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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 -
Expert Review of Hematology Jun 2024
Topics: Humans; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; High-Throughput Nucleotide Sequencing; Philadelphia Chromosome
PubMed: 38726703
DOI: 10.1080/17474086.2024.2354922 -
JAMA Jun 2024
Topics: Humans; Randomized Controlled Trials as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Imatinib Mesylate; Antineoplastic Agents; Philadelphia Chromosome
PubMed: 38722663
DOI: 10.1001/jama.2024.5871 -
JAMA Jun 2024In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.
OBJECTIVE
To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.
DESIGN, SETTING, AND PARTICIPANTS
Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.
INTERVENTION
Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission.
MAIN OUTCOMES AND MEASURES
The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.
RESULTS
Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).
CONCLUSIONS AND RELEVANCE
Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03589326.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fusion Proteins, bcr-abl; Imatinib Mesylate; Imidazoles; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Protein Kinase Inhibitors; Pyridazines; Remission Induction; Adolescent
PubMed: 38722621
DOI: 10.1001/jama.2024.4783