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Journal of Investigative Medicine High... 2024Skin lesions in chronic lymphocytic leukemia (CLL) have been reported in between 4% and 20% of patients with CLL and are a rare entity compared with T-cell leukemia....
Skin lesions in chronic lymphocytic leukemia (CLL) have been reported in between 4% and 20% of patients with CLL and are a rare entity compared with T-cell leukemia. They can present mainly as leukemic cutis or, frequently, as secondary lesions such like urticaria, itching, pyoderma gangrenosum, cutaneous vasculitis, Sweet's syndrome, and erythroderma. We report on an adult patient who developed a skin lesion of forearms and hands, leading to the discovery of isolated cutaneous CLL after two biopsies. Isolated CLL cutaneous location is very rare and may be diagnosed late, as in the case of our patient. A better knowledge of the course of the illness and rapid diagnosis of this CLL cutis leukemia will enhance the therapeutic efficacy of the disease.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Skin Neoplasms; Male; Biopsy; Skin; Aged; Middle Aged
PubMed: 38813875
DOI: 10.1177/23247096231204736 -
Frontiers in Neurology 2024Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with...
BACKGROUND
Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents.
METHODS
From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT).
RESULTS
Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness ( = 4), headache ( = 2), confusion ( = 2), and nausea ( = 2), with ring-enhancing ( = 5), typically solitary ( = 3) and supratentorial ( = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy ( = 4) or craniotomy ( = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases ( = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab ( = 3), surgical resection ( = 2), zanubrutinib ( = 1), whole-brain radiation ( = 1), and methotrexate ( = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive.
CONCLUSION
In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.
PubMed: 38813246
DOI: 10.3389/fneur.2024.1392691 -
Turkish Journal of Medical Sciences 2023T-cell acute lymphoblastic leukemia (T-ALL) is a form of leukemia characterized by the proliferation of immature T lymphocytes. NOTCH1 is one of the most frequently...
BACKGROUND/AIM
T-cell acute lymphoblastic leukemia (T-ALL) is a form of leukemia characterized by the proliferation of immature T lymphocytes. NOTCH1 is one of the most frequently mutated genes in T-ALL. NOTCH1 expression in T-cell development depends on plant homeodomain finger protein 6 (PHF6), which plays a tumor suppressor role in T-ALL. Several studies have shown that PHF6 expression is essential for NOTCH1 expression. Therefore, whether posttranslational modification of PHF6 plays a role in the regulation of NOTCH1 expression and T-ALL cell line proliferation was investigated herein.
MATERIALS AND METHODS
The amino acid sequence of PHF6 was analyzed and it was found that a putative protein kinase A (PKA) phosphorylation motif RDRS199 was conserved in several vertebrate species and the S199 site was expected to be phosphorylated according to the PhosphoSite database. Therefore, an eukaryotic expression vector of human PHF6 was constructed, and the codon 199 was changed to the codon encoding the nonphosphorylatable alanine and the phosphorylation-mimicking aspartic acid via site-directed mutagenesis. After confirming the ectopic expressions of the PHF6 vectors by western blot analysis, the effects of these proteins were identified on the NOTCH1 expression using western blot analysis, leukemic cell proliferation using MTT assay, and expressions of the cell surface markers of T-cells using flow cytometry.
RESULTS
The ectopic expression of wild-type PHF6 stimulated the formation of CD4 + T-cells. While the expression of the wild-type PHF6 suppressed the growth of the leukemic cell line, this effect was diminished in both the alanine and aspartic acid mutants of PHF6. In addition, both mutants also seemed to negatively affect the NOTCH1 expression, although the effect of the alanine mutant was more severe.
CONCLUSION
Taken together, the different biological activities exerted by the conserved S199 phosphorylation-site mutants shown in this study implicate that signaling pathway(s) leading to differential phosphorylation of this residue may have a substantial effect on the activity of PHF6, and thus may constitute a potential therapeutic target in T-ALL.
Topics: Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptor, Notch1; Repressor Proteins; Cell Proliferation; Phosphorylation; Mutation; Cell Line, Tumor
PubMed: 38812997
DOI: 10.55730/1300-0144.5689 -
Frontiers in Immunology 2024To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis... (Review)
Review
OBJECTIVE
To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).
METHODS
A child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.
RESULTS
A ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.
CONCLUSION
The diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.
Topics: Humans; Female; Child; Churg-Strauss Syndrome; Treatment Outcome; Granulomatosis with Polyangiitis; Cyclophosphamide; Antibodies, Antineutrophil Cytoplasmic
PubMed: 38812515
DOI: 10.3389/fimmu.2024.1406424 -
Clinical and Translational Medicine Jun 2024
Topics: Histone Deacetylase Inhibitors; Humans; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Lymphoma
PubMed: 38812093
DOI: 10.1002/ctm2.1691 -
BMC Medical Genomics May 2024Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be...
Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.
Topics: Humans; Child; Male; Female; Child, Preschool; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Sequence Analysis, RNA; Adolescent; Drug Resistance, Neoplasm; Infant; Retrospective Studies; Oncogene Proteins, Fusion
PubMed: 38811988
DOI: 10.1186/s12920-024-01892-w -
Blood Cancer Journal May 2024We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell...
