ABSTRACT
The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) and the 5th edition of the WHO classification (WHO 2022) have refined the diagnosis of myelodysplastic syndromes (MDS). Both classifications segregate MDS subtypes based on molecular or cytogenetic findings but rely on the subjective assessment of blast cell percentage and dysplasia in hematopoietic cell lineages. This study aimed to evaluate interobserver concordance among 13 cytomorphologists from eight hospitals in assessing blast percentages and dysplastic features in 44 MDS patients. The study found fair interobserver agreement for the PB blast percentage and moderate agreement for the BM blast percentage, with the best concordance in cases with <5% BM blasts and >10% BM blasts. Monocyte count agreement was fair, and dysplasia assessment showed moderate concordance for megakaryocytic lineage but lower concordance for erythroid and granulocytic lineages. Overall, interobserver concordance for MDS subtypes was moderate across all classifications, with slightly better results for WHO 2022. These findings highlight the ongoing need for morphological evaluation in MDS diagnosis despite advances in genetic and molecular techniques. The study supports the blast percentage ranges established by the ICC but suggests refining BM blast cutoffs. Given the moderate interobserver concordance, a unified classification approach for MDS is recommended.
ABSTRACT
Studies prior to next-generation sequencing (NGS) showed that the frequent indolent course of chronic lymphocytic leukaemia (CLL) is related to most cells remaining quiescent in the G0 -G1 cell cycle phase, due to the expression of dysregulated cyclin genes. Of note, the activating nature of the NOTCH1 mutation in T lymphoblastic leukaemia also drives the dysregulation of cell cycle genes. Our goal was to comprehensively revisit the cell cycle in NOTCH1-mutated CLL (NOTCH1MUT ) to test for potential therapeutic targets. Among 378 NGS-annotated CLL cases, NOTCH1MUT cells displayed a unique transcriptome profile of G0 -G1 cell cycle components, with an overexpression of early-phase effectors, reaching a 38-, 27- and ninefold change increase for the complex elements CCND3, CDK4 and CDK6, respectively. This NOTCH1MUT cells' profile was related to more cells traversing through the cell cycle. In-vitro targeted inhibition of NOTCH1 gamma-secretase and CDK4/6 reversed the distribution of cells through the cycle phases and enhanced the killing of NOTCH1MUT CLL cells, suggesting new therapeutic approaches.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Cyclins/genetics , Cell Cycle/genetics , Cell Division , Mutation , Receptor, Notch1/genetics , Receptor, Notch1/metabolismABSTRACT
BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.
Subject(s)
Lymphoma, Follicular , Positron Emission Tomography Computed Tomography , Humans , Positron Emission Tomography Computed Tomography/methods , Fluorodeoxyglucose F18 , Lymphoma, Follicular/diagnostic imaging , Lymphoma, Follicular/pathology , Bone Marrow/diagnostic imaging , Bone Marrow/pathology , Prognosis , Cohort Studies , Retrospective Studies , Positron-Emission Tomography/methods , BiopsyABSTRACT
The game-changing outcome effect, due to the generalized use of novel agents in MM, has cre-ated a paradigm shift. Achieving frequent deep responses has placed MM among those neoplasms where the rationale for assessing MRD is fulfilled. However, its implementation in MM has raised specific questions: how might we weight standard measures against deep MRD in the emerging CAR-T setting? Which high sensitivity method to choose? Are current response criteria still useful? In this work, we address lessons learned from the use of MRD in other neoplasms, the steps followed for the harmonization of current methods for comprehensively measuring MRD, and the challenges that new therapies and concepts pose in the MM clinical field.
Subject(s)
Hematopoietic Stem Cell Transplantation , Neoplasms , Exome , Humans , Stem Cell Transplantation , Exome SequencingSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Follicular/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Abnormal Karyotype , Antigens, Neoplasm/analysis , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Asparaginase/administration & dosage , Biomarkers, Tumor/analysis , Biopsy , Cyclophosphamide/administration & dosage , DNA Nucleotidylexotransferase/analysis , Disease Progression , Doxorubicin/administration & dosage , Fatal Outcome , Female , Humans , Lymphoma, Follicular/drug therapy , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Pancytopenia/etiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisone/administration & dosage , Recurrence , Rituximab/administration & dosage , Salvage Therapy , Splenic Rupture/etiology , Splenomegaly/etiology , Stomach/pathology , Vincristine/administration & dosageSubject(s)
Lymphoma, Follicular , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Diagnosis, Differential , Female , Humans , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/pathology , Middle Aged , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.
Subject(s)
Bone Marrow/diagnostic imaging , Bone Marrow/pathology , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/pathology , Positron Emission Tomography Computed Tomography , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Cyclophosphamide/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Follow-Up Studies , Health Status , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Prednisone/therapeutic use , Retrospective Studies , Rituximab/administration & dosage , Survival Rate , Vincristine/therapeutic use , Young Adult , beta 2-Microglobulin/bloodABSTRACT
Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.
