RESPONSE TO CHEMOTHERAPY DIRECTED TOWARD AGGRESSIVE GERM CELL TUMORS. THIS CASE EMPHASIZES THE IMPORTANCE OF IMMUNOHISTOCHEMICAL, GENOMIC, AND EPIGENETIC ANALYSES TO ACCURATELY CLASSIFY THESE EXCEEDINGLY RARE TUMORS AND DETERMINE THE OPTIMAL THERAPY. 2023 17 4334 20 MICRORNAS: NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS FOR PANCREATIC DUCTAL ADENOCARCINOMA? PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS KNOWN FOR ITS VERY POOR OVERALL PROGNOSIS, MAKING TOOLS FOR EARLY DIAGNOSIS AND NEW THERAPEUTIC MODALITIES URGENTLY NEEDED. MICRORNAS (MIRNAS), ENDOGENOUS NONCODING RNA MOLECULES OF APPROXIMATELY 22 NT, HAVE GAINED ATTENTION AS AN EPIGENETIC COMPONENT INVOLVED IN THE DEVELOPMENT OF MANY CANCERS, INCLUDING PDAC. MIRNA EXPRESSION PROFILES OF VARYING PANCREATIC TISSUES HAVE IDENTIFIED A NUMBER OF DIFFERENTIALLY EXPRESSED MIRNAS AND SEEM TO BE ABLE TO DIFFERENTIATE BETWEEN THREE TISSUES OF CLINICAL IMPORTANCE: NORMAL PANCREAS, CHRONIC PANCREATITIS, AND PDAC. THIS ARTICLE GATHERS OUR CURRENT KNOWLEDGE OF DIFFERENTIALLY EXPRESSED MIRNAS IN PANCREATIC TISSUES WITH RELEVANCE TO PDAC AND PRESENTS POTENTIAL DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES. 2009 18 1044 32 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE. 2021 19 3811 34 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 20 3985 38 LONG-TERM MAINTENANCE OF THE MUCOSAL HEALING INDUCED BY AZACITIDINE THERAPY IN A PATIENT WITH INTESTINAL BEHCET'S-LIKE DISEASE ACCOMPANIED WITH MYELODYSPLASTIC SYNDROME INVOLVING TRISOMY 8. MYELODYSPLASTIC SYNDROMES (MDSS) ARE A GROUP OF MYELOID NEOPLASMS CHARACTERIZED BY BLOOD CELL DEFORMATION AND DYSFUNCTION, AND MDS WITH TRISOMY 8 IS CLOSELY LINKED WITH INTESTINAL BEHCET'S-LIKE DISEASES. INTESTINAL BEHCET'S-LIKE DISEASE IS REFRACTORY TO CONVENTIONAL THERAPIES, INCLUDING PREDNISOLONE, IMMUNOMODULATORS, AND ANTI-TUMOR NECROSIS FACTOR ALPHA AGENTS. HERE, WE DESCRIBE A 56-YEAR-OLD WOMAN WITH INTESTINAL BEHCET'S-LIKE DISEASE ASCRIBED TO MDS WITH TRISOMY 8 WHO HAD MULTIPLE INTRACTABLE INTESTINAL ULCERS. SHE PRESENTED WITH PERIODIC FEVER AND ABDOMINAL PAIN. THE GENETIC ANALYSIS SHOWED A HETEROZYGOUS E148Q MUTATION IN THE MEDITERRANEAN FEVER GENE. THE PATIENT DID NOT TOLERATE TREATMENT WITH COLCHICINE BECAUSE OF DIARRHEA; THEREFORE, AZACITIDINE THERAPY WAS INITIATED. ONE CYCLE OF AZACITIDINE THERAPY IMPROVED THE MULTIPLE INTESTINAL ULCERS, AND THE PERIODIC FEVER AND ABDOMINAL PAIN GRADUALLY DISAPPEARED. AFTER EIGHT CYCLES OF AZACITIDINE THERAPY, ILEOCOLONOSCOPY, HISTOLOGICAL ASSESSMENT AND CAPSULE ENDOSCOPY REVEALED MUCOSAL HEALING. AZACITIDINE THERAPY WAS CONTINUED, AND MUCOSAL HEALING WAS MAINTAINED FOR MORE THAN 2 YEARS. THIS CASE SUGGESTS THAT AZACITIDINE THERAPY WHICH HAS IMMUNOREGULATORY EFFECTS AND EPIGENETIC MODULATIONS, MIGHT CONTROL INTESTINAL BEHCET'S-LIKE DISEASE ASSOCIATED WITH MDS INVOLVING TRISOMY 8. 2019