We evaluated the efficacy and safety of 24 cycles of Dara in combination with carfilzomib (K), lenalidomide (R), and dexamethasone (d) without autologous stem cell transplant (ASCT) in newly diagnosed multiple myeloma (NDMM) irrespective of ASCT eligibility in a single-arm, phase II study. The primary endpoint was the rate of stringent complete response (sCR) and/or measurable residual disease (MRD) < 10 by next-generation sequencing (NGS) at the end of cycle 8 (C8). MRD was also assessed on peripheral blood samples using both the EXENT system and liquid chromatography-mass spectrometry (LC-MS). Forty-two patients entered the treatment phase; forty were evaluable for the primary endpoint. The rate of sCR and/or MRD < 10 following C8 was 30/40 (75%), meeting the statistical threshold for efficacy. The 10 MRD negative rate improved with treatment beyond C8. Agreement between EXENT and NGS was high and increased over time; agreement between LC-MS and NGS was lower. The estimated 3-year progression-free survival progression-free survival was 85%, and 3-year overall survival was 95%. Upper respiratory infections occurred in 67% (7% grade 3-4). There were no treatment-related deaths. Extended frontline Dara-KRd induced a high rate of sCR and/or MRD negativity; the rate and depth of MRD negativity improved beyond C8.
Topics: Humans; Multiple Myeloma; Dexamethasone; Lenalidomide; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Oligopeptides; Antibodies, Monoclonal; Adult; Neoplasm, Residual; Treatment Outcome
PubMed: 38811560
DOI: 10.1038/s41408-024-01045-3 -
Nature Communications May 2024Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the...
Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.
Topics: Receptors, CXCR4; Humans; Animals; Signal Transduction; Drug Resistance, Neoplasm; Dexamethasone; Type C Phospholipases; Cell Line, Tumor; Glucocorticoids; Mice; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Mice, Inbred NOD; Cell Survival
PubMed: 38811530
DOI: 10.1038/s41467-024-48818-9 -
Asian Pacific Journal of Cancer... May 2024Multiple myeloma (MM) is the second most prevalent blood cancer after non-Hodgkin lymphoma. It is identified by the excessive production of abnormal monoclonal...
BACKGROUND
Multiple myeloma (MM) is the second most prevalent blood cancer after non-Hodgkin lymphoma. It is identified by the excessive production of abnormal monoclonal immunoglobulins, which can result in various clinical symptoms such as destructive bone lesions, renal dysfunction, anemia, and immunodeficiency. The current study aims to evaluate the serum levels of carboxy-terminal collagen crosslinks 1 (CTX-1), Fibulin-1, vitamin D3, LDH, and albumin in MM patients and their significance for early diagnosis.
MATERIALS AND METHODS
This study included 30 healthy controls (11 males, 19 females) and 60 patients with multiple myeloma (37 males and 23 females), aged between 40-60 years. Five-milliliter blood samples were collected and stored at -20°C. Afterward, enzyme-linked immunosorbent assay (ELISA) kits were used to estimate the concentrations of CTX-1, Fibulin-1, and vitamin D3. Additionally, LDH and albumin levels were determined using the automated biochemistry analyzer.
RESULTS
This study revealed that the majority of patients with multiple myeloma are between the ages of 51 and 60 years. The serum concentrations of CTX-1, Fibulin-1, and LDH were significantly increased in the multiple myeloma patients compared to the healthy control group. In contrast, the serum level of vitamin D3 was significantly decreased in patients with MM.
CONCLUSION
Our results indicate that the incidence of multiple myeloma is higher in males than in females. Additionally, the serum concentrations of CTX-1 and Fibulin-1 were significantly higher in the multiple myeloma patients compared to the healthy control group, indicating their potential for early detection and as therapeutic targets.
Topics: Humans; Multiple Myeloma; Female; Male; Middle Aged; Adult; Case-Control Studies; Calcium-Binding Proteins; Biomarkers, Tumor; Prognosis; Follow-Up Studies; Collagen Type I; Peptides; Peptide Fragments
PubMed: 38809631
DOI: 10.31557/APJCP.2024.25.5.1599 -
Asian Pacific Journal of Cancer... May 2024This study seeks to elucidate the association between HLA-A, HLA-B, and HLA-DRB1 alleles and their relative risk contributions to ALL within an Iranian cohort.
Human Leukocyte Antigen Alleles (HLA-A, HLA-B, and HLA-DRB1) are associated with Acute Lymphoblastic Leukemia (ALL) : A Case-Control Study in a Sample of Iranian Population.
OBJECTIVE
This study seeks to elucidate the association between HLA-A, HLA-B, and HLA-DRB1 alleles and their relative risk contributions to ALL within an Iranian cohort.
METHODS
Utilizing a robust case-control design, this research involved 71 ALL patients and 71 age and sex-matched healthy individuals. Genotyping of specified HLA alleles was performed using the advanced PCR-SSP technique.
RESULTS
Our findings reveal a marked increase in the prevalence of the HLA-DRB1*04 allele among patients diagnosed with ALL compared to the control group (P<0.027). Conversely, the alleles HLA-A*26 (P=0.025), HLA-A*33 (P=0.020), and HLA-DRB1*03 (P=0.035) were observed at significantly reduced frequencies within the patient population.
CONCLUSION
Our findings highlight HLA-DRB1*04 as a potential genetic marker for increased susceptibility to ALL, while HLA-A*26, HLA-A*33, and HLA-DRB1*03 emerge as protective factors.
Topics: Humans; Case-Control Studies; HLA-DRB1 Chains; Female; Male; Iran; HLA-B Antigens; HLA-A Antigens; Genetic Predisposition to Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Alleles; Prognosis; Follow-Up Studies; Adult; Genotype; Adolescent; Child; Young Adult; Child, Preschool; Biomarkers, Tumor
PubMed: 38809622
DOI: 10.31557/APJCP.2024.25.5.1507