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Clinical Laboratory May 2024The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis.
BACKGROUND
The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis.
METHODS
The clinical manifestations and laboratory results (bone marrow cell morphology, multiparameter flow cytometry, and cytogenetics) of a case of Ph-positive mixed phenotype acute leukemia were analyzed, and related literature was reviewed.
RESULTS
Blood routine: WBC 386.35 x 109/L, HGB 117.00 g/L, PLT 31 x 109/L; 80% of the original cells can be seen by artificial classification. Morphological examination of bone marrow cells showed that the proliferation of nucleated cells was obviously active, and the original cells accounted for 76%. The size of the original cells was somewhat uniform, most of the cells had less mass, were stained light grayish blue, the cytoplasm particles were not obvious, the nuclei were mostly round or quasi-round, some of them showed distortion and nuclear notch, and the chromatin was coarse. Some of the cells were rich in mass, small azurin granules were seen, the nuclei were regular, most of them were round, the chromatin was fine, the myeloperoxidase and esterase staining were negative, the eosinophils accounted for 2.5%, and the basophils accounted for 0.5%. Flow cytometry immunotyping: Two groups of abnormal cells were seen in the bone marrow. 1. A group included 12.32% of nuclear cells and showed abnormal myeloid primitive cell phenotype. Main expression: CD117, CD34, CD38, HLA-DR, CD33, CD64, CD123, weak expression: CD13, CD19. 2. The other group included 45.61% of the nuclear cells and had a B-lymphoblastic phenotype. Main expression: CD34, CD38, HLA-DR, CD123, CD19, CD10, CD9, cCD79a, TDT, weak expression of CD13, CD22. Mixed phenotype acute leukemia (M/B) immunophenotype was considered. Chromosome: 46,XY,t(9; 22)(q34;q11.2) [20]. BCR-ABL (P210) fusion gene was positive.
CONCLUSIONS
Mixed phenotype acute leukemia (MPAL) is a rare type of malignant hematologic disease. Its diagnosis is based on the comprehensive evaluation of bone marrow cell morphology, immunophenotype, molecular and cytogenetic features.
Topics: Humans; Phenotype; Flow Cytometry; Male; Immunophenotyping; Bone Marrow Cells; Philadelphia Chromosome; Leukemia, Biphenotypic, Acute; Leukemia; Adult; Female; Middle Aged
PubMed: 38747916
DOI: 10.7754/Clin.Lab.2023.231220 -
BioRxiv : the Preprint Server For... Apr 2024Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in , the microtubule-associated...
Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in , the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.
PubMed: 38746388
DOI: 10.1101/2024.04.29.591661 -
Journal of Nanobiotechnology May 2024Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph) leukemia. However, a series of issues, including drug...
Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph leukemic cell lines for gene therapy of Ph leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph leukemia, but also enabled gene therapy against a less druggable target.
Topics: Fusion Proteins, bcr-abl; Animals; Humans; Mice; Cell Line, Tumor; Nanoparticles; Ubiquitin-Protein Ligases; Gene Silencing; RNA, Small Interfering; NEDD8 Protein; Mice, Inbred BALB C; Apoptosis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Genetic Therapy; Cell Proliferation; Female
PubMed: 38741123
DOI: 10.1186/s12951-024-02505-5 -
Nature Genetics May 2024We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated...
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.
Topics: Humans; Female; Genome-Wide Association Study; Genetic Predisposition to Disease; Breast Neoplasms; Polymorphism, Single Nucleotide; Black People; Case-Control Studies; Risk Factors; Triple Negative Breast Neoplasms; Alleles; Multifactorial Inheritance; Middle Aged; Genetic Loci; White People
PubMed: 38741014
DOI: 10.1038/s41588-024-01736-4 -
Leukemia Research Reports 2024A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of...
A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of mutations, including and mutations. Novel combination therapy with azacitidine, venetoclax and ponatinib allowed her to successfully achieve a complete response (CR) and undergo an allogeneic hematopoietic stem cell transplant (HSCT). This case report provides an overview of her clinical course, emphasizing the significance of integrated therapy and the challenges associated with balancing treatment for AML. It also underscores the importance of a multidisciplinary approach and careful monitoring of patients with complex hematologic conditions.