Subject(s)
Biomarkers, Tumor/genetics , Chromosome Deletion , Chromosomes, Human, Pair 8 , Karyotype , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Female , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Multivariate Analysis , Mutation , Phenotype , Proportional Hazards Models , Risk Factors , Spain , Time Factors , Treatment OutcomeABSTRACT
No disponible
Subject(s)
Female , Humans , Mastocytosis/congenital , Mastocytosis/metabolism , Leukemia, Biphenotypic, Acute/blood , Leukemia, Biphenotypic, Acute/genetics , Asthenia/complications , Asthenia/metabolism , Hematinics/administration & dosage , Hematinics/metabolism , Mastocytosis/genetics , Mastocytosis/pathology , Leukemia, Biphenotypic, Acute/metabolism , Leukemia, Biphenotypic, Acute/pathology , Asthenia/diagnosis , Asthenia/prevention & control , Hematinics , Hematinics/supply & distributionSubject(s)
Bone Marrow/pathology , Hodgkin Disease/diagnosis , Lymphoma, Non-Hodgkin/diagnosis , Female , Humans , MaleABSTRACT
Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non-Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary.
Subject(s)
Bone Marrow/pathology , Hodgkin Disease/diagnosis , Lymphoma, Non-Hodgkin/diagnosis , Adolescent , Adult , Aged , Biopsy , Female , Fluorodeoxyglucose F18/metabolism , Hodgkin Disease/metabolism , Hodgkin Disease/pathology , Humans , Lymphoma, Non-Hodgkin/classification , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Multimodal Imaging/methods , Neoplasm Grading , Neoplasm Staging , Positron-Emission Tomography , Tomography, X-Ray ComputedSubject(s)
Leukemia, Mast-Cell/etiology , Leukemia, Myeloid, Acute/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/administration & dosage , Disease Progression , Drug Resistance, Neoplasm , Fatal Outcome , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Transplantation , Humans , Idarubicin/administration & dosage , Immunophenotyping , Leukemia, Mast-Cell/diagnosis , Leukemia, Mast-Cell/drug therapy , Leukemia, Mast-Cell/pathology , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mast Cells/pathology , Mutation , Neoplasm Proteins/analysis , Neoplastic Stem Cells/pathology , Prognosis , Vidarabine/administration & dosage , Vidarabine/analogs & derivativesABSTRACT
Deletion of 13q14 as the sole abnormality is a good prognostic marker in chronic lymphocytic leukemia (CLL). Nonetheless, the prognostic value of reciprocal 13q14 translocations [t(13q)] with related 13q losses has not been fully elucidated. We described clinical and biological characteristics of 25 CLL patients with t(13q), and compared with 62 patients carrying interstitial del(13q) by conventional G-banding cytogenetics (CGC) [i-del(13q)] and 295 patients with del(13q) only detected by fluorescence in situ hybridization (FISH) [F-del(13q)]. Besides from the CLL FISH panel (D13S319, CEP12, ATM, TP53), we studied RB1 deletions in all t(13q) cases and a representative group of i-del(13q) and F-del(13q). We analyzed NOTCH1, SF3B1, and MYD88 mutations in t(13q) cases by Sanger sequencing. In all, 25 distinct t(13q) were described. All these cases showed D13S319 deletion while 32% also lost RB1. The median percentage of 13q-deleted nuclei did not differ from i-del(13q) patients (73% vs. 64%), but both were significantly higher than F-del(13q) (52%, P < 0.001). Moreover, t(13q) patients showed an increased incidence of biallelic del(13q) (52% vs. 11.3% and 14.9%, P < 0.001) and higher rates of concomitant 17p deletion (37.5% vs. 8.6% and 7.2%, P < 0.001). RB1 involvement was significantly higher in the i-del(13q) group (79%, P < 0.001). Two t(13q) patients (11.8%) carried NOTCH1 mutations. Time to first treatment in t(13q) and i-del(13q) was shorter than F-del(13q) (67, 44, and 137 months, P = 0.029), and preserved significance in the multivariate analysis. In conclusion, t(13q) and del(13q) patients detected by CGC constitute a subgroup within the 13q-deleted CLL patients associated with a worse clinical outcome.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Cohort Studies , Female , Humans , Karyotype , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Myeloid Differentiation Factor 88/genetics , Phosphoproteins/genetics , Prognosis , RNA Splicing Factors , Receptor, Notch1/genetics , Retinoblastoma Protein/genetics , Ribonucleoprotein, U2 Small Nuclear/geneticsABSTRACT
No disponible
No disponible