PubMed: 38736691
DOI: 10.1016/j.lrr.2024.100461 -
Blood Reviews Jul 2024There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the... (Review)
Review
There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the introduction of new immunotherapies and targeted agents, adoption of pediatric-type chemotherapy protocols in younger adults as well as chemotherapy light approaches in older adults and the incorporation of measurable residual disease (MRD) testing to inform clinical decision making. With this, treatment outcomes in adult Ph- ALL have improved across all age groups. However, a subset of patients will still develop relapsed disease, which can be challenging to treat and associated with poor outcomes. Here we review the treatment of Ph- ALL in both younger and older adults, including the latest advancements and future directions.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome; Neoplasm, Residual; Disease Management; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38734488
DOI: 10.1016/j.blre.2024.101208 -
Cancers Apr 2024Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis.... (Review)
Review
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
PubMed: 38730657
DOI: 10.3390/cancers16091705 -
Cancers Apr 2024The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key...
The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key diagnostic feature and is usually performed by the human eyes through an optical microscope with consequent inter-observer and intra-observer variability. Thus, the use of an automated tool may reduce variability, improving the uniformity of the evaluation. The aim of this work is to develop an accurate AI-based tool for the automated quantification of cellularity in BMB histology. A total of 55 BMB histological slides, diagnosed as Ph- MPN between January 2018 and June 2023 from the archives of the Pathology Unit of University "Luigi Vanvitelli" in Naples (Italy), were scanned on Ventana DP200 or Epredia P1000 and exported as whole-slide images (WSIs). Fifteen BMBs were randomly selected to obtain a training set of AI-based tools. An expert pathologist and a trained resident performed annotations of hematopoietic tissue and adipose tissue, and annotations were exported as .tiff images and .png labels with two colors (black for hematopoietic tissue and yellow for adipose tissue). Subsequently, we developed a semantic segmentation model for hematopoietic tissue and adipose tissue. The remaining 40 BMBs were used for model verification. The performance of our model was compared with an evaluation of the cellularity of five expert hematopathologists and three trainees; we obtained an optimal concordance between our model and the expert pathologists' evaluation, with poorer concordance for trainees. There were no significant differences in cellularity assessments between two different scanners.
PubMed: 38730640
DOI: 10.3390/cancers16091687 -
Medicine May 2024The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute... (Review)
Review
Philadelphia chromosome-positive acute myeloid leukemia successfully treated by allogeneic hematopoietic stem cell transplantation: A case report and review of the literature.
RATIONAL
The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute myeloid leukemia (Ph + AML) is a rare entity with a poor prognosis and a short median survival period. To date, there have been few clinical reports on this disease. And the treatment regimen of this disease has not been uniformly determined.
PATIENT CONCERNS
We report a case of a Ph + AML. A 32-year-old male who was admitted to our hospital with weakness for 2 months.
DIAGNOSIS
Philadelphia chromosome-positive acute myeloid leukemia.
INTERVENTIONS
The patient achieved complete remission by the administration of a tyrosine kinase inhibitor, combined with low-intensity chemotherapy and a B-cell lymphoma 2 inhibitor. Then, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his sister was successfully performed.
OUTCOMES
The patient has been in a continuous remission state for 6 months after transplantation.
LESSONS
We reported a rare Ph + AML case, successfully treated with allo-HSCT. This case provided strong support for treating Ph + AML with allo-HSCT.
Topics: Humans; Male; Hematopoietic Stem Cell Transplantation; Adult; Leukemia, Myeloid, Acute; Philadelphia Chromosome; Transplantation, Homologous; Remission Induction
PubMed: 38728478
DOI: 10.1097/MD.0000000000038110 -
American Journal of Hematology May 2024Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including... (Review)
Review
Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including T315I-mutated disease, which is resistant to first- and second-generation TKIs. Ponatinib was approved for T315I-mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph-positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I-mutated CML and Ph-positive ALL. The response-based dosing of ponatinib in chronic phase CML (CP-CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib-based therapy also resulted in significantly better outcomes in frontline Ph-positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third-generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph-positive ALL.
PubMed: 38727135
DOI: 10.1002/ajh.27355